Multifactorial effects of short duration early exposure low intensity magnetic field stimulation in Streptozotocin induced Alzheimer's disease rat model.

Alzheimer's disease (AD) is an approaching, progressive public health crisis which presently lacks an effective treatment. Various non-invasive novel therapies like repetitive transcranial magnetic stimulation have shown potential to improve cognitive performance in AD patients. In the present study, the effect of extremely low intensity magnetic field (MF) stimulation on neurogenesis and cortical electrical activity was explored. Adult Wistar rats were divided into Sham, AD and AD + MF groups. Streptozotocin (STZ) was injected intracerebroventricularly, at a dose of 3 mg/kg body weight for developing AD model. The AD rats were then exposed to MF (17.96 µT) from 8th day of STZ treatment until 15th day, followed by cognitive assessments and electrocortical recording. In brain tissue samples, cresyl violet staining and BrdU immunohistochemistry were done. MF exposure, improved passive avoidance and recognition memory, attenuated neuronal degeneration and enhanced cell proliferation (BrdU positive cells) in comparison to AD rats. It also significantly restores delta wave power from frontal lobe. Our results suggest that early-stage MF exposure could be an asset for AD research and open new avenues in slowing down the progression of Alzheimer's disease.

Application of electrostimulation and magnetic stimulation in patients with optic neuropathy: A mechanistic review.

Visual impairment caused by optic neuropathies is irreversible because retinal ganglion cells (RGCs), the specialized neurons of the retina, do not have the capacity for self-renewal and self-repair. Blindness caused by optic nerve neuropathies causes extensive physical, financial, and social consequences in human societies. Recent studies on different animal models and humans have established effective strategies to prevent further RGC degeneration and replace the cells that have deteriorated. In this review, we discuss the application of electrical stimulation (ES) and magnetic field stimulation (MFS) in optic neuropathies, their mechanisms of action, their advantages, and limitations. ES and MFS can be applied effectively in the field of neuroregeneration. Although stem cells are becoming a promising approach for regenerating RGCs, the inhibitory environment of the CNS and the long visual pathway from the optic nerve to the superior colliculus are critical barriers to overcome. Scientific evidence has shown that adjuvant treatments, such as the application of ES and MFS help direct thetransplanted RGCs to extend their axons and form new synapses in the central nervous system (CNS). In addition, these techniques improve CNS neuroplasticity and decrease the inhibitory effects of the CNS. Possible mechanisms mediating the effects of electrical current on biological tissues include the release of anti-inflammatory cytokines, improvement of microcirculation, stimulation of cell metabolism, and modification of stem cell function. ES and MFS have the potential to promote angiogenesis, direct axon growth toward the intended target, and enhance appropriate synaptogenesis in optic nerve regeneration.

Static Magnetic Field Stimulation Enhances Shunting Inhibition via a SLC26 Family Cl- Channel, Inducing Intrinsic Plasticity.

Magnetic fields are being used for detailed anatomical and functional examination of the human brain. In addition, evidence for their efficacy in treatment of brain dysfunctions is accumulating. Transcranial static magnetic field stimulation (tSMS) is a recently developed technique for noninvasively modifying brain functions. In tSMS, a strong and small magnet when placed over the skull can temporarily suppress brain functions. Its modulatory effects persist beyond the time of stimulation. However, the neurophysiological mechanisms underlying tSMS-induced plasticity remain unclear. Here, using acute motor cortical slice preparation obtained from male C57BL/6N mice, we show that tSMS alters the intrinsic electrical properties of neurons by altering the activity of chloride (Cl-) channels in neurons. Exposure of mouse pyramidal neurons to a static magnetic field (SMF) at a strength similar to human tSMS temporarily decreased their excitability and induced transient neuronal swelling. The effects of SMF were blocked by DIDS and GlyH-101, but not by NPPB, consistent with the pharmacological profile of SLC26A11, a transporter protein with Cl- channel activity. Whole-cell voltage-clamp recordings of the GlyH-101-sensitive Cl- current component showed significant enhancement of the component at both subthreshold and depolarized membrane potentials after SMF application, resulting in shunting inhibition and reduced repetitive action potential (AP) firing at the respective potentials. Thus, this study provides the first neurophysiological evidence for the inhibitory effect of tSMS on neuronal activity and advances our mechanistic understanding of noninvasive human neuromodulation.

