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Neural Regen Res. 2016 Dec; 11(12): 1888–1895.
doi:  10.4103/1673-5374.195277
PMCID: PMC5270416

Extremely low frequency electromagnetic fields stimulation modulates autoimmunity and immune responses: a possible immuno-modulatory therapeutic effect in neurodegenerative diseases

Fabio Guerriero, M.D., Ph.D.1,2,* and Giovanni Ricevuti1,2
1Department of Internal Medicine and Medical Therapy, Section of Geriatrics, University of Pavia, Pavia, Italy
2Azienda di Servizi alla Persona, Istituto di Cura Santa Margherita of Pavia, Pavia, Italy
*Correspondence to: Fabio Guerriero, ti.aivapidatisrevinu@10oreirreug.oibaf.

Author contributions: All authors contributed to developing the concepts, designing the structure, and writing/revising the manuscript, and approved the final version before submission and agree to be accountable.

Author information ? Article notes ? Copyright and License information ?
Accepted 2016 Nov 25.

Abstract

Increasing evidence shows that extremely low frequency electromagnetic fields (ELF-EMFs) stimulation is able to exert a certain action on autoimmunity and immune cells. In the past, the efficacy of pulsed ELF-EMFs in alleviating the symptoms and the progression of multiple sclerosis has been supported through their action on neurotransmission and on the autoimmune mechanisms responsible for demyelination. Regarding the immune system, ELF-EMF exposure contributes to a general activation of macrophages, resulting in changes of autoimmunity and several immunological reactions, such as increased reactive oxygen species-formation, enhanced phagocytic activity and increased production of chemokines. Transcranial electromagnetic brain stimulation is a non-invasive novel technique used recently to treat different neurodegenerative disorders, in particular Alzheimer’s disease. Despite its proven value, the mechanisms through which EMF brain-stimulation exerts its beneficial action on neuronal function remains unclear. Recent studies have shown that its beneficial effects may be due to a neuroprotective effect on oxidative cell damage. On the basis of in vitro and clinical studies on brain activity, modulation by ELF-EMFs could possibly counteract the aberrant pro-inflammatory responses present in neurodegenerative disorders reducing their severity and their onset. The objective of this review is to provide a systematic overview of the published literature on EMFs and outline the most promising effects of ELF-EMFs in developing treatments of neurodegenerative disorders. In this regard, we review data supporting the role of ELF-EMF in generating immune-modulatory responses, neuromodulation, and potential neuroprotective benefits. Nonetheless, we reckon that the underlying mechanisms of interaction between EMF and the immune system are still to be completely understood and need further studies at a molecular level.

Keywords: electromagnetic fields, Alzheimer’s disease, transcranial magnetic stimulation, autoimmunity, immunomodulation

Introduction

The etiology of neurodegenerative diseases is multifactorial. Genetic polymorphisms, increasing age and environmental cues are recognized to be primary risk factors. Although different neuronal cell populations are affected across diverse neurodegenerative disorders, hallmark protein modifications is a common feature that supports the differential disease diagnosis and provides a mechanistic basis to gauge disease progression (Bossy-Wetzel et al., 2004).

It is becoming increasingly clear that, particularly for chronic neurodegenerative disorders occurring late in life, a complex combination of risk factors can initiate disease development and modify proteins that have a physiological function into ones with pathological roles via a number of defined mechanisms (Moreno-Gonzalez and Soto, 2011).

Amyloid-beta plaques and tau protein tangles – hallmarks of the pathology – are most likely a non-specific result of the disease process, rather than a cause (Lee et al., 2007). A large body of evidence supports the direct contribution of inflammation in the development and progression of neurodegeneration (Tweedie et al., 2007). A common denominator in the occurrence of different pathogenic mechanisms is oxidative stress accompanied by redox dysregulation, which have a role in mitochondrial dysfunction, toxicity, missignalling by calcium, glial cell dysfunction and neuroinflammation itself. Each of these can influence one another at multiple different levels, and hence oxidative stress can both be secondary to them as well as have a primary part in their initiation (von Bernhardi and Eugenin, 2012).

In the last years, evidence are remarkably revealing that Alzheimer’s disease (AD) has an autoimmune component (D’Andrea, 2005). In older patients the presence of anti-neuronal autoantibodies in the serum frequently occurs; if blood-brain barrier (BBB) dysfunction comes up, these autoantibodies are able to reach their targets and determine deleterious effect (D’Andrea, 2003). In fact, a profound change in BBB permeability has been observed in AD. In these patients amyloid deposits have been observed in microvessels and this overload is associated with degenerating endothelium (decreased mitochondrial content, increased pinocytotic vesicles), damaged smooth muscle cells and pericytes, and basement membrane changes (focal necrosis, reduplication, increased collagen content, disintegrating) (Thomas et al., 1996; Wardlaw et al., 2003). All these components strengthen the possibility that the ‘major pathological role of amyloid in AD may be to inflict vascular damage’ and hence, impair BBB function (Franzblau et al., 2013; Attems and Jellinger, 2014).

Immunoglobulins (IGs) have been detected in serum, cerebrospinal fluid and amyloid plaques of patients with AD. IGs are associated with vessel-associated amyloid, which has been linked to a faulty BBB (Franzblau et al., 2013). As a consequence, the presence of neuronal autoantibodies associated with a BBB dysfunction seems to be a relevant part of AD neuropathology (Attems and Jellinger, 2014).

Additional data about relationship between autoimmune diseases (e.g., thyroid dysfunction, diabetes) and AD has been proven. In fact, patients with AD have a significant increase in the values of anti-thyroglobulin and anti-microsomial autoantibodies compared to healthy controls (Genovesi et al., 1996).

Moreover, typical features of autoimmunity have been associated with both AD and diabetes (e.g., high levels of advanced glycation end products and their receptor have been detected in tissues and in the circulation in both disease) (Mruthinti et al., 2006).

In summary, these data in the context of the underlying mechanisms of many autoimmune diseases indicated that AD has proven autoimmune mechanisms, which provide a link between vascular pathology (altered BBB function) and neuronal cell death. Furthermore, according to these data, BBB dysfunction precedes neuronal degeneration and dementia (Rhodin and Thomas, 2001).

Electromagnetic Brain Stimulation and Immunomodulation in Neurodegenerative Diseases

Over the past decades, neuroscientists and clinicians have been exploring the properties of the brain’s electromagnetic activity for both diagnostic and therapeutic purposes. In the 1990s, research on electromagnetic radiation was motivated by the need to better understand the potential harmful effects of environmental magnetic fields (Bennett, 1995; Bracken and Patterson, 1996); actually, it is becoming increasingly clear that interactions between magnetic fields and biological systems deserve to be studied in their own right because these interactions appear to be fundamental to life processes and could represent a therapeutic agent in several diseases.

In our opinion, one of the more striking observations related to the effects of EMFs on biological systems concerns the presence of a “window effect,” showing that biological effects occur only at particular combinations of frequency and field intensity (Panagopoulos and Margaritis, 2010). These effects have been reported especially for changes in calcium ion flux in cells and tissues. Related window effects are reports of signal-specific quantitative and qualitative response to EMFs in several different tissues (Azanza and del Moral, 1994).

ELF-EMFs interact readily with the central nervous system (CNS). While the high-frequency EMFs encountered in industry can expose workers to an increased risk of AD (Hakansson et al., 2003), amyotrophic lateral sclerosis and multiple sclerosis (MS) (Johansen, 2004), EMFs of weak and very weak intensity can exert interesting and proven therapeutic effects on the CNS (Sandyk, 1992; Sandyk and Iacono, 1994; Boggio et al., 2012). The level of radiation is typically in the range of 1 millitesla (mT) in most studies.

Transcranial magnetic brain stimulation (TMS) is a commonly-used neurostimulation and a neuromodulation technique, based on the principle of electromagnetic induction of an electrical field in the brain. This field can be of sufficient magnitude and density to depolarize neurons, and when TMS pulses are applied repetitively they can modulate cortical excitability, decreasing or increasing it, depending on the parameters of stimulation, even beyond the duration of the train of stimulation (Fregni and Pascual-Leone, 2007; Ridding and Rothwell, 2007).

