Synaptic Effect of Aδ-Fibers by Pulse-Train Electrical Stimulation.

Electrical stimulation of specific small fibers (Aδ- and C-fibers) is used in basic studies on nociception and neuropathic pain and to diagnose neuropathies. For selective stimulation of small fibers, the optimal stimulation waveform parameters are an important aspect together with the study of electrode design. However, determining an optimal stimulation condition is challenging, as it requires the characterization of the response of the small fibers to electrical stimulation. The perception thresholds are generally characterized using single-pulse stimulation based on the strength-duration curve. However, this does not account for the temporal effects of the different waveforms used in practical applications. In this study, we designed an experiment to characterize the effects of multiple pulse stimulation and proposed a computational model that considers electrostimulation of fibers and synaptic effects in a multiscale model. The measurements of perception thresholds showed that the pulse dependency of the threshold was an exponential decay with a maximum reduction of 55%. In addition, the frequency dependence of the threshold showed a U-shaped response with a reduction of 25% at 30 Hz. Moreover, the computational model explained the synaptic effects, which were also confirmed by evoked potential recordings. This study further characterized the activation of small fibers and clarified the synaptic effects, demonstrating the importance of waveform selection.

Dosimetry Analysis in Non-brain Tissues During TMS Exposure of Broca's and M1 Areas.

For human protection, the internal electric field is used as a dosimetric quantity for electromagnetic fields lower than 5-10 MHz. According to international standards, in this frequency range, electrostimulation is the main adverse effect against which protection is needed. One of the topics to be investigated is the quantification of the internal electric field threshold levels of perception and pain. Pain has been reported as a side effect during transcranial magnetic stimulation (TMS), especially during stimulation of the Broca's (speech) area of the brain. In this study, we designed an experiment to conduct a dosimetry analysis to quantify the internal electric field corresponding to perception and pain thresholds when targeting the Broca's and M1 areas from magnetic stimulator exposure. Dosimetry analysis was conducted using a multi-scale analysis in an individualized head model to investigate electrostimulation in an axonal model. The main finding is that the stimulation on the primary motor cortex has higher perception and pain thresholds when compared to Broca's area. Also, TMS-induced electric field applied to Broca's area exhibited dependence on the coil orientation at lower electric field threshold which was found to be related to the location and thickness of pain fibers. The derived dosimetry quantities provide a scientific rationale for the development of human protection guidelines and the estimation of possible side effects of magnetic stimulation in clinical applications.

Figure-Eight Coils for Magnetic Stimulation: From Focal Stimulation to Deep Stimulation.

This article reviews the evolution and recent developments of transcranial magnetic brain stimulation using figure-eight coils to stimulate localized areas in the human brain. Geometric variations of figure-eight coils and their characteristics are reviewed and discussed for applications in neuroscience and medicine. Recent topics of figure-eight coils, such as focality of figure-eight coils, tradeoff between depth and focality, and approaches for extending depth, are discussed.

Electrical Characterisation of Aδ-Fibres Based on Human in vivo Electrostimulation Threshold.

Electrical stimulation of small fibres is gaining attention in the diagnosis of peripheral neuropathies, such as diabetes mellitus, and pain research. However, it is still challenging to characterise the electrical characteristics of axons in small fibres (Aδ and C fibres). In particular, in vitro measurement for human Aδ-fibre is difficult due to the presence of myelin and ethical reason. In this study, we investigate the in vivo electrical characteristics of the human Aδ-fibre to derive strength-duration (S-D) curves from the measurement. The Aδ-fibres are stimulated using coaxial planar electrodes with intraepidermal needle tip. For human volunteer experiments, the S-D curve of Aδ-fibre is obtained in terms of injected electrical current. With the computational analysis, the standard deviation of the S-D curve is mostly attributed to the thickness of the stratum corneum and depth of the needle tip, in addition to the fibre thickness. Then, we derive electrical parameters of the axon in the Aδ-fibre based on a conventional fibre model. The parameters derived here would be important in exploring the optimal stimulation condition of Aδ-fibres.

Group-level analysis of induced electric field in deep brain regions by different TMS coils.