Therapeutic Potential of Low-Intensity Magnetic Field Stimulation in 6-Hydroxydopamine Rat Model of Parkinson's Disease: From Inflammation to Motor Function.

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder that mainly affects the aged population. Transcranial magnetic field (MF) stimulation has shown to provide temporary motor recovery in neurological disorders. Purpose: The aim of this study was to understand the cellular and molecular mechanism of low-intensity MF stimulation (17.96 µT; 50Hz; 2 h/day, four weeks) in a rat model of severe PD. Methods: A clinically relevant, bilateral striatal 6-hydroxydopamine (6-OHDA) lesioned rat model of severe PD was employed to test the efficacy of low-intensity MF stimulation in the management of motor symptoms. The mechanism of action of MF was dissected by assessing the microglial activation, tissue ultrastructure, and cerebrospinal fluid (CSF) metabolomics using microdialysis. Results: We observed a significant improvement in the postural balance and gait after MF exposure with a significant reduction in the number of activated microglia. There was an improvement in striatal dopaminergic innervation and glutamate levels but it did not reach a level of statistical significance. Conclusion: MF stimulation helped ameliorate the motor deficits and reduced inflammation but was unable to provide a significant change in terms of dopaminergic innervation and metabolic profile in the severe 6-OHDA PD rat model.

External magnetic field non-invasively stimulates spinal cord regeneration in rat via a magnetic-responsive aligned fibrin hydrogel.

Magnetic stimulation is becoming an attractive approach to promote neuroprotection, neurogenesis, axonal regeneration, and functional recovery in both the central nervous system and peripheral nervous system disorders owing to its painless, non-invasive, and deep penetration characteristics. Here, a magnetic-responsive aligned fibrin hydrogel (MAFG) was developed to import and amplify the extrinsic magnetic field (MF) locally to stimulate spinal cord regeneration in combination with the beneficial topographical and biochemical cues of aligned fibrin hydrogel (AFG). Magnetic nanoparticles (MNPs) were embedded uniformly in AFG during electrospinning to endow it magnetic-responsive feature, with saturation magnetization of 21.79 emu g-1. It is found that the MNPs under the MF could enhance cell proliferation and neurotrophin secretion of PC12 cellsin vitro. The MAFG that was implanted into a rat with 2 mm complete transected spinal cord injury (SCI) effectively enhanced neural regeneration and angiogenesis in the lesion area, thus leading to significant recovery of motor function under the MF (MAFG@MF). This study suggests a new multimodal tissue engineering strategy based on multifunctional biomaterials that deliver multimodal regulatory signals with the integration of aligned topography, biochemical cues, and extrinsic MF stimulation for spinal cord regeneration following severe SCI.

Noninvasive modulation of human corticostriatal activity.

Corticostriatal activity is an appealing target for nonpharmacological treatments of brain disorders. In humans, corticostriatal activity may be modulated with noninvasive brain stimulation (NIBS). However, a NIBS protocol with a sound neuroimaging measure demonstrating a change in corticostriatal activity is currently lacking. Here, we combine transcranial static magnetic field stimulation (tSMS) with resting-state functional MRI (fMRI). We first present and validate the ISAAC analysis, a well-principled framework that disambiguates functional connectivity between regions from local activity within regions. All measures of the framework suggested that the region along the medial cortex displaying greater functional connectivity with the striatum is the supplementary motor area (SMA), where we applied tSMS. We then use a data-driven version of the framework to show that tSMS of the SMA modulates the local activity in the SMA proper, in the adjacent sensorimotor cortex, and in the motor striatum. We finally use a model-driven version of the framework to clarify that the tSMS-induced modulation of striatal activity can be primarily explained by a change in the shared activity between the modulated motor cortical areas and the motor striatum. These results suggest that corticostriatal activity can be targeted, monitored, and modulated noninvasively in humans.

Effects of transcranial static magnetic field stimulation over the left dorsolateral prefrontal cortex on random number generation.