The last decade has seen a rapid increase in the applications of TMS to study cognition, neurobehavioral relations and the pathophysiology of several neurologic and psychiatric disorders. Evidence has accumulated that demonstrates that TMS provides a valuable tool for modulating brain activity in a specific, distributed, cortico-subcortical network through control and manipulation of cognition, neuromotoricity and behavior (George et al., 2007; Guerriero et al., 2015).

Since the immune system plays a primary role in the control of many diseases and tumor growth, many laboratories have investigated the influence of ELF-EMF stimulation on blood mononuclear cells, various cellular components and cellular processes; other studies have examined electromagnetic effects on specific genes expressions and signal transduction pathways, but the experimental data obtained are currently controversial (Cossarizza et al., 1993; Onodera et al., 2003).

The mechanisms by which ELF-EMFs elicit cellular responses are somewhat still unknown, and it is still unclear which cellular components mediate these fields’ effects. However, there are several hypotheses to explain EMF interaction with the living matter.

It is assumed that some type of initial interaction occurs at the level of the cell membrane and that specific signal amplification processes carry the membrane-mediated effect into the cell (Frey, 1993). Molecular studies of the membrane signaling processes have shown, for example, that the involved cells can use mechanisms such as intracellular second-messenger (e.g., Ca2+, cyclic adenosine monophosphate [cAMP], cyclic guanosine monophosphate [cGMP]) cascades, positive feedback, and linear membrane channel-gating (Grundler et al., 1992). Some of the most important calcium-related processes such as synaptic neurotransmitter and synthesis and release and levels of cAMP (Matthews and Gersdorff, 1996), essential for the functioning of the neurons that are influenced by EMFs (Rosen, 1992). In addition, amplification via calcium flux could also provide the means by which the membrane-mediated effects of EMFs could be carried into the cell (Karabakhtsian et al., 1994).

As described below, EMFs proved to exert a certain immune function modulation. Modulation of neural activity by ELF-EMFs could possibly counteract the aberrant pro-inflammatory responses present in neurodegenerative and neuropsychiatric disorders reducing their severity and, possibly, their onset.

Thus, in the next sections we will address the influence of ELF-EMFs on autoimmunity and immune cells, supposing that ELF-EMF may act on the basis of mechanisms centered on immunomodulation. This could have particular relevance for the treatment of neurodegenerative disorders, such as AD.

Low-frequency Electromagnetic Fields Stimulation and Autoimmunity

Regarding a possible relationship between EMF and autoimmunity, the researches conducted by Sandyk and colleagues deserve great interest. In the 1990s, Sandyk amply demonstrated the efficacy of pulsed ELF-EMFs of a few mT in alleviating the symptoms of MS through their action on axonal and synaptic neurotransmission (Sandyk and Iacono, 1993; Sandyk and Dann, 1995). Weekly treatment administered for years with very weak ELF-EMFs can alter the clinical course of chronic progressive MS, arresting progression of the disease for as long as four years (Sandyk, 1995a, 1997). This observation prompts the hypothesis that, in addition to effects on axonal and synaptic neurotransmission, effects may also be exerted on the autoimmune mechanisms responsible for demyelination.

Other proposals that to use pulsed ELF-EMFs of a few mT aims to modify the autoimmune pathology of the disease by eliciting profound membrane changes (Bistolfi, 2002) (the so-called Marinozzi effect) (Marinozzi et al., 1982) in the MS plaque cells.

While the action of ELF fields of a few pT is characterized by an improvement in neurotransmission, the use of ELF fields of a few mT aims to exert an action of local immunomodulation on the cells of the MS plaque through the induction of the Marinozzi effect. It therefore follows that the targets of ELF fields in the mT range will be the plaque cells (T-lymphocytes, macrophagic monocytes, microglia cells and dendritic cells), those cells disseminated in the seemingly normal nervous tissue (macrophages and microglia cells) (Bistolfi, 2007).

More specifically, the target should be the plasma membrane of these cells, which is almost always carpeted with microvilli and protrusions of various types. Since the plasma membrane is central to the relationships among immune cells (Lassmann et al., 2007) and since the plasma membrane itself is the elective target of ELF-EMF, a possible induction of the Marinozzi effect could slow down the activity of autoimmune cells in the plaque. It may determine an effect of local (on the brain) or regional immunomodulation (on the entire CNS) (Baureus Koch et al., 2003).

In far 1998, Richards et al. (1998) expressed the hope that electromagnetic fields might find application in the therapy of MS, both to manage symptoms and to achieve long-term effects by eliciting beneficial changes in the immune system and in nerve regeneration.

Our personal hypothesis is that – as observed in MS – similar effects could be present and relevant during EMF brain stimulation in patients with other CNS neurodegenerative disorders and be responsible for their therapeutic effect.

Low-frequency Electromagnetic Fields Stimulation and Immunomodulation

ELF-EMF effects on macrophages, nitric oxide and heat shock proteins

Macrophages are responsible for eliminating infectious agents and other cellular debris (Tintut et al., 2002). The recruitment of monocytes/macrophages to inflammatory sites and neoplastic tissues and their activation therein is crucial to the success of an immune reaction, in part because further cell migration is intimately related to leukocyte function. Resting macrophages have low levels of phagocytic activity and become fully active through the binding of pathogens or by local cytokine release. Once activated, macrophages exhibit an increased level of phagocytic activity and an increased production of reactive oxygen species (ROS) enabling the killing of microbes within phagosomes. The first step is the phagocytosis of the infectious agent, which is then transferred to the phagosome where it is killed by ROS and reactive nitrogen oxide species. The main protagonist of this process is nitric oxide (NO), which in turn induces the formation of cGMP, which in turn triggers a cascade of intracellular signaling. In the other hand, ROS also act as a signaling molecule and targets a wide range of physiological pathways. Activation of these cellular pathways also causes the secretion of inflammatory cytokines including IL-1b and TNF-alpha (Laskin and Laskin, 2001). Therefore when stimulated with bacterial toxins, NO and ROS stimulate cells to synthesize heat shock proteins (HSPs) (Polla et al., 1996).

Several studies have shown the effect of ELF-EMFs on macrophages. Kawczyk-Krupka and colleagues aimed to determine the effect of ELF-EMFs on the physiological response of phagocytes to an infectious agent. Human monocytic leukemia cell lines were cultured and 50 Hz, 1 mT EMF was applied for 4–6 hours to cells induced with Staphylococcus aureus. The growth curve of exposed bacteria was lower than the control, while field application increased NO levels. The increase was more prominent for Staphylococcus aureus-induced cells and appeared earlier than the increase in cells without field application (Kawczyk-Krupka et al., 2002). Increased cGMP levels in response to field application were closely correlated with increased NO levels (Azanza and del Moral, 1994).

Another study on mouse macrophages after short-term (45 minutes) exposure to 50 Hz EMF at 1.0 mT showed a significant uptake of carboxylated latex beads in macrophages, suggesting EMFs stimulate the phagocytic activity of their macrophages (Frahm et al., 2006). Tetradecanoylphorbol acetate (TPA) was used as positive control to prove the activating capacity of cells, as TPA is known to activate the protein kinase C and induce cellular processes including pinocytosis and phagocytosis (Laskin et al., 1980). On the basis of these data, ELF-EMF seems to potentially play a role in decreasing the growth rate of bacteria and other pathogens eliminated by phagocytosis.

A significant increase of free radical production has been observed after exposure to 50 Hz electromagnetic fields at a flux density of 1 mT to mouse macrophages (Aktan, 2004). To elucidate whether NADPH- or NADH-oxidase functions are influenced by EMF interaction, the flavoprotein inhibitor diphenyleneiodonium chloride (DPI) was used. EMF-induced free radical production was not inhibited by DPI, whereas TPA-induced free radical production was diminished by approximately 70%. Since DPI lacks an inhibitory effect in EMF-exposed cells, 50 Hz EMF stimulates the NADH-oxidase pathway to produce superoxide anion radicals, but not the NADPH pathway. Furthermore, the oscillation in superoxide anion radical release in mouse macrophages suggests a cyclic pattern of NADH-oxidase activity (Rollwitz et al., 2004).

