Electric Field Distribution during Non-Invasive Electric and Magnetic Stimulation of the Cervical Spinal Cord.

Experimental studies on transcutaneous spinal cord direct current and magnetic stimulation (tsDCS and tsMS) show promising results in the neuromodulation of spinal sensory and motor pathways, with possible application in spinal functional rehabilitation. Modelling studies on the electric field (EF) distribution during tsDCS and tsMS are powerful tools to understand the underlying biophysics and to select and optimize stimulation protocols for a specific clinical target. The study presented here compares the EF during cervical tsDCS and tsMS. The EF predictions show the same spatial profiles along the cervical spinal cord using both types of stimulation. tsMS presents higher average magnitudes per spinal segment, with a maximum value of 14.61 V/m, whereas tsDCS is approximately 30 times lower, reaching 0.44 V/m. According to previous studies, tsDCS and tsMS induce EF values which are sufficient for spinal neuromodulation.

Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines.

Low intensity transcranial electrical stimulation (TES) in humans, encompassing transcranial direct current (tDCS), transcutaneous spinal Direct Current Stimulation (tsDCS), transcranial alternating current (tACS), and transcranial random noise (tRNS) stimulation or their combinations, appears to be safe. No serious adverse events (SAEs) have been reported so far in over 18,000 sessions administered to healthy subjects, neurological and psychiatric patients, as summarized here. Moderate adverse events (AEs), as defined by the necessity to intervene, are rare, and include skin burns with tDCS due to suboptimal electrode-skin contact. Very rarely mania or hypomania was induced in patients with depression (11 documented cases), yet a causal relationship is difficult to prove because of the low incidence rate and limited numbers of subjects in controlled trials. Mild AEs (MAEs) include headache and fatigue following stimulation as well as prickling and burning sensations occurring during tDCS at peak-to-baseline intensities of 1-2mA and during tACS at higher peak-to-peak intensities above 2mA. The prevalence of published AEs is different in studies specifically assessing AEs vs. those not assessing them, being higher in the former. AEs are frequently reported by individuals receiving placebo stimulation. The profile of AEs in terms of frequency, magnitude and type is comparable in healthy and clinical populations, and this is also the case for more vulnerable populations, such as children, elderly persons, or pregnant women. Combined interventions (e.g., co-application of drugs, electrophysiological measurements, neuroimaging) were not associated with further safety issues. Safety is established for low-intensity 'conventional' TES defined as <4mA, up to 60min duration per day. Animal studies and modeling evidence indicate that brain injury could occur at predicted current densities in the brain of 6.3-13A/m2 that are over an order of magnitude above those produced by tDCS in humans. Using AC stimulation fewer AEs were reported compared to DC. In specific paradigms with amplitudes of up to 10mA, frequencies in the kHz range appear to be safe. In this paper we provide structured interviews and recommend their use in future controlled studies, in particular when trying to extend the parameters applied. We also discuss recent regulatory issues, reporting practices and ethical issues. These recommendations achieved consensus in a meeting, which took place in Göttingen, Germany, on September 6-7, 2016 and were refined thereafter by email correspondence.

A novel binuclear copper complex incorporating a nalidixic acid derivative displaying a one-dimensional coordination polymeric structure.