OBJECTIVE: Focal application of transcranial static magnetic field stimulation (tSMS) is a neuromodulation technique, with predominantly inhibitory effects when applied to the motor, somatosensory or visual cortex. Whether this approach can also transiently interact with dorsolateral prefrontal cortex (DLPFC) function remains unclear. The suppression of habitual or competitive responses is one of the core executive functions linked to DLPFC function. This study aimed to assess the impact of tSMS on the prefrontal contributions to inhibitory control and response selection by means of a RNG task. METHODS: We applied 20 min of tSMS over the left DLPFC of healthy subjects, using a real/sham cross-over design, during performance of a RNG task. We used an index of randomness calculated with the measures of entropy and correlation to assess the impact of stimulation on DLPFC function. RESULTS: The randomness index of the sequences generated during the tSMS intervention was significantly higher compared to those produced in the sham condition. CONCLUSIONS: Our results indicate that application of tSMS transiently modulates specific functional brain networks in DLPFC, which indicate a potential use of tSMS for treatment of neuropsychiatric disorders. SIGNIFICANCE: This study provides evidence for the capacity of tSMS for modulating DLPFC function.

Triple tSMS system ("SHIN jiba") for non-invasive deep brain stimulation: a validation study in healthy subjects.

BACKGROUND: Transcranial static magnetic field stimulation (tSMS) using a small and strong neodymium (NdFeB) magnet can temporarily suppress brain functions below the magnet. It is a promising non-invasive brain stimulation modality because of its competitive advantages such as safety, simplicity, and low-cost. However, current tSMS is insufficient to effectively stimulate deep brain areas due to attenuation of the magnetic field with the distance from the magnet. The aim of this study was to develop a brand-new tSMS system for non-invasive deep brain stimulation. METHODS: We designed and fabricated a triple tSMS system with three cylindrical NdFeB magnets placed close to each other. We compared the strength of magnetic field produced by the triple tSMS system with that by the current tSMS. Furthermore, to confirm its function, we stimulated the primary motor area in 17 healthy subjects with the triple tSMS for 20 min and assessed the cortical excitability using the motor evoked potential (MEP) obtained by transcranial magnetic stimulation. RESULTS: Our triple tSMS system produced the magnetic field sufficient for neuromodulation up to 80 mm depth from the magnet surface, which was 30 mm deeper than the current tSMS system. In the stimulation experiment, the triple tSMS significantly reduced the MEP amplitude, demonstrating a successful inhibition of the M1 excitability in healthy subjects. CONCLUSION: Our triple tSMS system has an ability to produce an effective magnetic field in deep areas and to modulate the brain functions. It can be used for non-invasive deep brain stimulation.

Transient Modulation of Working Memory Performance and Event-Related Potentials by Transcranial Static Magnetic Field Stimulation over the Dorsolateral Prefrontal Cortex.

Transcranial static magnetic field stimulation (tSMS) can modulate human cortical excitability and behavior. To better understand the neuromodulatory effect of tSMS, this study investigates whether tSMS applied over the left dorsolateral prefrontal cortex (DLPFC) modulates working memory (WM) performance and its associated event-related potentials (ERPs). Thirteen healthy participants received tSMS or sham stimulation over the left DLPFC for 26 min on different days. The participants performed a 2-back version of the n-back task before, during (20 min after the start of stimulation), immediately after, and 15 min after the stimulation. We examine reaction time for correct responses, d-prime reflecting WM performance, and the N2 and P3 components of ERPs. Our results show that there was no effect of tSMS on reaction time. The d-prime was reduced, and the N2 latency was prolonged immediately after tSMS. These findings indicate that tSMS over the left DLPFC affects WM performance and its associated electrophysiological signals, which can be considered an important step toward a greater understanding of tSMS and its use in studies of higher-order cognitive processes.

Null Effect of Transcranial Static Magnetic Field Stimulation over the Dorsolateral Prefrontal Cortex on Behavioral Performance in a Go/NoGo Task.

The purpose of this pilot study was to investigate whether transcranial static magnetic field stimulation (tSMS), which can modulate cortical excitability, would influence inhibitory control function when applied over the dorsolateral prefrontal cortex (DLPFC). Young healthy adults (n = 8, mean age ± SD = 24.4 ± 4.1, six females) received the following stimulations for 30 min on different days: (1) tSMS over the left DLPFC, (2) tSMS over the right DLPFC, and (3) sham stimulation over either the left or right DLPFC. The participants performed a Go/NoGo task before, immediately after, and 10 min after the stimulation. They were instructed to extend the right wrist in response to target stimuli. We recorded the electromyogram from the right wrist extensor muscles and analyzed erroneous responses (false alarm and missed target detection) and reaction times. As a result, 50% of the participants made erroneous responses, and there were five erroneous responses in total (0.003%). A series of statistical analyses revealed that tSMS did not affect the reaction time. These preliminary findings suggest the possibility that tSMS over the DLPFC is incapable of modulating inhibitory control and/or that the cognitive load imposed in this study was insufficient to detect the effect.