An important aspect of these phagocytic cells is that they produce high levels of free radicals in response to infection, and the effect of ELF-EMF on free radicals has been widely proposed as a probable direct mechanism for the action of ELF-EMF on the living systems (Simko and Mattsson, 2004).

NO, a free radical, is an intra-cellular and inter-cellular signaling molecule and it constitutes an important host defense effector for the phagocytic cells of the immune system. It is synthesized by NO synthase, which has two major types: “constitutive” and “inducible”. Inducible nitric oxide synthase (iNOS) is particularly expressed in macrophages and other phagocytic cells that are stimulated during an immune response to infection (Aktan, 2004). Although high concentration of NO can be beneficial as an antibacterial and antitumor agent, an excess of NO can be fatal and can lead to cell injury. For example the excessive activity of iNOS has detrimental effects on oligodendrocytes, cells responsible for the myelination of neuron in the CNS (Klostergaard et al., 1991). The roles of NO in the pathophysiology of disease are still being defined, but there is a growing body of evidence that the neutralization of iNOS activity may have a therapeutic value (Parmentier et al., 1999).

Some studies have focused on the potential toxicity of the ensuing high-output NO-synthesis serving as a mean to eliminate pathogens or tumor cells, but the expression of iNOS, contributes to local tissue destruction during chronic inflammation. NO increases the ability of monocytes to respond to chemotactic agents more effectively, and it is considered to be one of the principal effector molecules involved in macrophage-mediated cytotoxicity (Desai et al., 2003).

It has been observed that exposure to ELF-EMFs modifies both NOS and MCP-1 chemokine expression and that these modifications are related to each other and are furthermore mediated by increased NF-?B protein expression (Goodman et al., 1994). EMF represents a non-pharmacological inhibitor of NO and an inducer of MCP-1, the latter of which activates one of these molecules and leads to inhibition of the former and vice versa, establishing a mechanism that protects cells from excess stimulation and contributes to the regulation of cellular homeostasis (Biswas et al., 2001). Moreover in vitro study observed a slight decrease was observed in iNOS levels was observed in cells induced with Staphlococcus aureus after ELF-EMF stimulation (Azanza and del Moral, 1994).

HSPs are evolutionarily conserved proteins known to play a key role in cellular defense against the effect of stressors and their function in modulating apoptosis has been well assessed (Beere, 2004). Concerning the relationship between EMF stimulus and HSPs expressions, Goodman et al. (1994) first demonstrated that HSP expression was enhanced by exposure to electromagnetic fields. Tokalov and Gutzeit (2004) showed the effect of ELF-EMF on heat shock genes and demonstrated that even a low dose of ELF-EMF (10 mT) caused an increase in HSPs, especially hsp70, implying that the cell senses ELF-EMF as a physical stressor.

ELF-EMF stimulation and oxidative stress

Oxidative stress derives from two primary sources: 1) chronic ROS creation that is generated from the mitochondrial electron transport chain during normal cellular function; 2) high levels of acute ROS generation resulting from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, particularly associated with the activation of the CNS immune system (Barja, 1998). In both circumstances, oxidative stress comes up when an imbalance between ROS production and clearance of radical species occurs.

ROS have been implicated as second messengers that activate protein kinase cascades, although the means by which ROS regulate signal transduction remains unclear. ROS release and cytokine production, such as IL-1?, are common cell activation markers in immune relevant cells. ROS is involved in the activation of IL-1? signal transduction pathway (Li and Engelhardt, 2006). To neutralize the detrimental effects of ROS, cells have evolved a hierarchy of sophisticated antioxidant response mechanisms regulated by NF-E2-related factor 2 (Nrf2) transcription factor (Tasset et al., 2010).

Environmental factors including EMFs, stressors or diseases that augment the former or lower the latter can amplify and drive the process. Thus, in practical terms, oxidative stress is determined by excessive exposure to oxidant molecules when there is insufficient availability of antioxidant mechanisms, with the resulting free ROS oxidizing vulnerable cellular constituents, including proteins, nucleic acids and lipids, inducing microglial activation, inducing pro-inflammatory and suppressing anti-inflammatory cytokines and related signaling pathways and ultimately causing both synaptic and neuronal damage and dysfunction (Bonda et al., 2010). Whereas most environmental electromagnetic radiations cause oxidative stress in the brain (Sahin and Gumuslu, 2007), ELF-EMF seems to have an antioxidant and neuroprotective effect (Medina and Tunez, 2010).

As shown by Tunez et al. (2006), ELF-EMF induces the antioxidant pathway Nrf2, which is closely associated with its protective effect against neurotoxicity induced by 3-nitropropionic acid (3-NP) (Tunez et al., 2006). This effect may be due to the induction of Nrf2, increasing its concentration in the nucleus as a result, at least in part, on its translocation from the cytoplasm to the nucleus. These changes in antioxidant systems were associated with a reduction of cell and oxidative damage biomarkers. In fact given that Nrf2 regulates the expression of antioxidant protein systems, its decrease may plausibly be related to a reduction in antioxidant system levels. Thus, the depletion of Nrf2 showed that 3-NP induced a significant decrease in antioxidant enzyme activity in the striatum and an intense depletion of glutathione levels. This was accompanied by clear and intense oxidative damage characterized by lipid and protein oxidation, an increase in cell death and damage markers and neuronal loss. Thus, the reduction in Nrf2 in both cytoplasm and nucleus may have been due to significant cell loss induced by 3-NP (Tunez et al., 2006).

Animal studies have demonstrated that ELF-EMF exposure, in the form of TMS (60 Hz, 0.7 mT) applied to rats for 2 hours twice daily, can be neuroprotective (Tunez et al., 2006; Tasset et al., 2012). Administered prior to and after a toxic insult to the brain, for example in the systemic injection of 3-nitropropionic acid to induce an animal model of Huntington’s disease (Tunez and Santamaria, 2009), ELF-EMF can mitigate oxidative damage, elevate neurotrophic protein levels in brain and potentially augment neurogenesis (Arias-Carrion et al., 2004).

EMF 1.0 mT exposure of mouse macrophages showed a significant increase in extracellular IL-1b release after only 4 hours of exposure, which was continuously increased after 12–24 hours of exposure. This data suggests that EMF stimulation is able to increase cytokines in murine macrophages. Cossarizza and colleagues described the increased release of IL-2, IL-1, and IL-6 in peritoneal lymphocytes after long-term exposure to ELF-EMF (Cossarizza et al., 1989). On the other hand, investigation on cytokine production by Pessina et al. showed no effects after EMF on peritoneal blood cells (Pessina and Aldinucci, 1998).

Beyond these results, such studies reiterate the importance that the cellular effects of ELF-EMFs depend, in a large part, on their intensity and exposure time, as well as on the phenotype of the cellular target and interactions with intracellular structures. The level and timing of exposure can potentially be scheduled to optimize endogenous compensatory mechanisms following an adverse reaction.

ELF-EMF effects on pro-inflammatory chemokines

Chemokines are produced by a variety of cells including monocytes, T lymphocytes, neutrophils, fibroblasts, endothelial cells and epithelial cells (Murdoch and Finn, 2000). Chemokines play a relevant role in inflammatory events, such as trans-endothelial migration and accumulation of leucocytes at the site of damage. In addition, they modulate a number of biological responses, including enzyme secretion, cellular adhesion, cytotoxicity, T-cell activation and tissue regeneration (Zlotnik and Yoshie, 2000).

Since their discovery, chemokines have emerged as important regulators of leukocyte trafficking, and MCP-1, one of the best-studied chemokines, is known to exert multiple effects on target cells, such as increased cytosolic calcium levels, superoxide anion production, lysosomal enzyme release, production of anti-inflammatory cytokines and adhesion molecules in monocytes. MCP-1 is involved in the induction of polarized type Th2 responses and in the enhancement of IL-4 production. A possible feedback loop for Th2 activation would be the production of IL-4 and IL-13 by Th2, which stimulates MCP-1 production and leads to further recruitment of Th2 cells (Moser and Loetscher, 2001).

The fine control of inflammatory mediator levels is critical to neuronal homeostasis and health. For example, a deficiency in neuronal TGF-? signaling promotes neurodegeneration and AD, whereas augmented TGF-? can act as an anti-inflammatory cytokine and has potential neuroprotective action in AD and following other insults to the central nervous system (Ren et al., 1997).

