Prediction of Force Recruitment of Neuromuscular Magnetic Stimulation From 3D Field Model of the Thigh.

Neuromuscular magnetic stimulation is a promising tool in neurorehabilitation due to its deeper penetration, notably lower distress, and respectable force levels compared to surface electrical stimulation. However, this method faces great challenges from a technological perspective. The systematic design of better equipment and the incorporation into modern training setups requires better understanding of the mechanisms and predictive quantitative models of the recruited forces. This article proposes a model for simulating the force recruitment in isometric muscle stimulation of the thigh extensors based on previous theoretical and experimental findings. The model couples a 3D field model for the physics with a parametric recruitment model. This parametric recruitment model is identified with a mixed-effects design to learn the most likely model based on available experimental data with a wide range of field conditions. This approach intentionally keeps the model as mathematically simple and statistically parsimonious as possible in order to avoid over-fitting. The work demonstrates that the force recruitment particularly depends on the effective, i.e., fiber-related cross section of the muscles, and that the local median electric field threshold amounts to about 65 V/m, which agrees well with values for magnetic stimulation in the brain. The coupled model is able to accurately predict key phenomena observed so far, such as a threshold shift for different distances between coil and body, the different recruiting performance of various coils with available measurement data in the literature, and the saturation behavior with its onset amplitude. The presented recruitment model could also be readily incorporated into dynamic models for biomechanics as soon as sufficient experimental data are available for calibration.

Evaluation and Utility of Submaximal Stimulation Intensity in Transcranial Magnetic Stimulation in the Standing Horse☆.

Transcranial magnetic stimulation (TMS) has been successfully used in horses to evaluate function and integrity of descending motor pathways in patients affected by neurological gait abnormalities. In preceding studies, lengthening latency times (LT) of cranially evoked limb muscle potentials have been considered a reliable diagnostic parameter. Standardized settings use device output signal intensities of 100%. The aim of this study was to determine the effect of submaximal stimulation intensities (SI) and to determine the minimum coil output necessary to evoke motor unit potentials. As an additional effect, lower stimulation intensities are supposed to decrease sensory irritation of the equine patient. Altogether, 36 neurologically healthy horses underwent TMS under sedation with a dome coil at stimulation intensities varying from 40% to 100% of device output intensity. Motor potentials were recorded by surface electrodes from all four limbs and LT was calculated in milliseconds. To further refine the stimulation settings, cortical motor thresholds (CMT) were assessed in triplets, using IFCN recommendations. The electromyographic recordings were evaluated in 30 horses. Increasing stimulation intensities resulted in significant (P < .05) LT shortening until application of 80% of maximal output intensity. Further increase to maximal SI of 100%, brought up no significant differences (P > .05). Gating effects were excluded as there was no difference of LT upon ascending and descending SI changes (P > .05). CMT revealed a large inter-individual variability amongst horses independent of their body size. There was a strong linearity in between CMT and LT even within submaximal SI ranges (P < .001). The inverse impact of SI on LT may be explained by deeper penetration of the magnetic field, circumvention of interposed neurons and subsequent activation of fast acting motor pathways. However, in warmblood horses a stimulation intensity of 80% coil output already appeared sufficient for reproducible activation of lower motor neurons in all limbs. Furthermore, due to the strong linear correlation of CMT and LT, the tested CMT algorithms may be used to estimate the normal LT on submaximal stimulation for equine myelopathy patients in future.

Influence of extremely low frequency, low energy electromagnetic fields and combined mechanical stimulation on chondrocytes in 3-D constructs for cartilage tissue engineering.

Articular cartilage, once damaged, has very low regenerative potential. Various experimental approaches have been conducted to enhance chondrogenesis and cartilage maturation. Among those, non-invasive electromagnetic fields have shown their beneficial influence for cartilage regeneration and are widely used for the treatment of non-unions, fractures, avascular necrosis and osteoarthritis. One very well accepted way to promote cartilage maturation is physical stimulation through bioreactors. The aim of this study was the investigation of combined mechanical and electromagnetic stress affecting cartilage cells in vitro. Primary articular chondrocytes from bovine fetlock joints were seeded into three-dimensional (3-D) polyurethane scaffolds and distributed into seven stimulated experimental groups. They either underwent mechanical or electromagnetic stimulation (sinusoidal electromagnetic field of 1 mT, 2 mT, or 3 mT; 60 Hz) or both within a joint-specific bioreactor and a coil system. The scaffold-cell constructs were analyzed for glycosaminoglycan (GAG) and DNA content, histology, and gene expression of collagen-1, collagen-2, aggrecan, cartilage oligomeric matrix protein (COMP), Sox9, proteoglycan-4 (PRG-4), and matrix metalloproteinases (MMP-3 and -13). There were statistically significant differences in GAG/DNA content between the stimulated versus the control group with highest levels in the combined stimulation group. Gene expression was significantly higher for combined stimulation groups versus static control for collagen 2/collagen 1 ratio and lower for MMP-13. Amongst other genes, a more chondrogenic phenotype was noticed in expression patterns for the stimulated groups. To conclude, there is an effect of electromagnetic and mechanical stimulation on chondrocytes seeded in a 3-D scaffold, resulting in improved extracellular matrix production.