A combinatorial approach to modulate microenvironment toward regeneration and repair after spinal cord injury in rats.

Traumatic spinal cord injury (SCI) is a devastating condition of CNS which leads to loss of sensory as well as motor functions. Secondary damage after SCI initiates cascade of events that creates an inhibitory milieu for axonal growth and repair. Combinatorial therapies are the hope to attenuate secondary injury progression and make the microenvironment growth and repair friendly for the neurons. We fabricated gelatin- genipin hydrogel system which was impregnated with IONPs and injected at the lesion site in a clinically relevant contusion rat model of SCI. 24 h later, the rats were exposed to magnetic fields (17.96 µT, 50 Hz uniform EMF) for 2 h/day for 5 weeks. A significant (P < 0.001) improvement in Basso, Beattie and Bresnahan (BBB) locomotor score, amplitude and threshold of spinally mediated reflexes and motor and somatosensory evoked potentials (MEP & SSEP) was observed following IONPs implantation and EMF exposure. Moreover, retrograde tracing showed a higher level of neuronal connectivity and survival after the intervention. There was also a reduction in activated microglia and lesion volume which attenuate secondary damage as evident by reduction in the scaring following intervention for 5 weeks. Moreover, we observed increase in the neuronal growth cone marker, GAP-43, growth promoting neurotrophins (GDNF, BDNF & NT-3) and reduction in the inhibitory molecule (Nogo-A) after this combinatorial therapy. We obsrvered that a significant improvement in behavioral, electrophysiological and morphological parameters was due to an alteration in neurotrophin levels, reduction in activated microglia and increase in GAP-43 expression after the combinatorial therapy. We propose that implantation of IONPs embedded gelatin-genipin hydrogel system along with MF exposure modulated the microenvironment, making it conducive for neural repair and regeneration.

Effect of Low Intensity Magnetic Field Stimulation on Calcium-Mediated Cytotoxicity After Mild Spinal Cord Contusion Injury in Rats.

BACKGROUND: Magnetic field (MF) stimulation has the potential to reduce secondary damage and promote functional recovery after neural tissue injury. The study aimed to observe the effect of very low intensity (17.96µT) MF on general body condition, secondary damage, pain status, and locomotion. METHODS: We exposed rats to MF (2 h/day × 3 weeks) after 6.25 mm contusion spinal injury. Locomotor behavior was evaluated by BBB score, pain assessment was done by recording threshold for tail flick, expression of voltage-gated calcium channels and extent of secondary damage in the spinal cord was assessed by immunofluorescence and Cresyl violet staining, respectively. RESULTS: A significant (p ≤ .001) improvement in bladder function as well as BBB score was observed after MF exposure in comparison with sham and SCI over the observation period of 3 weeks. SCI group showed an increase in the threshold for vocalization after discharge, which decreased following MF exposure. Cresyl violet staining showed significantly higher tissue sparing (73%) at the epicenter after MF exposure when compared to SCI group. This was accompanied with a significant decrease in calcium channel expression in MF group as compared to SCI. CONCLUSION: The results suggest facilitation of sensory-motor recovery after MF exposure, which could be due to attenuation of secondary damage and calcium-mediated excitotoxicity in a mild contusion rat model of SCI.

Influence of Static Magnetic Field Stimulation on the Accuracy of Tachystoscopically Presented Line Bisection.