Studies have shown the anti-inflammatory effects of ELF-EMF in vivo; for instance, Selvam used a coil system emitting a 5 Hz frequency to treat rats with rheumatoid arthritis for 90 minutes, producing significant anti-exhudative effects and resulting in the restoration of normal functional parameters (Vianale et al., 2008). This anti-inflammatory effect was reported to be partially mediated through the stabilizing action of ELF-EMF on cell membranes, reflected the restoration of intracellular Ca2+ levels in plasma lymphocytes (Selvam et al., 2007). Other investigators have suggested that ELF-EMF can interact with cells through mechanisms that involve extracellular calcium channels (Cho et al., 1999).

Moreover, incubating mononuclear cells with an iNOS inhibitor showed a significant reduction of iNOS and an increase of MCP-1 levels, and these effects are consistent with iNOS and MCP-1 level modifications observed in mononuclear cells exposed to ELF-EMF. Selective inhibition of the NF-?B signaling pathway by ELF-EMF may be involved in the decrease of chemokine production. If so, ELF-EMF exposure, interfering with many cellular processes, may be included in the plethora of stimuli that modulate NF-?B activation (including pro-inflammatory cytokines such as tumor necrosis factor-? and IL-1?, chemokines, phorbol 12-myristate 13-acetate, growth factors, lipopolysaccharide, ultraviolet irradiation, viral infection, as well as various chemical and physical stresses) (Vianale et al., 2008).

Lymphocyte activity and electrotaxis: a possible link to ELF-EMF stimulation

Recent studies have shown that cells can directionally respond to applied electric fields, in both in vitro and in vivo settings, a phenomenon called electrotaxis. However, the exact cellular mechanisms for sensing electrical signals are still not fully well understood, and it is thus far unknown how cells recognize and respond to electric fields, although some studies have suggested that electro-migration of some cell surface receptors and ion channels in cells could be involved (Cortese et al., 2014). Directed cell migration is essential to numerous physiological processes including immune responses, wound healing, cancer metastasis and neuron guidance (Kubes, 2002). Normal blood lymphocytes and monocytes respond to a steady electric field in Transwell assays. All lymphocyte subsets, including naive and memory CD4+, CD8+ T cells and B cells migrated toward the cathode. Electrotaxisis highly directional and the uniform migration of circulating lymphocytes suggests that other leukocyte subsets (e.g., tissue memory cells) may undergo electrotaxis as well.

Lymphocytes respond to electric fields with activation of Erk-kinases and Akt, which are involved in chemo-attractant receptor signaling and in electrotactic signaling in other cells (Sotsios et al., 1999; Zhao et al., 2006). Activation of these pathways suggests that electrotaxis and chemotaxis engage common intracellular cell motility programs in responding lymphocytes. In fact, electric field exposure induces Erk1/2 and Akt activation in lymphocytes, consistent with the activation of the MAPK and PI3K signaling pathways implicated in coordinated cell motility. Furthermore, it has been proven that an applied electric field induced the electrotactic migration of endogenous lymphocytes to mouse skin (Lin et al., 2008). These data thus define electrotaxis andpotentially present an additional mechanism for the control of lymphocyte and monocyte migration.

ELF-EMFs can either inhibit or stimulate lymphocyte activity as a function not only of the exposure (Petrini et al., 1990), but also of the biological conditions to the cells are exposed, with mitogen-activated cells being more responsive than resting cells (Conti et al., 1986). To explain this ambivalence of the effects of ELF magnetic fields on the immune system, Marino and colleagues have presented the hypothesis that the biological effects of ELF magnetic fields are governed by non-linear laws, and that deterministic responses may therefore occur that are both real and inconsistent, thereby yielding two conflicting types of results (Marino et al., 2000). A particular role in the interaction of ELF-EMFs with lymphocytes seems to be played by the mobilization of intracellular Ca2+from the calciosomes and of extracellular Ca2+ through the membrane channels (Conti et al., 1985). The action of ELF-EMFs on lymphoid cells, however, can also be exerted on the functions of the plasma membrane: the duration of the ligand-receptor bond (Chiabrera et al., 1984), the clustering of membrane proteins (Bersani et al., 1997), the activity of enzymatic macro-molecules (Lindstrom et al., 2001), and the active ion pumps (Ca2+ ATPase and Na+ K+ATPase).

Conclusions

Several studies have shown that ELF-EMF exposure is able to activate primary monocytes and macrophages from different species and also in cell lines. This activation potential is comparable to the activation by certain chemicals resulting in physiologically relevant cellular responses.

In the past, several findings have demonstrated the efficacy of pulsed ELF-EMFs of a few mT in alleviating the symptoms of MS through their action on synaptic neurotransmission and autoimmunity (by determining cell membrane changes in plaques).

Moreover, ELF-EMF exposure contributes to a general activation of macrophages, resulting in changes of numerous immunological reactions, such as increased ROS formation, in an enhanced phagocytic activity, and in an increased IL-1? release. Therefore, we can deduce that EMFs activate physiological functions of immune cells. However, the underlying mechanisms of interaction between EMF and immune system are still to be completely understood and need further studies at the molecular level.

Animal studies have demonstrated that ELF-EMF exposure, in the form of transcranial magnetic stimulation (60 Hz, 0.7 mT) applied to rats for 2 hours twice daily, has been seen to be neuroprotective (Sahin and Gumuslu, 2007; Medina and Tunez, 2010).

The effects of low flux density magnetic fields are exerted on altered functional states, in the sense of hyper- or hypo-function, rather than on normal functional states. The neurophysiological interpretation is that neurotransmission is favored at various sites: partially synapses, the cerebellum, and interhemisphere transcallosal connections, an idea which is strongly supported by the rapid regression seen in certain symptoms in patients with MS (Sandyk, 1995b). Based on all these evidences such effect could be attributed to the correction of perturbations of synaptic conductivity and immunomodulation (Bistolfi, 2007), resulting in clinical therapeutic effect as observed in neurodegenerative disorders such as AD (Mruthinti et al., 2006; Attems and Jellinger, 2014).

However, so far there is still no general agreement on the exact biological effect elicited by EMFs on the physical mechanisms that may be behind their interaction with biological systems. Of course the biological effects of EMFs are dependent on frequency, amplitude, timing and length of exposure, but are also related to intrinsic susceptibility and responsiveness of different cell types (Tenuzzo et al., 2006). Level and timing of exposure can be potentially scheduled to optimize endogenous compensatory mechanisms following an adverse challenge.

In the light of results reviewed here, we conclude that there is growing evidence of the potential role of EMFs in biological modulation of autoimmunity, immune functions and oxidative stress. As a consequence, the hypothesis that ELF-EMFs explicit their therapeutic effect through modulation of immune relevant cells is of clear interest, in particular in neurodegenerative diseases.

It is notable to underline that the effects of ELF-EMFs are not unique as they depend on their intensity, exposure time and cellular targets; further efforts towards more scheduled and well defined level and timing of exposure should be warranted.

Hence, it is necessary to proceed with substantial research on this issue, paying particular attention to the choice of the appropriate biological model and controlled experimental conditions.

Footnotes

Conflicts of interest: The authors report no conflicts of interest in this work. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Articles from Neural Regeneration Research are provided here courtesy of Medknow Publications
Altern Ther Health Med.  2011 Nov-Dec;17(6):22-8.

Long-term Effects of Bio-electromagnetic-energy regulation Therapy on Fatigue in Patients With Multiple Sclerosis.

Ziemssen T, Piatkowski J, Haase R.

Abstract

Background Electromagnetic-field therapy has beneficial short-term effects in multiple sclerosis (MS) patients with major fatigue, but long-term data are lacking.

Primary Study Objectives To evaluate the long-term effects of a specific electromagnetic therapy device (Bio-Electromagnetic- Energy-Regulation [BEMER]) on MS-related fatigue, we designed a crossover control of a previously performed randomized controlled trial and a long-term open-label follow-up trial.

