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Background and purpose: Next‐generation sequencing has greatly improved the diagnostic success rates for genetic neuromuscular disorders (NMDs). Nevertheless, most patients still remain undiagnosed, and there is a need to maximize the diagnostic yield. Methods: A retrospective study was conducted on 72 patients with NMDs who underwent exome sequencing (ES), partly followed by genotype‐guided diagnostic reassessment and secondary investigations. The diagnostic yields that would have been achieved by appropriately chosen narrow and comprehensive gene panels were also analysed. Results: The initial diagnostic yield of ES was 30.6% (n = 22/72 patients). In an additional 15.3% of patients (n = 11/72) ES results were of unknown clinical significance. After genotype‐guided diagnostic reassessment and complementary investigations, the yield was increased to 37.5% (n = 27/72). Compared to ES, targeted gene panels (<25 kilobases) reached a diagnostic yield of 22.2% (n = 16/72), whereas comprehensive gene panels achieved 34.7% (n = 25/72). Conclusion: Exome sequencing allows the detection of pathogenic variants missed by (narrowly) targeted gene panel approaches. Diagnostic reassessment after genetic testing further enhances the diagnostic outcomes for NMDs. [ABSTRACT FROM AUTHOR]

Background and purpose Hereditary spastic paraplegia is a clinically and genetically heterogeneous group of rare, inherited disorders causing an upper motor neuron syndrome with (complex) or without (pure) additional neurological symptoms. Mutations in the KIF1A gene have already been associated with recessive and dominant forms of hereditary spastic paraplegia ( SPG30) in a few cases. Methods All family members included in the study were examined neurologically. Whole-exome sequencing was used in affected individuals to identify the responsible candidate gene. Conventional Sanger sequencing was conducted to validate familial segregation. Results A family of Macedonian origin with two affected siblings, one with slowly progressive and the other one with a more complex and rapidly progressing hereditary spastic paraplegia is reported. In both affected individuals, two novel pathogenic mutations outside the motor domain of the KIF1A gene were found ( NM_001244008.1:c.2909G>A, p.Arg970His and c.1214dup, p.Asn405Lysfs*40) that segregate with the disease within the family establishing the diagnosis of autosomal recessive SPG30. Conclusions This report provides the first evidence that mutations outside the motor domain of the gene can cause (recessive) SPG30 and extends the genotype−phenotype association for KIF1A-related diseases. [ABSTRACT FROM AUTHOR]

Neuromuscular electrical stimulation (NMES) is a widely used technique for clinical diagnostic, treatment, and research. Normally, it applies charge-balanced biphasic pulses, which several publications have reported to be less efficient than monophasic pulses. A good alternative is the use of interphase intervals (IPI) on biphasic pulses that allows to achieve similar responses than those evoked by monophasic stimulation. This study analyzes the enhancing mechanism of the IPI and provides guidelines on how to optimize the IPI in order to reduce secondary effects such as the electrode corrosion. The tibial nerve was excited by NMES biphasic pulses with different IPI durations and polarities. Then, the elicited responses were recorded on the soleus muscle via electromyography. When cathodic-first pulses were applied, the responses increased proportionally to the IPI until the duration of 250 µs, where the increase saturated at 30% of the original amplitude. The responses evoked during anodic-first were 6% to 30% smaller than those evoked during cathodic-first pulses and continuously increased until the IPI duration of 2500 µs, where the responses reached an increase of around 30%. The results suggest that when a cathodic-first pulse is used, the IPI could be optimized (based on the setup geometry) to allow the action potentials to travel out of the hyperpolarization zone induced by the anodic phase. When anodic-first stimuli are applied, the IPI duration allows the fiber to recover from an apparent insensitive state induced by the anodic phase. The use of IPI is a viable option to improve the efficiency of actual stimulation systems, since only small modifications are required to significantly reduce the electrical charge required and boost the stimulation efficiency., (© 2017 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Neuromuscular electrical stimulation (NMES) is an established method for functional restoration of muscle function, rehabilitation, and diagnostics. In this work, NMES was applied with surface electrodes placed on the anterior thigh to identify the main differences between current-controlled (CC) and voltage-controlled (VC) modes. Measurements of the evoked knee extension force and the myoelectric signal of quadriceps and hamstrings were taken during stimulation with different amplitudes, pulse widths, and stimulation techniques. The stimulation pulses were rectangular and symmetric biphasic for both stimulation modes. The electrode-tissue impedance influences the differences between CC and VC stimulation. The main difference is that for CC stimulation, variation of pulse width and amplitude influences the amount of nerve depolarization, whereas VC stimulation is only dependent on amplitude variations for pulse widths longer than 150 μs. An important remark is that these findings are strongly dependent on the characteristics of the electrode-skin interface. In our case, we used large stimulation electrodes placed on the anterior thigh, which cause higher capacitive effects. The controllability, voltage compliance, and charge characteristics of each stimulation technique should be considered during the stimulators design. For applications that require the activation of a large amount of nerve fibers, VC is a more suitable option. In contrast, if the application requires a high controllability, then CC should be chosen prior to VC., (Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Interest in transcutaneous electrical stimulation of the lumbosacral spinal cord is increasing in human electrophysiological and clinical studies. The stimulation effects on lower limb muscles depend on the depolarization of segmentally organized posterior root afferents and, thus, the rostro-caudal stimulation site. In previous studies, selective stimulation was achieved by varying the positions of single self-adhesive electrodes over the thoracolumbar spine. Here, we developed a multi-electrode surface array consisting of 3 × 8 electrode pads and tested its stimulation-site specificity. The array was placed longitudinally over the spine covering the T10-L2 vertebrae. Two different hydrogel layer configurations were utilized: a single layer adhered to all electrode pads of the array and a configuration comprised of eight separate strips attached to the three transverse electrode pads of each level. Voltage measurements demonstrated that an effectively focused field distribution along the longitudinal extent of the array was not accomplished when using the single continuous hydrogel layer, and segmental selective stimulation of the posterior root afferents was not possible. The separate strips produced a focused electric field distribution at the rostro-caudal level of the electrode pads selected for stimulation. This configuration allowed for the preferential elicitation of posterior root-muscle reflexes in either the L2-L4 innervated quadriceps or the L5-S2 innervated triceps surae muscle groups. Such multi-electrode array for transcutaneous spinal cord stimulation shall allow for improved control of stimulation conditions in electrophysiological studies and time-dependent and site-specific stimulation patterns for neuromodulation applications., (Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