Analysis and optimization of pulse dynamics for magnetic stimulation.

Magnetic stimulation is a standard tool in brain research and has found important clinical applications in neurology, psychiatry, and rehabilitation. Whereas coil designs and the spatial field properties have been intensively studied in the literature, the temporal dynamics of the field has received less attention. Typically, the magnetic field waveform is determined by available device circuit topologies rather than by consideration of what is optimal for neural stimulation. This paper analyzes and optimizes the waveform dynamics using a nonlinear model of a mammalian axon. The optimization objective was to minimize the pulse energy loss. The energy loss drives power consumption and heating, which are the dominating limitations of magnetic stimulation. The optimization approach is based on a hybrid global-local method. Different coordinate systems for describing the continuous waveforms in a limited parameter space are defined for numerical stability. The optimization results suggest that there are waveforms with substantially higher efficiency than that of traditional pulse shapes. One class of optimal pulses is analyzed further. Although the coil voltage profile of these waveforms is almost rectangular, the corresponding current shape presents distinctive characteristics, such as a slow low-amplitude first phase which precedes the main pulse and reduces the losses. Representatives of this class of waveforms corresponding to different maximum voltages are linked by a nonlinear transformation. The main phase, however, scales with time only. As with conventional magnetic stimulation pulses, briefer pulses result in lower energy loss but require higher coil voltage than longer pulses.

Muscle force development after low-frequency magnetic burst stimulation in dogs.

INTRODUCTION: Magnetic stimulation allows for painless and non-invasive extrinsic motor nerve stimulation. Despite several advantages, the limited coupling to the target reduces the application of magnetic pulses in rehabilitation. According to experience with electrical stimulation, magnetic bursts could remove this constraint. METHODS: A novel burst stimulator was used to apply single and burst pulses to the femoral nerve in 10 adult dogs. A figure-of-eight coil was connected, and pulses were applied at 7.5 HZ. Contractions of the quadriceps muscle were measured via an angle force transducer. RESULTS: Muscle forces were significantly higher upon burst stimulation than after single pulses. Four consecutive burst pulses proved most effective. Stimulation by more bursts resulted in fatigue. CONCLUSION: Burst stimulation is superior to standard magnetic single pulses, and 4 consecutive burst pulses proved most effective.

Evaluation of lumbosacral nerve root conduction in chickens by electrophysiological testing including high-resolution spinal magnetic stimulation.

The value of avian models in peripheral nerve research recently became substantiated by the immunobiological similarity of avian inflammatory demyelinating polyradiculoneuropathy to human Guillain-Barré syndrome providing an alternative animal model for experimental autoimmune neuritis. As electrophysiologic evaluation of nerve roots is essential part of the diagnosis of polyradiculoneuropathies in humans, it would be favourable to have similar research methods available for juvenile chickens. Hence, this study was performed (1) to establish a tool-set that allows for reproducible evaluation of the tibial/sciatic nerve and its nerve roots, (2) to achieve age-matched reference values, and (3) to trace the kinetics of peripheral nerve maturation within chickens. Nine chickens underwent serial electrodiagnostic examinations between the age of 6 and 15 weeks. Several methods of sensory and motor nerve fiber stimulation of the tibial/sciatic nerve were tested and modified or established. Ultimately, scalp-recorded somatosensory evoked potentials, compound muscle action potentials elicited by tibial/sciatic nerve electrical as well as spinal magnetic stimulation and motor nerve conduction velocity were available for tibial/sciatic nerve and nerve root evaluation in chickens. Base values were obtained for all investigations and parameters. Results indicated that the maturation of the nerve fibers is incomplete up to the age of 15 weeks. The methods tested here provide an excellent tool-set for quantitative tibial/sciatic nerve and nerve root assessment in avian polyradiculoneuropathies, especially within the scope of longitudinal monitoring of the disease course.