The identification of the antibacterial action of nalidixic acid (nx) was central to the development of the quinolone antibacterial compounds. The ability of the nx naphthyridyl ring to interact with and inhibit some proteins has encouraged the investigation of similar structures in the search for more active compounds with less adverse effects. The possibility of structural modification by attachment of other biologically active moieties to the naphthyridyl ring of nx allowed the development of new active antimicrobial molecules. Hydrazone derivatives of nx can be synthesized easily based on the condensation of the hydrazide derivative of nx with the desired aldehyde or ketone. Only a few complexes with nx hydrazone derivatives have been described but for none were the crystal structures elucidated. The synthesis of a new one-dimensional Cu(II) coordination polymer, namely catena-poly[[copper(II)-di-µ-chlorido-copper(II)-{µ-1-ethyl-N'-[(1H-imidazol-4-yl)methylidene]-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbohydrazidato}-[dimethanolcopper(II)]-{µ-1-ethyl-N'-[(1H-imidazol-3-yl)methylidene]-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbohydrazidato}] dichloride methanol tetrasolvate], {[Cu3(C16H15N6O2)2Cl2(CH3OH)2]Cl2·4CH3OH}n, with the (1H-imidazol-4-yl)methylidene carbohydrazide derivative of nalidixic acid (denoted h4imi), is presented and its structure is compared to the density functional theory (DFT) optimized structure of free h4imi. The title structure presents an octahedral Cu(II) ion on an inversion centre alternating along a polymer chain with a square-pyramidal Cu(II) ion, with the two Cu(II) centres bridged by two chloride ligands. Hydrogen bonds involving chloride counter-ions and methanol solvent molecules mediate the three-dimensional packing of the polymer. Comparison of the geometrical results from the structure analysis with those derived from a DFT study of the free ligand reveal the differences that arise upon coordination.

Reduced Current Spread by Concentric Electrodes in Transcranial Electrical Stimulation (tES).

OBJECTIVE: We propose the use of a new montage for transcranial direct current stimulation (tDCS), called concentric electrodes tDCS (CE-tDCS), involving two concentric round electrodes that may improve stimulation focality. METHODS: To test efficacy and focality of CE-tDCS, we modelled the current distribution and tested physiological effects on cortical excitability. Motor evoked potentials (MEPs) from first dorsal interosseous (FDI) and abductor digiti minimi (ADM) were recorded before and after the delivery of anodal, cathodal and sham stimulation on the FDI hotspot for 10 minutes. RESULTS: MEP amplitude of FDI increased after anodal-tDCS and decreased after cathodal-tDCS, supporting the efficacy of CE-tDCS in modulating cortical excitability. Moreover, modelled current distribution and no significant effects of stimulation on MEP amplitude of ADM suggest high focality of CE-tDCS. CONCLUSIONS: CE-tDCS may allow a better control of current distribution and may represent a novel tool for applying tDCS and other transcranial current stimulation approaches.

A technical guide to tDCS, and related non-invasive brain stimulation tools.

Transcranial electrical stimulation (tES), including transcranial direct and alternating current stimulation (tDCS, tACS) are non-invasive brain stimulation techniques increasingly used for modulation of central nervous system excitability in humans. Here we address methodological issues required for tES application. This review covers technical aspects of tES, as well as applications like exploration of brain physiology, modelling approaches, tES in cognitive neurosciences, and interventional approaches. It aims to help the reader to appropriately design and conduct studies involving these brain stimulation techniques, understand limitations and avoid shortcomings, which might hamper the scientific rigor and potential applications in the clinical domain.

Modelling Tumor Treating Fields for the treatment of lung-based tumors.

Tumor Treating Fields (TTFields), low-intensity electric fields in the frequency range of 100-500 kHz, exhibit antimitotic activity in cancer cells. TTFields were approved by the U. S. Food and Drug Administration for the treatment of recurrent glioblastoma in 2011. Preclinical evidence and pilot studies suggest that TTFields could be effective for treating certain types of lung cancer, and that treatment efficacy depends on the electric field intensity. To optimize TTFields delivery to the lungs, it is important to understand how TTFields distribute within the chest. Here we present simulations showing how TTFields are distributed in the thorax and torso, and demonstrate how the electric field distribution within the body can be controlled by personalizing the layout of the arrays used to deliver the field.

Transcranial alternating current stimulation reduces symptoms in intractable idiopathic cervical dystonia: a case study.

Idiopathic cervical dystonia (ICD) is a movement disorder often resulting in profound disability and pain. Treatment options include oral medications or other invasive procedures, whereas intractable ICD has been shown to respond to invasive (deep) brain stimulation. In the present blinded, placebo-controlled case study, transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS) has been applied to a 54-year old patient with intractable ICD. Results showed that 15 Hz tACS had both immediate and cumulative effects in dystonic symptom reduction, with a 54% reduction in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score, and a 75% in the TWSTRS Pain Scale. These effects were persistent at 30-days follow-up. This is the first report to demonstrate a significant and lasting therapeutic effect of non-invasive electrical brain stimulation in dystonia.