Design and Setting: Crossover and open-label follow-up trials at a single neurological outpatient center. Participants Patients with relapsing-remitting MS who had major fatigue (N = 37 patients). Intervention After a previous randomized controlled trial (exposure to low-frequency pulsed magnetic fields for 8 min twice daily or to placebo treatment for 12 wk), a crossover from control to treatment for another 12 weeks, followed by an openlabel follow-up trial to 3 years, were done.

Primary Outcome Measures The outcome criteria were the Modified Fatigue Impact Scale (MFIS), Fatigue Severity Scale (FSS), German long version of the Center for Epidemiologic Studies Depression Scale (CES-D), Multiple Sclerosis Functional Scale (MSFC), and Expanded Disability Status Scale (EDSS). Results Patients previously on placebo during the randomized controlled trial experienced significant reductions in fatigue after crossing over to treatment. The MFIS and FSS scores were significantly lower in the open-label group than in the control subjects after follow-up. Participation in the open-label treatment was the strongest predictor of low fatigue outcome after followup. Electromagnetic-field therapy was well tolerated.

Conclusions In this long-term study, a beneficial effect of long-term BEMER therapy on MS fatigue was demonstrated. Electromagnetic-field therapy may be a useful therapeutic modality in MS patients with severe fatigue.

 J Altern Complement Med.  2009 May;15(5):507-11.

Effect of BEMER magnetic field therapy on the level of fatigue in patients with multiple sclerosis: a randomized, double-blind controlled trial.

Piatkowski J, Kern S, Ziemssen T.

Source

Neurological Outpatient Center Reichenbachstrasse, Dresden, Germany.

Abstract

OBJECTIVES:

Electromagnetic field therapy has been reported to be beneficial in patients with multiple sclerosis (MS) with significant fatigue. This study was designed to evaluate the long-term effects of Bio-Electro-Magnetic-Energy-Regulation (BEMER) on MS-related fatigue.

DESIGN:

This was a monocenter, patient- and rater-blinded, placebo-controlled trial.

PATIENTS:

There were 37 relapsing-remitting patients with MS with significant fatigue in the study.

INTERVENTION:

The intervention consisted of BEMER magnetic field treatment for 8 minutes twice daily in comparison to placebo for 12 weeks.

OUTCOME MEASURES:

The primary outcome criterion was change in the Modified Fatigue Impact Scale (MFIS) between baseline and 12 weeks. The secondary outcome criteria were changes of the Fatigue Severity Scale (FSS), a general depression scale-long version (ADS-L), Multiple Sclerosis Functional Scale (MSFC), and the Expanded Disability Status Scale (EDSS).

RESULTS:

There was evidence of a significant difference of MFIS value (primary outcome criterion) after 12 weeks in favor of the verum group (26.84 versus 36.67; p = 0.024). In addition, FSS values were significantly lower in the verum group after 12 weeks (3.5 versus 4.7; p = 0.016). After 6 weeks’ follow-up, verum and placebo groups did not differ in experienced fatigue (MFIS, FSS). Regarding the subscales of the MFIS, there was a significant decrease in physical (p = 0.018) and cognitive (p = 0.041), but not in psychologic subscales only in the verum group regarding the timepoints baseline and 12 weeks. BEMER therapy was well tolerated.

DISCUSSION:

In this pilot study, we were able to demonstrate a beneficial effect of BEMER intervention on MS fatigue. As this was only a pilot study, trials with more patients and longer duration are mandatory to describe long-term effects.

Electromagn Biol Med. 2007;26(4):311-3.

Utilization of extremely low frequency (ELF) magnetic fields in chronic disease; five years experience: three case reports.

Mancuso M, Ghezzi V, Di Fede G.

Institute of Biological Medicine, Milano, Italy.

Abstract

We present three examples of the use of ELF magnetic therapy, two cases of multiple sclerosis and one of chronic pulmonary disease. In each of the two MS cases the Seqex device was applied as an adjunct to antioxidant medication two times a week for six weeks. Radiological and MRI examination indicated improvement in the two MS patients and stabilization in the patient with obstructive pulmonary disease following merely five treatments.

Altern Ther Health Med. 2003 Jul-Aug;9(4):38-48.

Effects of a pulsed electromagnetic therapy on multiple sclerosis fatigue and quality of life: a double-blind, placebo controlled trial.

Lappin MS, Lawrie FW, Richards TL, Kramer ED.

Energy Medicine Developments, (North America), Inc., Burke, Va., USA.

CONTEXT: There is a growing literature on the biological and clinical effects of pulsed electromagnetic fields. Some studies suggest that electromagnetic therapies may be useful in the treatment of chronic illnesses. This study is a follow-up to a placebo controlled pilot study in which multiple sclerosis (MS) patients exposed to weak, extremely low frequency pulsed electromagnetic fields showed significant improvements on a composite symptom measure.

OBJECTIVE: To evaluate the effects of a pulsed electromagnetic therapy on MS related fatigue, spasticity, bladder control, and overall quality of life.

DESIGN: A multi-site, double-blind, placebo controlled, crossover trial. Each subject received 4 weeks of the active and placebo treatments separated by a 2-week washout period.

SETTING: The University of Washington Medical Center in Seattle Wash, the Neurology Center of Fairfax in Fairfax, Va, and the headquarters of the Multiple Sclerosis Association of America in Cherry Hill, NJ.

SUBJECTS: 117 patients with clinically definite MS.

INTERVENTION: Daily exposure to a small, portable pulsing electromagnetic field generator.

MAIN OUTCOME: The MS Quality of Life Inventory (MSQLI) was used to assess changes in fatigue, bladder control, spasticity, and a quality of life composite.

RESULTS: Paired t-tests were used to assess treatment differences in the 117 subjects (81% of the initial sample) who completed both treatment sessions. Improvements in fatigue and overall quality of life were significantly greater on the active device. There were no treatment effects for bladder control and a disability composite, and mixed results for spasticity.

CONCLUSIONS: Evidence from this randomized, double-bind, placebo controlled trial is consistent with results from smaller studies suggesting that exposure to pulsing, weak electromagnetic fields can alleviate symptoms of MS. The clinical effects were small, however, and need to be replicated. Additional research is also needed to examine the possibility that ambulatory patients and patients taking interferons for their MS may be most responsive to this kind of treatment.

Int J Neurosci. 1998 Apr;93(3-4):239-50.

Treatment with AC pulsed electromagnetic fields normalizes the latency of the visual evoked response in a multiple sclerosis patient with optic atrophy.

Sandyk R.

Department of Neuroscience at the Institute for Biomedical Engineering and Rehabilitation Services of Touro College, Dix Hills, NY 11746, USA.

Visual evoked response (VER) studies have been utilized as supportive information for the diagnosis of multiple sclerosis (MS) and may be useful in objectively monitoring the effects of various therapeutic modalities. Delayed latency of the VER, which reflects slowed impulse transmission in the optic pathways, is the most characteristic abnormality associated with the disease. Brief transcranial applications of AC pulsed electromagnetic fields (EMFs) in the picotesla flux density are efficacious in the symptomatic treatment of MS and may also reestablish impulse transmission in the optic pathways. A 36 year old man developed an attack of right sided optic neuritis at the age of 30. On presentation he had blurring of vision with reduced acuity on the right and fundoscopic examination revealed pallor of the optic disc. A checkerboard pattern reversal VER showed a delayed latency to right eye stimulation (P100 = 132 ms; normal range: 95-115 ms). After he received two successive applications of AC pulsed EMFs of 7.5 picotesla flux density each of 20 minutes duration administered transcranially, there was a dramatic improvement in vision and the VER latency reverted to normal (P100= 107 ms). The rapid improvement in vision coupled with the normalization of the VER latency despite the presence of optic atrophy, which reflects chronic demyelination of the optic nerve, cannot be explained on the basis of partial or full reformation of myelin. It is proposed that in MS synaptic neurotransmitter deficiency is associated with the visual impairment and delayed VER latency following optic neuritis and that the recovery of the VER latency by treatment with pulsed EMFs is related to enhancement of synaptic neurotransmitter functions in the retina and central optic pathways. Recovery of the VER latency in MS patients may have important implications with respect to the treatment of visual impairment and prevention of visual loss. Specifically, repeated pulsed applications of EMFs may maintain impulse transmission in the optic nerve and thus potentially sustain its viability.