First theoretic analysis of magnetic drug targeting in the lung.

Magnetic drug targeting in the bloodstream has been intensively studied recently, but also other interesting access and transport pathways fulfill the basic conditions for this method. More recently, magnetic drug targeting has even been accomplished for aerosol application in mouse models and indicated unmistakable advantages over all currently available therapies for lung tumors and any other very localized lung disease. In this paper, the application of magnetically labeled aerosols to the lung via the airways is theoretically highlighted for the first time in the literature. The fundamental difference compared to targeting via the bloodstream lies in the medium and the presence of the bronchial surface: When touching the epithelium of the lung outside the target region, a particle will deposit on the surface and not enter the air stream again. We are the first to compose a comprehensive physical description and provide a fundamental understanding of this potential expedient for treating cancer and other localized diseases. With our approach, we found optimal conditions for this sort of therapy. As a main parameter for optimization, the droplet size could be identified by minimizing unwanted deposition outside the target due to secondary effects, which compete with the magnetic forces. This may improve therapeutic efficiency and reduce side effects of otherwise not well-tolerated compounds, such as chemotherapeutics at the same time.

Combined targeting of lentiviral vectors and positioning of transduced cells by magnetic nanoparticles.

Targeting of viral vectors is a major challenge for in vivo gene delivery, especially after intravascular application. In addition, targeting of the endothelium itself would be of importance for gene-based therapies of vascular disease. Here, we used magnetic nanoparticles (MNPs) to combine cell transduction and positioning in the vascular system under clinically relevant, nonpermissive conditions, including hydrodynamic forces and hypothermia. The use of MNPs enhanced transduction efficiency of endothelial cells and enabled direct endothelial targeting of lentiviral vectors (LVs) by magnetic force, even in perfused vessels. In addition, application of external magnetic fields to mice significantly changed LV/MNP biodistribution in vivo. LV/MNP-transduced cells exhibited superparamagnetic behavior as measured by magnetorelaxometry, and they were efficiently retained by magnetic fields. The magnetic interactions were strong enough to position MNP-containing endothelial cells at the intima of vessels under physiological flow conditions. Importantly, magnetic positioning of MNP-labeled cells was also achieved in vivo in an injury model of the mouse carotid artery. Intravascular gene targeting can be combined with positioning of the transduced cells via nanomagnetic particles, thereby combining gene- and cell-based therapies.

Targeted delivery of magnetic aerosol droplets to the lung.

The inhalation of medical aerosols is widely used for the treatment of lung disorders such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, respiratory infection and, more recently, lung cancer. Targeted aerosol delivery to the affected lung tissue may improve therapeutic efficiency and minimize unwanted side effects. Despite enormous progress in optimizing aerosol delivery to the lung, targeted aerosol delivery to specific lung regions other than the airways or the lung periphery has not been adequately achieved to date. Here, we show theoretically by computer-aided simulation, and for the first time experimentally in mice, that targeted aerosol delivery to the lung can be achieved with aerosol droplets comprising superparamagnetic iron oxide nanoparticles--so-called nanomagnetosols--in combination with a target-directed magnetic gradient field. We suggest that nanomagnetosols may be useful for treating localized lung disease, by targeting foci of bacterial infection or tumour nodules.

Stimulus intensity and coil characteristics influence the efficacy of rTMS to suppress cortical excitability.