Effects of tissue dielectric properties on the electric field induced in tDCS: a sensitivity analysis.

Numerical modeling studies remain the only viable way to accurately predict the electric field (E-field) distribution in transcranial direct current stimulation (tDCS). Despite the existence of multiple studies of this kind, a wide range of different values and properties for the electrical conductivities of the tissues represented is employed. This makes it difficult to predict whether the changes observed between models are due to differences in the geometries of the volume conductors or to the different electrical properties of the tissues. In this study we used the finite element method to calculate the E-field distribution in several spherical head models whose tissues were represented with different isotropic and anisotropic conductivity profiles. Results show that the distribution of the E-field is especially sensitive to the conductivity of the skull, skin and GM. These results might help comparing numerical modeling studies that employ different conductivity values.

The relationship between transcranial current stimulation electrode montages and the effect of the skull orbital openings.

Due to its low electric conductivity, the skull has a major impact on the electric field distribution in the brain in transcranial current stimulation (tCS). However, the skull has several openings that are filled with higher conductivity soft tissues, and through which a significant fraction of the injected current may pass. We show that current entering the brain via the orbital openings increases the electric field intensity in the cortical regions near the orbit. Furthermore, this depends on the how far electrodes are placed from the orbital openings.

Determining which mechanisms lead to activation in the motor cortex: a modeling study of transcranial magnetic stimulation using realistic stimulus waveforms and sulcal geometry.

OBJECTIVE: To determine which mechanisms lead to activation of neurons in the motor cortex during transcranial magnetic stimulation (TMS) with different current directions and pulse waveforms. METHODS: The total electric field induced in a simplified model of a cortical sulcus by a figure-eight coil was calculated using the finite element method (FEM). This electric field was then used as the input to determine the response of compartmental models of several types of neurons. RESULTS: The modeled neurons were stimulated at different sites: fiber bends for pyramidal tract neurons, axonal terminations for cortical interneurons and axon collaterals, and a combination of both for pyramidal association fibers. All neurons were more easily stimulated by a PA - directed electric field, except association fibers. Additionally, the second phase of a biphasic pulse was found to be more efficient than the first phase of either monophasic or biphasic pulses. CONCLUSIONS: The stimulation threshold for different types of neurons depends on the pulse waveform and relative current direction. The reported results might account for the range of responses obtained in TMS of the motor cortex when using different stimulation parameters. SIGNIFICANCE: Modeling studies combining electric field calculations and neuronal models may lead to a deeper understanding of the effect of the TMS-induced electric field on cortical tissue, and may be used to improve TMS coil and waveform design.

Modeling the electric field induced in a high resolution realistic head model during transcranial current stimulation.

Much of our knowledge about the electric field distribution in transcranial current stimulation (tCS) still relies on results obtained from layered spherical head models. In this work we created a high resolution finite element model of a human head by segmentation of MRI images, and paid particular attention to the representation of the cortical sheet. This model was then used to calculate the electric field induced by two electrodes: an anode placed above the left motor cortex, and a cathode placed over the right eyebrow. The results showed that the maxima of the current density appear located on localized hotspots in the bottom of sulci and not on the cortical surface as would be expected from spherical models. This also applies to the components of the current density normal and tangential to the cortical surface. These results show that such highly detailed head models are needed to correctly predict the effects of tCS on cortical neurons.

Transcranial magnetic stimulation of small animals: a modeling study of the influence of coil geometry, size and orientation.

Several recent studies have investigated the mechanisms of repetitive transcranial magnetic stimulation (rTMS) using small animals. However, there is still limited knowledge about the distribution of the induced electric field, and its dependence on coil size, geometry and orientation. In this work we calculate the electric field induced in a realistically shaped homogeneous mouse model by commercially available coils in several different orientations. The results show that the secondary field, resulting from charge accumulation at the skin - air interface, drastically changes the magnitude, decay and focality of the primary field induced by the coil. Accurate knowledge about the distribution of the field is invaluable in designing experimental protocols and new coils for small animal stimulation.