Transcranial static magnetic stimulation (tSMS) has been known to reduce human cortical excitability. Here, we investigated whether tSMS would modulate visuo-spatial cognition in healthy humans. Subjects performed a visuo-spatial task requiring judgements about the symmetry of pre-bisected lines. Visual stimuli consisted of symmetrically or asymmetrically transected lines, tachystoscopically presented for 150 ms on a computer monitor. Task performance was examined before, immediately after, and 10 min after tSMS/sham stimulation of 20 min over the posterior parietal cortex (PPC: P4 from the international 10-20 system) or superior temporal gyrus (STG: C6). Nine out of 16 subjects misjudged pre-bisected lines by consistently underestimating the length of the right-side segment (judging lines to be exactly pre-bisected when the transector was located to the left of the midpoint, or judging the left-side segment to be longer when the transector was located at the midpoint). In these subjects showing a leftward bias, tSMS over the right STG reduced the magnitude of the leftward bias. This did not occur with tSMS over the right PPC or sham stimulation. In the remaining right-biased subjects, no intervention effect was observed with any stimulation. Our findings indicate that application of tSMS over the right STG modulates visuo-spatial cognition in healthy adults.

Modulatory effects of magnetic vestibular stimulation on resting-state networks can be explained by subject-specific orientation of inner-ear anatomy in the MR static magnetic field.

Strong static magnetic fields, as used in magnetic resonance imaging (MRI), stimulate the vestibular inner ear leading to a state of imbalance within the vestibular system that causes nystagmus. This magnetic vestibular stimulation (MVS) also modulates fluctuations of resting-state functional MRI (RS-fMRI) networks. MVS can be explained by a Lorentz force model, indicating that MVS is the result of the interaction of the static magnetic field strength and direction (called "B0 magnetic field" in MRI) with the inner ear's continuous endolymphatic ionic current. However, the high variability between subjects receiving MVS (measured as nystagmus slow-phase velocity and RS-fMRI amplitude modulations) despite matching head position, remains to be explained. Furthermore, within the imaging community, an "easy-to-acquire-and-use" proxy accounting for modulatory MVS effects in RS-fMRI fluctuations is needed. The present study uses MRI data of 60 healthy volunteers to examine the relationship between RS-fMRI fluctuations and the individual orientation of inner-ear anatomy within the static magnetic field of the MRI. The individual inner-ear anatomy and orientation were assessed via high-resolution anatomical CISS images and related to fluctuations of RS-fMRI networks previously associated with MVS. More specifically, we used a subject-specific proxy for MVS (pMVS) that corresponds to the orientation of the individual inner-ear anatomy within the static magnetic field direction (also called "z-direction" in MR imaging). We found that pMVS explained a considerable fraction of the total variance in RS-fMRI fluctuations (for instance, from 11% in the right cerebellum up to 36% in the cerebellar vermis). In addition to pMVS, we examined the angle of Reid's plane, as determined from anatomical imaging as an alternative and found that this angle (with the same sinus transformation as for pMVS) explained considerably less variance, e.g., from 2 to 16%. In our opinion, an excess variability due to MVS should generally be addressed in fMRI research analogous to nuisance regression for movement, pulsation, and respiration effects. We suggest using the pMVS parameter to deal with modulations of RS-fMRI fluctuations due to MVS. MVS-induced variance can easily be accounted by using high-resolution anatomical imaging of the inner ear and including the proposed pMVS parameter in fMRI group-level analysis.

Transcranial Static Magnetic Field Stimulation Over the Temporal Cortex Modulating the Right Ear Advantage in Dichotic Listening.

OBJECTIVE: Transcranial static magnetic field stimulation (tSMS) has proposed a new, promising, and simple non-invasive brain stimulation method. While several studies gained certain evidence about tSMS effects in the motor, somatosensory, and visual domains, there is still a controversial debate about its general effectiveness. In the present study, we investigated potential tSMS effects on auditory speech processing as measured by a dichotic listening (DL) task. MATERIALS AND METHODS: Fifteen healthy participants received in randomized order on three different days one session of either sham, tSMS over the left, or tSMS over the right auditory cortex (AC). Under stimulation, participants performed a standard DL task with consonant-vowel syllables. Simultaneously, we recorded electroencephalogram from central sites (Fz, Cz, Pz). RESULTS: TSMS over the left AC changed the behavioral performance and modulated auditory evoked potentials. Stimulation of the left AC significantly reduced the right ear advantage during the DL task and the N1 component of auditory evoked potentials in response to these syllables. CONCLUSIONS: The preliminary results of the present exploratory study demonstrate the ability of tSMS to modulate human brain activity on a behavioral as well as physiologic level. Furthermore, tSMS effects on acoustic processing may have clinical implications by fostering potential approaches for a treatment of speech-related pathologies associated with hyperexcitability in the AC.