Deep transcranial magnetic stimulation (dTMS) is a non-invasive technique used for the treatment of depression and obsessive compulsive disorder. In this study, we computationally evaluated group-level dosage for dTMS to characterize the targeted deep brain regions to overcome the limitations of using individualized head models to characterize coil performance in a population. We used an inter-subject registration method adapted to the deep brain regions that enable projection of computed electric fields (EFs) from individual realistic head models (n = 18) to the average space of deep brain regions. The computational results showed consistent group-level hotspots of the EF in the deep brain regions. The halo circular assembly coils induced the highest EFs in deep brain regions (up to 50% of the maximum EF in the cortex) for optimized positioning. In terms of the trade-off between field spread and penetration, the performance of the H7 coil was the best. The computational model allowed the optimization of generalized dTMS-induced EF on deep region targets despite inter-individual differences while informing and possibly minimizing unintended stimulation of superficial regions and possible mixed stimulation effects from deep and cortical areas. These results will facilitate the decision process during dTMS interventions in clinical practice.

Comparison of the induced fields using different coil configurations during deep transcranial magnetic stimulation.

Stimulation of deeper brain structures by transcranial magnetic stimulation (TMS) plays a role in the study of reward and motivation mechanisms, which may be beneficial in the treatment of several neurological and psychiatric disorders. However, electric field distributions induced in the brain by deep transcranial magnetic stimulation (dTMS) are still unknown. In this paper, the double cone coil, H-coil and Halo-circular assembly (HCA) coil which have been proposed for dTMS have been numerically designed. The distributions of magnetic flux density, induced electric field in an anatomically based realistic head model by applying the dTMS coils were numerically calculated by the impedance method. Results were compared with that of standard figure-of-eight (Fo8) coil. Simulation results show that double cone, H- and HCA coils have significantly deep field penetration compared to the conventional Fo8 coil, at the expense of induced higher and wider spread electrical fields in superficial cortical regions. Double cone and HCA coils have better ability to stimulate deep brain subregions compared to that of the H-coil. In the mean time, both double cone and HCA coils increase risk for optical nerve excitation. Our results suggest although the dTMS coils offer new tool with potential for both research and clinical applications for psychiatric and neurological disorders associated with dysfunctions of deep brain regions, the selection of the most suitable coil settings for a specific clinical application should be based on a balanced evaluation between stimulation depth and focality.

Computational Study Toward Deep Transcranial Magnetic Stimulation Using Coaxial Circular Coils.

OBJECTIVE: To investigate the possibility for stimulating deeper brain regions while decreasing the electrical field in superficial cortical regions by employing coaxial circular coils. METHODS: The Halo coil, Halo-circular assembly coil (HCA coil) and Halo coil working with two circular coils (HTC coil) were applied over a 36-tissue anatomically based head model. Three-dimensional distributions of magnetic flux density, induced electric field in head tissues were obtained by 3-D impedance method. RESULTS: For the case of HCA coil with current flowing in the same direction in each of two coils, the field penetration depth by the conventional circular coil can be effectively increased at the expense of reduced focality. For the case of the HTC coil with currents flowing in opposite direction in the neighboring coils, overthreshold electric fields can be produced in deep brain regions, while the subthreshold fields were produced in superficial cortical areas. CONCLUSION: The HTC coil with varied coil parameters and different injected currents provides a flexible way for deep brain stimulation with better ratio of deep region field relative to field at the shallow areas. SIGNIFICANCE: The HTC coil is promising for deep transcranial magnetic stimulation, which may offer a new tool with potential for both research and clinical applications for psychiatric and neurological disorders associated with dysfunctions of deep brain regions.

Effectiveness of magnetically aligned collagen for neural regeneration in vitro and in vivo.

We investigated the effectiveness of using magnetically aligned collagen (after exposure to a maximum 8-T magnetic field) for nerve regeneration in both an in vitro and in vivo model. Neurite outgrowth from embryonic chick dorsal root ganglion (DRG) neurons was significantly greater on magnetically aligned collagen gel than on control gel, and was dependent on magnetic field strength. Silicone tubes (15 mm length) filled with collagen gel formed bridges between severed rat sciatic nerves. We prepared tubes for four groups: collagen gel only (COL), magnetically aligned collagen gel (M-COL), collagen gel mixed with Schwann cells (S-COL), and magnetically aligned collagen gel mixed with Schwann cells (M-S-COL). The ratio of infiltrating regenerated nerves was higher in the M-COL group compared to the COL group at 8 weeks post-operation. There were no significant differences between the two groups with and without Schwann cells. Compound action potentials showed higher amplitude and shorter latency in the M-COL than COL group at 12 weeks post-operation. The number and diameter of regenerated axons increased significantly in the M-COL compared with the COL group at 12 weeks post-operation. Here we demonstrated that magnetically orientated collagen promoted nerve regeneration using both an in vitro and in vivo model.