High permeability cores to optimize the stimulation of deeply located brain regions using transcranial magnetic stimulation.

Efficient stimulation of deeply located brain regions with transcranial magnetic stimulation (TMS) poses many challenges, arising from the fact that the induced field decays rapidly and becomes less focal with depth. We propose a new method to improve the efficiency of TMS of deep brain regions that combines high permeability cores, to increase focality and field intensity, with a coil specifically designed to induce a field that decays slowly with increasing depth. The performance of the proposed design was investigated using the finite element method to determine the total electric field induced by this coil/core arrangement on a realistically shaped homogeneous head model. The calculations show that the inclusion of the cores increases the field's magnitude by as much as 25% while also decreasing the field's decay with depth along specific directions. The focality, as measured by the area where the field's norm is greater than 1/sq.rt.2 of its maximum value, is also improved by as much as 15% with some core arrangements. The coil's inductance is not significantly increased by the cores. These results show that the presence of the cores might make this specially designed coil even more suited for the effective stimulation of deep brain regions.

Golimumab, a human antibody to tumour necrosis factor {alpha} given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study.

OBJECTIVE: The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate therapy. METHODS: Patients were randomly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules (group 1, n = 133), golimumab 100 mg injections plus placebo capsules (group 2, n = 133), golimumab 50 mg injections plus methotrexate capsules (group 3, n = 89), or golimumab 100 mg injections plus methotrexate capsules (group 4, n = 89). Injections were administered subcutaneously every 4 weeks. The co-primary endpoints were the proportion of patients with 20% or greater improvement in the American College of Rheumatology criteria (ACR20) at week 14 and the change from baseline in the health assessment questionnaire-disability index (HAQ-DI) score at week 24. RESULTS: The proportion of patients who achieved an ACR20 response at week 14 was 33.1% in the placebo plus methotrexate group, 44.4% (p = 0.059) in the golimumab 100 mg plus placebo group, 55.1% (p = 0.001) in the golimumab 50 mg plus methotrexate group and 56.2% (p<0.001) in the golimumab 100 mg plus methotrexate group. At week 24, median improvements from baseline in HAQ-DI scores were 0.13, 0.13 (p = 0.240), 0.38 (p<0.001) and 0.50 (p<0.001), respectively. During the placebo-controlled portion of the study (to week 16), serious adverse events occurred in 2.3%, 3.8%, 5.6% and 9.0% of patients and serious infections occurred in 0.8%, 0.8%, 2.2% and 5.6%, respectively. CONCLUSION: The addition of golimumab to methotrexate in patients with active RA despite methotrexate therapy significantly reduced the signs and symptoms of RA and improved physical function.

Elucidating the mechanisms and loci of neuronal excitation by transcranial magnetic stimulation using a finite element model of a cortical sulcus.

OBJECTIVE: This work aims to elucidate by what physical mechanisms and where stimulation occurs in the brain during transcranial magnetic stimulation (TMS), taking into account cortical geometry and tissue heterogeneity. METHODS: An idealized computer model of TMS was developed, comprising a stimulation coil, a cortical sulcus, and surrounding tissues. The distribution of the induced electric field was computed, and estimates of the relevant parameters were generated to predict the locus and type of neurons stimulated during TMS, assuming three different stimulation mechanisms. RESULTS: Tissue heterogeneity strongly affects the spatial distribution of the induced electric field and hence which stimulation mechanism is dominant and where it acts. Stimulation of neurons may occur in the gyrus, in the lip of the gyrus, and in the walls of the sulcus. The stimulated cells can be either pyramidal cells having medium to large caliber axons, or intracortical fibers of medium caliber. CONCLUSIONS: The results highlight the influence of cortical folding on the action of magnetic and electric fields on cortical tissue. SIGNIFICANCE: Tissue geometry and heterogeneity in electrical conductivity both must be taken into account to predict accurately stimulation loci and mechanism in TMS.

High-permeability core coils for transcranial magnetic stimulation of deep brain regions.