Phys Med Rehabil Clin N Am. 1998 Aug;9(3):659-74.

Bioelectromagnetic applications for multiple sclerosis.

Richards TL, Lappin MS, Lawrie FW, Stegbauer KC.

Department of Radiology, University of Washington, Seattle, USA.

There are EM effects on biology that are potentially both harmful and beneficial. We have reviewed applications of EM fields that are relevant to MS. It is possible that EM fields could be developed into a reproducible therapy for both symptom management and long-term care for MS. The long-term care for MS would have to include beneficial changes in the immune system and in nerve regeneration.

Mult Scler. 2005 Jun;11(3):302-5.

Effect of pulsed magnetic field therapy on the level of fatigue in patients with multiple sclerosis–a randomized controlled tria.

Mostert S, Kesselring J.

Department of Neurology, Rehabilitation Centre, CH 7317 Valens, Switzerland.

Twenty-five multiple sclerosis patients, taking part in a rehabilitation program, were randomly assigned to treatment with pulsed magnetic field therapy (PMFT) or to sham therapy in order to study the additional effect of PMFT as part of a multimodal neurological rehabilitation program on fatigue. Patients demographic and disease specific characteristics were recorded. Level of fatigue was measured by fatigue severity scale (FSS) at entrance and discharge and with a visual analog scale (VAS) immediate before and after a single treatment session. The ‘Magnetic Cell Regeneration’ system by Santerra was used for PMFT. A single treatment lasted 16 minutes twice daily over 3-4 weeks and consisted of relaxed lying on a PMF mattress. Sham intervention was conducted in an identical manner with the PMF-device off. Patients and statistics were blinded. Level of fatigue measured by FSS was high at entrance in both treatment group (TG) and control group (CG) (5.6 versus 5.5). Over time of rehabilitation fatigue was reduced by 18% in TG and 7% in CG which was statistically not significant. There was a statistically significant immediate effect of the single treatment session which 18% reduction of fatigue measured by VAS in TG versus 11% in CG. Because of a high ‘placebo effect’ of simple bed rest, a only small and short lasting additional effect of PMFT and high costs of a PMF-device, we cannot recommend PMFT as an additional feature of a multimodal neurological rehabilitation program in order to reduce fatigue level of MS-patients.

Int J Neurosci. 1997 Nov;92(1-2):95-102.

Treatment with electromagnetic fields improves dual-task performance (talking while walking) in multiple sclerosis.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

Multiple sclerosis (MS) is associated with an increased risk of falling resulting from visual disturbances, difficulties with gait and balance, apraxia of gait and peripheral neuropathy. These factors often interact synergistically to compromise the patient’s gait stability. It has long been recognized that walking involves a cognitive component and that simultaneous cognitive and motor operations (dual-task) such as talking while walking may interfere with normal ambulation. Talking while walking reflects an example of a dual-task which is frequently impaired in MS patients. Impaired dual-task performance during walking may compromise the patient’s gait and explain why in some circumstances, MS patients unexpectedly lose their balance and fall. Frontal lobe dysfunction, which commonly occurs in MS patients, may disrupt dual-task performance and increase the risk of falling in these patients. This report concerns a 36 old man with remitting-progressive MS with an EDSS score of 5.5 who experienced marked increase in spasticity in the legs and trunk and worsening of his gait and balance, occasionally resulting in falling, when talking while walking. His gait and balance improved dramatically after he received two successive transcranial treatments, each of 45 minutes, with AC pulsed electromagnetic fields (EMFs) of 7.5 picotesla flux density. Simultaneously, there was improvement in dual-task performance to the extent that talking while walking did not adversely affect his ambulation. In addition, neuropsychological testing revealed an almost 5-fold increase in word output on the Thurstone’s Word-Fluency Test, which is sensitive to frontal lobe dysfunction. It is suggested that facilitation of dual-task performance during ambulation contributes to the overall improvement of gait and balance observed in MS patients receiving transcranial treatment with AC pulsed EMFs.

Int J Neurosci. 1997 Aug;90(3-4):177-85.

Treatment with electromagnetic fields reverses the long-term clinical course of a patient with chronic progressive multiple sclerosis.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

It is estimated that 10-20% of patients with multiple sclerosis (MS) have a chronic progressive (CP) course characterized by an insidious onset of neurological deficits followed by steady progression of disability in the absence of symptomatic remission. To date no therapeutic modality has proven effective in reversing the clinical course of CP MS although there are indications that prolonged treatment with picotesla electromagnetic fields (EMFs) alters the clinical course of patients with CP MS. A 40 year-old woman presented in December of 1992 with CP MS with symptoms of spastic paraplegia, loss of trunk control, marked weakness of the upper limbs with loss of fine and gross motor hand functions, severe fatigue, cognitive deficits, mental depression, and autonomic dysfunction with neurogenic bladder and bowel incontinence. Her symptoms began at the age of 18 with weakness of the right leg and fatigue with long distance walking and over the ensuing years she experienced steady deterioration of functions. In 1985 she became wheelchair dependent and it was anticipated that within 1-2 years she would become functionally quadriplegic. In December of 1992 she began experimental treatment with EMFs. While receiving regularly weekly transcortical treatments with AC pulsed EMFs in the picotesla range intensity she experienced during the first year improvement in mental functions, return of strength in the upper extremities, and recovery of trunk control. During the second year she experienced the return of more hip functions and recovery of motor functions began in her legs. For the first time in years she can now initiate dorsiflexion of her ankles and actively extend her knees voluntarily. Over the past year she started to show signs of redevelopment of reciprocal gait. Presently, with enough function restored in her legs, she is learning to walk with a walker and is able to stand unassisted and maintain her balance for a few minutes. She also regained about 80% of functions in the upper limbs and hands. Most remarkably, there was no further progression of the disease during the 4 years course of magnetic therapy. This patient’s clinical recovery cannot be explained on the basis of a spontaneous remission. It is suggested that pulsed applications of picotesla EMFs affect the neurobiological and immunological mechanisms underlying the pathogenesis of CP MS.

Int J Neurosci. 1997 Aug;90(3-4):145-57.

Resolution of sleep paralysis by weak electromagnetic fields in a patient with multiple sclerosis.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

Sleep paralysis refers to episodes of inability to move during the onset of sleep or more commonly upon awakening. Patients often describe the sensation of struggling to move and may experience simultaneous frightening vivid hallucinations and dreams. Sleep paralysis and other manifestations of dissociated states of wakefulness and sleep, which reflect deficient monoaminergic regulation of neural modulators of REM sleep, have been reported in patients with multiple sclerosis (MS). A 40 year old woman with remitting-progressive multiple sclerosis (MS) experienced episodes of sleep paralysis since the age of 16, four years prior to the onset of her neurological symptoms. Episodes of sleep paralysis, which manifested at a frequency of about once a week, occurred only upon awakening in the morning and were considered by the patient as a most terrifying experience. Periods of mental stress, sleep deprivation, physical fatigue and exacerbation of MS symptoms appeared to enhance the occurrence of sleep paralysis. In July of 1992 the patient began experimental treatment with AC pulsed applications of picotesla intensity electromagnetic fields (EMFs) of 5Hz frequency which were applied extracerebrally 1-2 times per week. During the course of treatment with EMFs the patient made a dramatic recovery of symptoms with improvement in vision, mobility, balance, bladder control, fatigue and short term memory. In addition, her baseline pattern reversal visual evoked potential studies, which showed abnormally prolonged latencies in both eyes, normalized 3 weeks after the initiation of magnetic therapy and remained normal more than 2.5 years later. Since the introduction of magnetic therapy episodes of sleep paralysis gradually diminished and abated completely over the past 3 years. This report suggests that MS may be associated with deficient REM sleep inhibitory neural mechanisms leading to sleep paralysis secondary to the intrusion of REM sleep atonia and dream imagery into the waking state. Pineal melatonin and monoaminergic neurons have been implicated in the induction and maintenance of REM sleep and the pathogenesis of sleep paralysis and it is suggested that resolution of sleep paralysis in this patient by AC pulsed applications of EMFs was related to enhancement of melatonin circadian rhythms and cerebral serotoninergic neurotransmission.