Calculating the induced electromagnetic fields in real human head by deep transcranial magnetic stimulation.

Stimulation of deeper brain structures by transcranial magnetic stimulation (TMS) may be beneficial in the treatment of several neurological and psychiatric disorders. This paper presents numerical simulation of deep transcranial magnetic stimulation (dTMS) by considering double cone, H-and Halo coils. Three-dimensional distributions of the induced fields i.e. magnetic flux density, current density and electric fields in realistic head model by dTMS coils were calculated by impedance method and the results were compared with that of figure-of-eight coil. It was found that double cone and H-coils have significantly deep field penetration at the expense of induced higher and wider spread electrical fields in superficial cortical regions. The Halo coil working with a circular coil carrying currents in opposite directions provides a flexible way to stimulate deep brain structures with much lower stimulation in superficial brain tissues.

Studies on magnetism and bioelectromagnetics for 45 years: from magnetic analog memory to human brain stimulation and imaging.

Forty-five years of studies on magnetism and bioelectromagnetics, in our laboratory, are presented. This article is prepared for the d'Arsonval Award Lecture. After a short introduction of our early work on magnetic analog memory, we review and discuss the following topics: (1) Magnetic nerve stimulation and localized transcranial magnetic stimulation (TMS) of the human brain by figure-eight coils; (2) Measurements of weak magnetic fields generated from the brain by superconducting quantum interference device (SQUID) systems, called magnetoencephalography (MEG), and its application in functional brain studies; (3) New methods of magnetic resonance imaging (MRI) for the imaging of impedance of the brain, called impedance MRI, and the imaging of neuronal current activities in the brain, called current MRI; (4) Cancer therapy and other medical treatments by pulsed magnetic fields; (5) Effects of static magnetic fields and magnetic control of cell orientation and cell growth; and (6) Effects of radio frequency magnetic fields and control of iron ion release and uptake from and into ferritins, iron cage proteins. These bioelectromagnetic studies have opened new horizons in magnetism and medicine, in particular for brain research and treatment of ailments such as depression, Parkinson's, and Alzheimer's diseases.

Biological effects of electromagnetic fields and recently updated safety guidelines for strong static magnetic fields.

Humans are exposed daily to artificial and naturally occurring magnetic fields that originate from many different sources. We review recent studies that examine the biological effects of and medical applications involving electromagnetic fields, review the properties of static and pulsed electromagnetic fields that affect biological systems, describe the use of a pulsed electromagnetic field in combination with an anticancer agent as an example of a medical application that incorporates an electromagnetic field, and discuss the recently updated safety guidelines for static electromagnetic fields. The most notable modifications to the 2009 International Commission on Non-Ionizing Radiation Protection guidelines are the increased exposure limits, especially for those who work with or near electromagnetic fields (occupational exposure limits). The recommended increases in exposure were determined using recent scientific evidence obtained from animal and human studies. Several studies since the 1994 publication of the guidelines have examined the effects on humans after exposure to high static electromagnetic fields (up to 9.4 tesla), but additional research is needed to ascertain further the safety of strong electromagnetic fields.

Short-term exposure to a 1439-MHz TDMA signal exerts no estrogenic effect in rats.

The aim of this study was to elucidate the possible effects of short-term exposure to a 1439-MHz electromagnetic field (EMF) employing time division multiple access (TDMA), which is the basis of the Japanese Personal Digital Cellular system, on estrogenic activity in rats. Sixty-four ovariectomized female Sprague-Dawley rats were divided into four groups: EMF exposure (EM), sham exposure, cage control, and 17 beta-estradiol injected (E2). The EM group was exposed, for 4 h per day on three consecutive days, to the 1439-MHz TDMA signal that produced 5.5-6.1 and 0.88-0.99 W/kg average specific absorption rates in the brain and the whole body, respectively. The uterine wet mass and serum estradiol level significantly increased in the E2 group, while there were no differences among the other three groups. Although negative effects of long-term EMF exposure must be thoroughly investigated before a final conclusion can be reached, our results do not support the assumption that the high frequency EMF used in cellular phones exerts estrogenic activity.