Stimulation of deep brain regions with Transcranial Magnetic Stimulation (TMS) may have an important role as a therapy to treat chemical dependency and depression. The coils traditionally used in TMS, however, have a poor performance in stimulating deep neurons. In this work we study the usage of high permeability cores combined with coils specifically designed to induce fields that decay slowly with depth. By using the finite elements method we show that the use of such cores increases the field's magnitude, decreases its decay rate and improves its focality. Such improvements make these high permeability core coils more suited to stimulate deep brain regions.

Tissue heterogeneity as a mechanism for localized neural stimulation by applied electric fields.

We investigate the heterogeneity of electrical conductivity as a new mechanism to stimulate excitable tissues via applied electric fields. In particular, we show that stimulation of axons crossing internal boundaries can occur at boundaries where the electric conductivity of the volume conductor changes abruptly. The effectiveness of this and other stimulation mechanisms was compared by means of models and computer simulations in the context of transcranial magnetic stimulation. While, for a given stimulation intensity, the largest membrane depolarization occurred where an axon terminates or bends sharply in a high electric field region, a slightly smaller membrane depolarization, still sufficient to generate action potentials, also occurred at an internal boundary where the conductivity jumped from 0.143 S m(-1) to 0.333 S m(-1), simulating a white-matter-grey-matter interface. Tissue heterogeneity can also give rise to local electric field gradients that are considerably stronger and more focal than those impressed by the stimulation coil and that can affect the membrane potential, albeit to a lesser extent than the two mechanisms mentioned above. Tissue heterogeneity may play an important role in electric and magnetic 'far-field' stimulation.

A complete 1H and 13C NMR data assignment for the diterpene methyl (-)-zanzibarate by 2D spectroscopy and NOE experiments.

The 1H and 13C NMR spectra of methyl (-)-zanzibarate (1), an ent-labdanic diterpene isolated from the epicarp of Hymenaea courbaril var. altissima (Leguminosaea, Cesalpinoideae, Detariae), was fully assigned by COSY experiments, 13C/1H shift correlation diagrams and NOE experiments.

Neurophysiological features of fasciculation potentials evoked by transcranial magnetic stimulation in amyotrophic lateral sclerosis.

We report 13 patients with amyotrophic lateral sclerosis in whom fasciculation potentials (FPs) driven by transcranial magnetic stimulation (TMS) were recorded. A total of 18 different FPs were analyzed. TMS-driven fasciculations had a simple morphology and were stable. Complex potentials were never cortically driven. Recruitment by a slight voluntary contraction was verified in 7 of 13 tested FPs. FPs were driven by threshold stimuli in 7 of 10 patients and by stimuli 5% below threshold in 3 of 6. Mapping demonstrated that FPs were driven in an area close to the center of gravity of the muscle cortical area. In one case FPs were evoked from most of the cortical representation area of a very weak muscle. Three other patients with profuse fasciculations associated with other clinical conditions were also studied. No TMS evoked fasciculation was observed in this group. The results of this systematic study suggest that cortically evoked FPs arise centrally, at spinal cord or even more proximally, and can represent a marker of increased corticomotor excitability, which is predominant at an earlier phase but can persist as the disease progresses.

Cortical muscle representation in amyotrophic lateral sclerosis patients: changes with disease evolution.

Transcranial magnetic stimulation (TMS) mapping was performed regularly on 11 patients with amyotrophic lateral sclerosis (ALS). Map area decreased by 25% (P = 0.03) and normalized volume decreased by 47% (P = 0.01) in those patients who were mapped four times over a period of 11.6 months. The center of gravity (CoG) position moved randomly along the interaural line by distances larger than could be explained by experimental error (P = 0.002). Central conduction time, threshold, and motor evoked potential:compound muscle action potential (MEP:CMAP) amplitude ratio did not change significantly with time (P > 0.05). There were significant linear correlations between strength and CMAP amplitude and between map area and volume. No correlation was found between strength or CMAP amplitude and area or volume. The changes in map parameters were attributed primarily to loss of cortical cells. These results indicate that map parameters may be more sensitive to cortical neuronal loss than other TMS parameters.