Int J Neurosci. 1997 Jun;90(1-2):59-74.

Immediate recovery of cognitive functions and resolution of fatigue by treatment with weak electromagnetic fields in a patient with multiple sclerosis.

Sandyk R.

Department of Neuroscience, Institute for Biomedical Engineering, Dix Hills, NY, USA.

Cognitive deficits are common among patients with multiple sclerosis (MS). The pathogenetic mechanisms underlying the cognitive impairment in MS are unknown and there is presently no effective therapeutic modality which has shown efficacy in improving cognitive deficits in MS. A 53 year old college professor with a long history of secondary progressive MS experienced, over the preceding year, noticeable deterioration in cognitive functions with difficulties in short and long term memory, word finding in spontaneous speech, attention and concentration span. Unable to pursue his academic activities, he was considering early retirement. Mental examination disclosed features of subcortical and cortical dementia involving frontal lobe, left hemispheric and right hemispheric dysfunction. Almost immediately following the extracerebral application of AC pulsed electromagnetic fields (EMFs) of 7.5 picotesla intensity and a 4-Hz sinusoidal wave, the patient experienced a heightend sense of well being, which he defined as enhancement of cognitive functions with a feeling “like a cloud lifted off my head.” He reported heightend clarity of thinking and during the application of EMFs he felt that words were formed faster and he experienced no difficulty finding the appropriate words. His speech was stronger and well modulated and he felt “energized” with resolution of his fatigue. There was improvement in manual dexterity and handwriting and testing of constructional praxis demonstrated improvement in visuospatial, visuoperceptive and visuomotor functions. It is suggested that some of the cognitive deficits associated with MS, which are caused by synaptic disruption of neurotransmitter functions, may be reversed through pulsed applications of picotesla range EMFs.

Int J Neurosci. 1996 Oct;87(1-2):5-15.

Suicidal behavior is attenuated in patients with multiple sclerosis by treatment with electromagnetic fields.

Sandyk R.

NeuroCommunication Research Laboratories, Danbury, CT 06811, USA.

A marked decrease in the levels of serotonin (5-HT) and its metabolite (5-HIAA) has been demonstrated in postmortem studies of suicide victims with various psychiatric disorders. Depression is the most common mental manifestation of multiple sclerosis (MS) which accounts for the high incidence of suicide in this disease. CSF 5-HIAA concentrations are reduced in MS patients and nocturnal plasma melatonin levels were found to be lower in suicidal than in nonsuicidal patients. These findings suggest that the increased risk of suicide in MS patients may be related to decreased 5-HT functions and blunted circadian melatonin secretion. Previous studies have demonstrated that extracerebral applications of pulsed electromagnetic fields (EMFs) in the picotesla range rapidly improved motor, sensory, affective and cognitive deficits in MS. Augmentation of cerebral 5-HT synthesis and resynchronization of circadian melatonin secretion has been suggested as a key mechanism by which these EMFs improved symptoms of the disease. Therefore, the prediction was made that this treatment modality would result in attenuation of suicidal behavior in MS patients. The present report concerns three women with remitting-progressive MS who exhibited suicidal behavior during the course of their illness. All patients had frequent suicidal thoughts over several years and experienced resolution of suicidal behavior within several weeks after introduction of EMFs treatment with no recurrence of symptoms during a follow-up of months to 3.5 years. These findings demonstrate that in MS pulsed applications of picotesla level EMFs improve mental depression and may reduce the risk of suicide by a mechanism involving the augmentation of 5-HT neurotransmission and resynchronization of circadian melatonin secretion.

Int J Neurosci. 1996 Jul;86(1-2):79-85.

Effect of weak electromagnetic fields on body image perception in patients with multiple sclerosis.

Sandyk R.

NeuroCommunication Research Laboratories, Danbury, CT 06811, USA.

Cerebellar ataxia is one of the most disabling symptoms of multiple sclerosis (MS) and also one of the least responsive to pharmacotherapy. However, cerebellar symptoms often improve dramatically in MS patients by brief, extracerebral applications of picotesla flux electromagnetic fields (EMFs). This report concerns two MS patients with chronic disabling ataxia who experienced rapid improvement in gait and balance after receiving a series of treatments with EMFs. To assess whether improvement in cerebellar gait is accompanied by changes in body image perception, a parietal lobe function, both patients were administered the Human Figure Drawing Test before and after a series of brief treatments with EMFs. Prior to application of EMFs these patients’ free drawings of a person showed a figure with a wide-based stance characteristic of cerebellar ataxia. After receiving a series of EMFs treatments both patients demonstrated a change in body image perception with the drawings of the human figure showing a normal stance. These findings demonstrate that in MS improvement in cerebellar symptoms by pulsed applications of picotesla EMFs is associated with changes in the body image.

Int J Neurosci. 1996 Jul;86(1-2):67-77.

Treatment with weak electromagnetic fields attenuates carbohydrate cravings in a patients with multiple sclerosis.

Sandyk R.

NeuroCommunication Research Laboratories, Danbury, CT 06811, USA.

Pharmacological studies have implicated serotonergic (5-HT) neurons in the regulation of food intake and food preference. It has been shown that the urge to consume carbohydrate rich foods is regulated by 5-HT activity and that carbohydrate craving is triggered by 5-HT deficiency in the medical hypothalamus. Ingestion of carbohydrate foods stimulates insulin secretion which accelerates the uptake of tryptophan, the precursor of 5-HT and melatonin, into the brain and pineal gland, respectively. Thus, carbohydrate craving might be considered a form of “self medication” aimed at correcting an underlying dysfunction of cerebral 5-HT and pineal melatonin functions. A 51 year old woman with remitting-progressive MS experienced carbohydrate craving during childhood and adolescence and again in temporal association with the onset of her first neurological symptoms at the age of 45. Carbohydrate craving, which resembled the pattern observed in patients with seasonal affective disorder (SAD), was attenuated by a series of extracranial AC pulsed applications of picotesla (10(-12) Tesla) flux intensity electromagnetic fields (EMFs). It is suggested that AC pulsed EMFs applications activated retinal mechanisms which, through functional interactions with the medial hypothalamus, initiated an increased release of 5-HT and resynchronization of melatonin secretion ultimately leading to a decrease in carbohydrate craving. The occurrence of carbohydrate craving in early life may have increased the patient’s vulnerability to viral infection given the importance of 5-HT and melatonin in immunomodulation and the regulation of the integrity of the blood brain barrier. The recurrence of this craving in temporal relation to the onset of neurological symptoms suggests that 5-HT deficiency and impaired pineal melatonin functions are linked to the timing of onset of the clinical symptoms of the disease. The report supports the role of experimental factors in the pathophysiology of MS.

Int J Neurosci. 1995 Nov;83(1-2):81-92.

Resolution of dysarthria in multiple sclerosis by treatment with weak electromagnetic fields.

Sandyk R.

NeuroCommunication Research Laboratories, Danbury, CT 06811, USA.

It has been reported that 50% or more of patients diagnosed with multiple sclerosis (MS) exhibit speech impairment (dysarthria) which in some cases can be exceedingly disabling. Currently there is no effective medical treatment for the dysarthria of MS which occurs as a result of lesions to the cerebellum and its outflow tracts. It was reported recently that extracranial application of brief AC pulsed electromagnetic fields (EMFs) in the picotesla (pT) range intensity produced in patients with MS sustained improvement in motor functions including cerebellar symptomatology. This communication concerns two MS patients with a chronic progressive course who exhibited severe dysarthria which improved already during the initial treatment with pulsed EMFs and which resolved completely 3-4 weeks later. Since application of EMFs has been shown to alter: (a) the resting membrane potential and synaptic neurotransmitter release through an effect involving changes in transmembrane calcium flux; and (b) the secretion of pineal melatonin which in turn influences the synthesis and release of serotonin (5-HT) and gamma-amino butyric acid (GABA) in the cerebellum, it is suggested that the immediate improvement of the dysarthria occurred as a result of changes in cerebellar neurotransmitter functions particularly 5-HT and GABA rather than from remyelination.

Int J Neurosci. 1995 Jun;82(3-4):223-42.