Radio frequency magnetic field effects on molecular dynamics and iron uptake in cage proteins.

The protein ferritin has a natural ferrihydrite nanoparticle that is superparamagnetic at room temperature. For native horse spleen ferritin, we measure the low field magnetic susceptibility of the nanoparticle as 2.2 x 10(-6) m(3) kg(-1) and its Néel relaxation time at about 10(-10) s. Superparamagnetic nanoparticles increase their internal energy when exposed to radio frequency magnetic fields due to the lag between magnetization and applied field. The energy is dissipated to the surrounding peptidic cage, altering the molecular dynamics and functioning of the protein. This leads to an increased population of low energy vibrational states under a magnetic field of 30 microT at 1 MHz, as measured via Raman spectroscopy. After 2 h of exposure, the proteins have a reduced iron intake rate of about 20%. Our results open a new path for the study of non-thermal bioeffects of radio frequency magnetic fields at the molecular scale.

Influence of coil current configuration in magnetic stimulation of a nerve fiber in inhomogeneous and anisotropic conducting media.

In this study, we used a computer simulation to investigate the effects of the coil current waveform and direction on the excitation processes of the nerve axon in inhomogeneous and anisotropic conducting media in magnetic stimulation. We assumed that the nerve axon was located in the media with 2 regions having different conductivities or electrical anisotropy that simulate different tissue types. The distribution of induced electric fields was calculated with the finite element method (FEM). The nerve fiber was modeled after equivalent electrical circuits having active nodes of Ranvier. The direction of the coil current at the intersection of a figure-eight coil was assumed to flow perpendicular to the nerve axon. We observed the excitation threshold when the coil current waveform and direction are changed with varying the electrical properties such as tissue electrical conductivity and anisotropy. The simulation results show that the threshold decreases with the increase of conductivity ratio between 2 regions and it also depends on the coil current waveform and direction. Biphasic coil current has lower threshold than monophasic one when the current direction is the same in both waveforms. The results also suggest that the tissue anisotropy strongly affects the excitation threshold. The threshold increases with the increase of tissue anisotropic ratio of longitudinal direction to the transverse one respect to the nerve axon. The results in this study give useful information to explain the experimental results of the magnetic stimulation of human peripheral nervous systems and the theoretical model is applicable to understand the characteristics in magnetic stimulation of both peripheral and central nervous systems.

Enhanced magnetic resonance imaging of experimental pancreatic tumor in vivo by block copolymer-coated magnetite nanoparticles with TGF-beta inhibitor.

Early detection of solid tumors, particularly pancreatic cancer, is of substantial importance in clinics. Enhanced magnetic resonance imaging (MRI) with iron oxide nanoparticles is an available way to detect the cancer. The effective and selective accumulation of these nanoparticles in the tumor tissue is needed for improved imaging, and in this regard, their longevity in the blood circulation time is crucial. We developed here block copolymer-coated magnetite nanoparticles for pancreatic cancer imaging, by means of a chelation between the carboxylic acid groups in poly(ethylene glycol)-poly(aspartic acid) block copolymer (PEG-PAsp) and Fe on the surface of the iron oxide nanoparticles. These nanoparticles had considerably narrow distribution, even upon increased ionic strength or in the presence of fetal bovine serum. The PEG-PAsp-coated nanoparticles were further shown to be potent as a contrast agent for enhanced MRI for an experimental pancreatic cancer, xenografts of the human-derived BxPC3 cell line in BALB/c nude mice, with combined administration of TGF-beta inhibitor. Iron staining of tumor tissue confirmed the accumulation of the nanoparticles in tumor tissue. Use of the PEG-PAsp-coated magnetite nanoparticles, combined with the TGF-beta inhibitor, is of promising clinical importance for the detection of intractable solid cancers, including pancreatic cancer.

Low-frequency conductivity tensor of rat brain tissues inferred from diffusion MRI.