Accuracy in Pinch Force Control Can Be Altered by Static Magnetic Field Stimulation Over the Primary Motor Cortex.

OBJECTIVE: Transcranial static magnetic field stimulation (tSMS) has recently been demonstrated to modulate cortical excitability and perceptual functions in humans, however, the effect of tSMS on motor behavior is still unknown. We investigated whether tSMS over the primary motor cortex (M1) alters voluntary ballistic force control. MATERIALS AND METHODS: Twenty healthy participants performed ballistic pinch contractions in both hands alternatively at a predetermined submaximal force level and without visual feedback, before, during and after tSMS and sham interventions. A compact magnet for tSMS and a stainless steel cylinder for sham stimulation were positioned over the either right or left M1 for 15 min. RESULTS: The absolute error to the target force level was significantly larger for the tSMS-intervened hand than for the sham-intervened hands during and after intervention (p < 0.05, respectively). Compared with the preintervention session, the absolute error increased in the tSMS-intervened hand during and after intervention (p < 0.05, respectively), but not in the sham-intervened hand. CONCLUSIONS: tSMS over M1 can impair the accuracy of submaximal ballistic pinch force control. This suggests that tSMS is strong enough to alter motor behavior in humans.

Transcranial Static Magnetic Field Stimulation over the Primary Motor Cortex Induces Plastic Changes in Cortical Nociceptive Processing.

Transcranial static magnetic field stimulation (tSMS) is a novel and inexpensive, non-invasive brain stimulation (NIBS) technique. Here, we performed non-invasive modulation of intra-epidermal electrical stimulation-evoked potentials (IES-EPs) by applying tSMS or sham stimulation over the primary motor (M1) and somatosensory (S1) cortices in 18 healthy volunteers for 15 min. We recorded EPs after IES before, right after, and 10 min after tSMS. The IES-EP amplitude was significantly reduced immediately after tSMS over M1, whereas tSMS over S1 and sham stimulation did not affect the IES-EP amplitude. Thus, tSMS may affect cortical nociceptive processing. Although the results of intervention for experimental acute pain in healthy subjects cannot be directly translated into the clinical situation, tSMS may be a potentially useful NIBS method for managing chronic pain, in addition to standard of care treatments.

3D Biomimetic Magnetic Structures for Static Magnetic Field Stimulation of Osteogenesis.

We designed, fabricated and optimized 3D biomimetic magnetic structures that stimulate the osteogenesis in static magnetic fields. The structures were fabricated by direct laser writing via two-photon polymerization of IP-L780 photopolymer and were based on ellipsoidal, hexagonal units organized in a multilayered architecture. The magnetic activity of the structures was assured by coating with a thin layer of collagen-chitosan-hydroxyapatite-magnetic nanoparticles composite. In vitro experiments using MG-63 osteoblast-like cells for 3D structures with gradients of pore size helped us to find an optimum pore size between 20-40 µm. Starting from optimized 3D structures, we evaluated both qualitatively and quantitatively the effects of static magnetic fields of up to 250 mT on cell proliferation and differentiation, by ALP (alkaline phosphatase) production, Alizarin Red and osteocalcin secretion measurements. We demonstrated that the synergic effect of 3D structure optimization and static magnetic stimulation enhances the bone regeneration by a factor greater than 2 as compared with the same structure in the absence of a magnetic field.

Transcranial static magnetic field stimulation (tSMS) of the visual cortex decreases experimental photophobia.

Background Transcranial static magnetic field stimulation (tSMS) reduces cortical excitability in humans. Methods The objective of this study was to determine whether tSMS over the occipital cortex is effective in reducing experimental photophobia. In a sham-controlled double-blind crossover study, tSMS (or sham) was applied for 10 minutes with a cylindrical magnet on the occiput of 20 healthy subjects. We assessed subjective discomfort induced by low-intensity and high-intensity visual stimuli presented in a dark room before, during and after tSMS (or sham). Results Compared to sham, tSMS significantly reduced the discomfort induced by high-intensity light stimuli. Conclusions The visual cortex may contribute to visual discomfort in experimental photophobia, providing a rationale for investigating tSMS as a possible treatment for photophobia in migraine.