The level of sustainable excitability within lumbar spinal cord circuitries is one of the factors determining the functional outcome of locomotor therapy after motor-incomplete spinal cord injury. Here, we present initial data using noninvasive transcutaneous lumbar spinal cord stimulation (tSCS) to modulate this central state of excitability during voluntary treadmill stepping in three motor-incomplete spinal cord-injured individuals. Stimulation was applied at 30 Hz with an intensity that generated tingling sensations in the lower limb dermatomes, yet without producing muscle reflex activity. This stimulation changed muscle activation, gait kinematics, and the amount of manual assistance required from the therapists to maintain stepping with some interindividual differences. The effect on motor outputs during treadmill-stepping was essentially augmentative and step-phase dependent despite the invariant tonic stimulation. The most consistent modification was found in the gait kinematics, with the hip flexion during swing increased by 11.3° ± 5.6° across all subjects. This preliminary work suggests that tSCS provides for a background increase in activation of the lumbar spinal locomotor circuitry that has partially lost its descending drive. Voluntary inputs and step-related feedback build upon the stimulation-induced increased state of excitability in the generation of locomotor activity. Thus, tSCS essentially works as an electrical neuroprosthesis augmenting remaining motor control., (Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

A stimulator for neuromuscular electrical stimulation (NMES) was designed, especially suiting the requirements of elderly people with reduced cognitive abilities and diminished fine motor skills. The aging of skeletal muscle is characterized by a progressive decline in muscle mass, force, and condition. Muscle training with NMES reduces the degradation process. The discussed system is intended for evoked muscle training of the anterior and posterior thigh. The core of the stimulator is based on a microcontroller with two modular output stages. The system has two charge-balanced biphasic voltage-controlled stimulation channels. Additionally, the evoked myoelectric signal (M-wave) and the myokinematic signal (surface acceleration) are measured. A central controller unit allows using the stimulator as a stand-alone device. To set up the training sequences and to evaluate the compliance data, a personal computer is connected to the stimulator via a universal serial bus. To help elderly people handle the stimulator by themselves, the user interface is kept very simple. For safety reasons, the electrode impedance is monitored during stimulation. A comprehensive compliance management with included measurements of muscle activity and stimulation intensity enables a scientific use of the stimulator in clinical trials., (© 2011, Copyright the Authors. Artificial Organs © 2011, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Considering that platelet response to thrombin receptor activation might be critical for the development of arterial thrombosis, we measured the dense granule release under stimulation by the thrombin receptor activating peptide (TRAP) in a series of 102 healthy volunteers. The threshold TRAP concentration which initiated a secretion ranged from 3 to 20 microM. A good concordance (79%, k=0.677) between two tests performed at a 1 month interval indicated that platelet response to thrombin receptor activation was characteristic of each individual donor. Since the threshold concentration required to initiate secretion corresponded to the threshold concentration which induced a biphasic aggregation, all volunteers were genotyped for the PlA2 polymorphism, the Pro33 variant of GPIIIa. Platelets from subjects with the PlA2 polymorphism required higher TRAP concentrations to aggregate than those from subjects with no PlA2 allele (P=0.0012). However, they also required a higher ADP concentration to aggregate. In order to exclude any influence of GPIIIa polymorphism on TRAP-induced secretion, we studied the variability of platelet response to TRAP among the 77 individuals with no PlA2 allele, and found the same interdonor variability with the same distribution of threshold TRAP concentrations as for the 102 individuals. The results suggest that (i) platelet secretion in response to thrombin receptor activation could be a genetically controlled phenotype independent of the GPIIIa polymorphism; (ii) the PlA2 polymorphism is associated with platelet hypoaggregability.