Conductivity tensor maps of the rat brain were obtained using diffusion magnetic resonance imaging (MRI). Signal attenuations in the cortex and the corpus callosum were measured using the stimulated echo acquisition mode (STEAM) sequence with b factors up to 6000 s/mm(2). Our previously published method was improved to infer 3 x 3 conductivity tensor at the low-frequency limit. The conductivity tensor of the tissue was inferred from the fast component of the diffusion tensor and a fraction of the fast component. The mean conductivity (MC) of the cortex and the corpus callosum was 0.52 and 0.62 S/m, respectively. Diffusion-weighted images were obtained with b factors up to 4500 s/mm(2). Conductivity tensor images were calculated from the fast diffusion tensor images. Tissues with highly anisotropic cellular structures, such as the corpus callosum, the internal capsule, and the trigeminal nerve, exhibited high anisotropy in conductivity. The resulting values corresponded to conductivities at the low-frequency limit because our method assumed electric currents flowing only through extracellular fluid.

Estimation of cell membrane permeability and intracellular diffusion coefficient of human gray matter.

The signal intensity of diffusion-weighted imaging (DWI) is sensitive to the intra- and extracellular diffusion coefficient of water and cell membrane permeability. We applied a method we proposed in previous papers to estimate noninvasively the membrane permeability and intracellular diffusion coefficient of normal human brain (gray matter) in 3 normal volunteers. We theoretically compared predicted signals and experiment results using a 1.5-tesla magnetic resonance (MR) imaging system. We acquired images using an echo planar imaging (EPI) sequence, applying motion-probing gradient (MPG) pulses in 3 directions. We periodically performed numerical simulations for various combinations of membrane permeability and intracellular diffusion coefficients using the finite-difference method. By minimizing the difference between signals obtained experimentally and those from numerical simulation, we could estimate membrane permeability (76+/-9 mm2/s mum) and intracellular diffusion coefficient (1.0+/-0.0 mm2/s) for the human brain. The estimated membrane permeability was the criterion value for diagnosing disease in gray matter.

Effects of radio frequency magnetic fields on iron release from cage proteins.

Ferritin, the iron cage protein, contains a superparamagnetic ferrihydrite nanoparticle formed from the oxidation and absorption of Fe(2+) ions. This nanoparticle increases its internal energy when exposed to alternating magnetic fields due to magnetization lag. The energy is then dissipated to the surrounding proteic cage, affecting its functioning. In this article we show that the rates of iron chelation with ferrozine, an optical marker, are reduced by up to a factor of 3 in proteins previously exposed to radio frequency magnetic fields of 1 MHz and 30 microT for several hours. The effect is non-thermal and depends on the frequency-amplitude product of the magnetic field.

The numeric calculation of eddy current distributions in transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is a method to stimulate neurons in the brain. It is necessary to obtain eddy current distributions and determine parameters such as position, radius and bend-angle of the coil to stimulate target area exactly. In this study, we performed FEM-based numerical simulations of eddy current induced by TMS using three-dimentional human head model with inhomogeneous conductivity. We used double-cone coil and changed the coil radius and bend-angle of coil. The result of computer simulation showed that as coil radius increases, the eddy current became stronger everywhere. And coil with bend-angle of 22.5 degrees induced stronger eddy current than the coil with bendangle of 0 degrees. Meanwhile, when the bend-angle was 45 degrees, eddy current became weaker than these two cases. This simulation allowed us to determine appropriate parameter easier.

The rTMS effect on perceptual reversal of ambiguous figures.

Past research about perceptual reversal of ambiguous figures indicate that the superior parietal lobule is involved in perceptual reversal. To investigate the rTMS effect over right superior parietal lobule on perceptual reversal, three trials were performed. In Trial 1, rTMS was applied over the right superior parietal lobule. In Trial 2, rTMS was applied over the right posterior temporal lobe. In Trial 3, no TMS was applied over the subject's skull. The inter-reversal time of perceptual reversal between these three trials were compared. It was suggested that the right superior parietal lobule plays a critical role in perceptual reversal of ambiguous figures. Furthermore, short-duration and long-duration rTMS were conducted in the present study, respectively. The rTMS duration effects on perceptual reversal were also compared.