OBJECTIVE: Low-frequency repetitive transcranial magnetic stimulation (rTMS) can reduce cortical excitability. Here we examined whether inhibitory after effects of low-frequency rTMS are influenced by stimulus intensity, the type of TMS coil and re-afferent sensory stimulation. METHODS: In fifteen healthy volunteers, we applied 900 biphasic pulses of 1Hz rTMS to the left primary motor cortex (M1) at an intensity that was 10% below or 15% above resting motor threshold. For rTMS, we used two different figure-of-eight shaped coils (Magstim or Medtronic coil) attached to the same stimulator. We recorded motor evoked potentials (MEPs) evoked with the same set-up used for rTMS (MEP-rTMS) before and twice after rTMS. Using a different TMS setup, we also applied monophasic pulses to the M1 in order to assess the effects of rTMS on corticospinal excitability, intracortical paired-pulse excitability and the duration of the cortical silent period (CSP). In a control experiment, the same measurements were performed after 15min of 1Hz repetitive electrical nerve stimulation (rENS) of the right ulnar nerve. RESULTS: Analysis of variance revealed an interaction between intensity, coil and time of measurement (p<0.035), indicating that the effect of 1Hz rTMS on MEP-rTMS amplitude depended on the intensity and the type of coil used for rTMS. Suppression of corticospinal excitability was strongest after suprathreshold 1Hz rTMS with the Medtronic coil (p<0.01 for both post-rTMS measurements relative to pre-intervention baseline). Regardless of the type of coil, suprathreshold but not subthreshold rTMS transiently prolonged the CSP and attenuated paired-pulse facilitation. Suprathreshold 1Hz rENS also induced a short-lasting inhibition of MEP-rTMS. CONCLUSIONS: Both the stimulation intensity and the type of TMS coil have an impact on the after effects of 1Hz rTMS. Re-afferent feedback activation may at least in part account for the stronger suppression of corticospinal excitability by suprathreshold 1Hz rTMS. SIGNIFICANCE: These data should be considered when rTMS is used as a therapeutic means.

MEP latency shift after implantation of deep brain stimulation systems in the subthalamic nucleus in patients with advanced Parkinson's disease.

Deep brain stimulation (DBS) into the subthalamic nucleus (STN) is a highly effective treatment for advanced Parkinson's disease (PD). The consequences of STN stimulation on intracortical and corticospinal excitability have been addressed in a few studies using transcranial magnetic stimulation (TMS). Although excitability measurements were compared between the STN stimulation OFF and ON condition, in these experiments, there are no longitudinal studies examining the impact of electrode implantation per se on motor excitability. Here, we explored the effects of STN electrode implantation on resting motor thresholds (RMT), motor evoked potential (MEP) recruitment curves, and MEP onset latencies on 2 consecutive days before and shortly after STN surgery with the stimulator switched off, thus avoiding the effects of chronic DBS on the motor system, in 8 PD patients not taking any dopaminergic medication. After surgery, RMT and MEP recruitment curves were unchanged. In contrast, MEP onset latencies were significantly shorter when examined in relaxed muscles but were unchanged under preactivation. We hypothesize that postoperatively TMS pulses induced small currents in scalp leads underneath the TMS coil connecting the external stimulator with STN electrodes leading to inadvertent stimulation of fast-conducting descending neural elements in the vicinity of the STN, thereby producing submotor threshold descending volleys. These "conditioning" volleys probably preactivated spinal motor neurons leading to earlier suprathreshold activation by the multiple corticospinal volleys produced by TMS of the motor cortex. These TMS effects need to be considered when interpreting results of excitability measurements in PD patients after implantation of STN electrodes.

Marked differences in the thermal characteristics of figure-of-eight shaped coils used for repetitive transcranial magnetic stimulation.

OBJECTIVE: To compare the heating behaviour of three figure-of-eight shaped coils during repetitive transcranial magnetic stimulation (rTMS). METHODS: A custom-made coil (referred to as test coil) with a resistance-optimized conductor geometry was compared with two commercially available eight-shaped coils. Each coil was attached to the same energy source, which generated trains of 50 biphasic magnetic pulses every 20s. Coil temperature was continuously measured during nine rTMS protocols using various combinations of stimulus frequencies (5, 10 or 20Hz) and intensities (40, 50 or 60% of maximum stimulator output). A heating curve relating coil temperature and the number of applied stimuli was generated for each coil and rTMS condition. In eleven healthy volunteers, we evaluated the effectiveness of motor cortex stimulation. For each coil, we determined the motor threshold (MT) in the right first dorsal interosseus muscle. RESULTS: The slope of the heating curves of the test coil was markedly flattened relative to the heating curves of the two standard coils. This allowed the application of at least twice as many stimuli until the temperature of the coil reached 40 degrees C. Based on these data, we showed that a one-mass model could be used to accurately describe the heating behaviour of each coil. MTs determined with the test coil were comparable to or lower than the MTs that were determined with the standard coils. CONCLUSIONS: The efficacy of the test coil to stimulate the M1 was comparable to the efficacy of the two standard coils, yet thermal characteristics were markedly improved. SIGNIFICANCE: Overheating of figure-of-eight shaped coils can be markedly delayed without reducing the efficacy of rTMS.