Chronic relapsing multiple sclerosis: a case report of rapid recovery by application of weak electromagnetic fields.

Sandyk R.

NeuroCommunication Research Laboratories, Danbury, CT 06811, USA.

A 54 year-old woman was diagnosed with multiple sclerosis (MS) in 1985 at the age of 45 after she developed diplopia, slurred speech, and weakness in the right leg. A Magnetic Resonance Imaging (MRI) scan obtained in 1985 showed several areas of plaque formation distributed in the periventricular white matter and centrum semiovale bilaterally. Coincident with slow deterioration in her condition since 1990 a second MRI scan was obtained in 1991 which showed a considerable increase in the number and size of plaques throughout both cerebral hemispheres, subcortical white matter, periventricularly and brainstem. In 1994, the patient received treatment with Interferon beta- 1b (Betaseron) for 6 months with no improvement in symptoms. However, following two successive extracranial applications of pulsed electromagnetic fields (EMFs) in the picotesla (pT) range each of 20 minutes duration the patient experienced an immediate improvement in symptoms most dramatically in gait, balance, speech, level of energy, swallowing, mood, and vision. On a maintenance program of 3 treatments per month the patient’s only symptom is mild right foot and leg weakness. The report points to the unique efficacy of externally applied pT range EMFs in the symptomatic treatment of MS, indicates a lack of an association between the extent of demyelinating plaques on MRI scan and rate and extent of recovery in response to EMFs, and supports the notion that dysfunction of synaptic conductivity due to neurotransmitter deficiency particularly of serotonin (5-HT) contributes more significantly to the development of MS symptoms than the process of demyelination which clinically seems to represent an epiphenomenon of the disease.

Int J Neurosci. 1994 Dec;79(3-4):199-212.

Weak electromagnetic fields attenuate tremor in multiple sclerosis.

Sandyk R, Dann LC.

NeuroCommunication Research Laboratories, Danbury, CT 06811, USA.

It has been estimated that about 75% of patients diagnosed with multiple sclerosis (MS) have tremor which can be exceedingly disabling. The most common tremor observed in patients with MS is a cerebellar intention tremor (‘kinetic tremor’) although postural tremor (‘static tremor’) is also common and often extremely incapacitating. Currently there is no effective medical treatment for the tremor of MS which, in some severe cases, may be abolished by stereotactic thalamotomy. It was reported recently that extracranial application of brief AC pulsed electromagnetic fields (EMFs) in the picotesla (pT) range produced improvement in motor and cognitive functions in patients with MS. The present communication concerns three MS patients with a chronic progressive course of the disease (mean age: 39.3 +/- 8.3 years; mean duration of illness: 11.3 +/- 3.2 years) in whom brief external applications of pulsed EMFs of 7.5 pT intensity reduced intention and postural tremors resulting in significant functional improvement. The report suggests that these extremely low intensity EMFs are beneficial also in the treatment of tremors in MS and that this treatment may serve as an alternative method to stereotactic thalamotomy in the management of tremor in MS. The mechanisms by which EMFs attenuate the tremors of MS are complex and are thought to involve augmentation of GABA and serotonin (5-HT) neurotransmission in the cerebellum and its outflow tracts.

Therapeutic effects of alternating current pulsed electromagnetic fields in multiple sclerosis

Sandyk R. Dep. of Neuroscience, Institute for Biomedical Engineering and Rehab Services of Touro College, Dix Hills, New York.

Multiple sclerosis is the third most common cause of severe disability in patients between the ages of 15 and 50 years. The cause of the disease and its pathogenesis remain unknown. The last 20 years have seen only meager advances in the development of effective treatments for the disease. No specific treatment modality can cure the disease or alter its long-term course and eventual outcome. Moreover, there are no agents or treatments that will restore premorbid neuronal function. A host of biological phenomena associated with the disease involving interactions among genetic, environmental, immunologic, and hormonal factors, cannot be explained on the basis of demyelination alone and therefore require refocusing attention on alternative explanations, one of which implicates the pineal gland as pivotal. The pineal gland functions as a magnetoreceptor organ. This biological property of the gland provided the impetus for the development of a novel and highly effective therapeutic modality, which involves transcranial applications of alternating current (AC) pulsed electromagnetic fields flux density. This review summarizes recent clinical work on the effects of transcranially applied pulsed electromagnetic fields for the symptomatic treatment of the disease.

Double-blind study of pulsing magnetic field effects on multiple sclerosis.

Richards T. et.al. Dep. Radiology, University of Washington

We performed a double-blind study to measure the clinical and sub-clinical effects of an alternative medicine electromagnetic device on disease activity in multiple sclerosis (MS). The MS patients were exposed to a magnetic pulsing device where the frequency of the magnetic pulse was in the 4-13 Hz range. A total of 30 MS patients wore the device on pre-selected sites between 10 and 24 hours a day for 2 months. Half of the patients (15) randomly received a device that was magnetically inactive and the other half received an active device. Each MS patient received a set of tests to evaluate MS disease status before and after wearing the device. The tests included (1) a clinical rating (Kurtzke, EDSS), (2) patient-reported performance scales, and (3) quantitative electro-encephalography (QEEG) during a language task. Although there was no significant change between pretreatment and post-treatment in the EDSS scale, there was a significant improvement in the performance scale (PS) combined rating for bladder control, cognitive function, fatigue level, mobility, spasticity, and vision (active group -3.83 +/- 1.08, p < 0.005; placebo group -0.17 +/- 1.07, change in PS scale). There was also a significant change between pre-treatment and post-treatment in alpha EEG magnitude during the language task recorded at various electrode sites on the left side. In this double-blind, placebo-controlled study, we have demonstrated a statistically significant effect of themagnetic pulsing device on patient performance scales and on alpha EEG magnitude during a language task.
J In Biologic Effects of Light 1998 Symposium

Pulsing magnetic field effects on brain electrical activity in multiple sclerosis.

Richards TL, Acosta-Urquidi,

Multiple sclerosis (MS) is a disease of the central nervous system. Clinical symptoms include central fatigue, impaired bladder control, muscle weakness, sensory deficits, impaired cognition, and others. The cause of MS is unknown, but from histologic, immunologic, and radiologic studies, we know that there are demyelinated brain lesions (visible on magnetic resonance images) that contain immune cells such as macrophages and T-cells (visible on microscopic analysis of brain sections). Recently, a histologic study has also shown that widespread axonal damage occurs in MS along with demyelination. What is the possible connection between MS and bio-electromagnetic fields? We recently published a review entitled “Bio-electromagnetic applications for multiple sclerosis,” which examined several scientific studies that demonstrated the effects of electromagnetic fields on nerve regeneration, brain electrical activity (electro-encephalography), neurochemistry, and immune system components. All of these effects are important for disease pathology and clinical symptoms in multiple sclerosis (MS). EEG was measured in this study in order to test our hypothesis that the pulsing magnetic device affects the brain electrical activity, and that this may be a mechanism for the effect we have observed on patient-reported symptoms. The EEG data reported previously were measured only during resting and language conditions. The purpose of the current study was to measure the effect of the electromagnetic device on EEG activity during and after photic stimulation with flashing lights. After photic stimulation, there was a statistically significant increase in alpha EEG magnitude that was greater in the active group compared to the placebo group in electrode positions P3, T5, and O1 (analysis of variance p<.001, F=14, DF = 1,16). In the comparison between active versus placebo, changes measured from three electrode positions were statistically significantly even after multiple comparison correction.

Treatment with weak electromagnetic fields improves fatigue associated with multiple sclerosis.

Sandyk R. NeuroCommunication Research Laboratories, Danbury, CT, USA

It is estimated that 75-90% of patients with multiple sclerosis (MS) experience fatigue at some point during the course of the disease and that in about half of these patients, subjective fatigue is a primary complaint. In the majority of patients fatigue is present throughout the course of the day being most prominent in the mid to late afternoon. Sleepiness is not prominent, but patients report that rest may attenuate fatigability. The pathophysiology of the fatigue of MS remains unknown. Delayed impulse conduction in demyelinated zones may render transmission in the brainstem reticular formation less effective. In addition, the observation that rest may restore energy and that administration of pemoline and amantadine, which increase the synthesis and release of monoamines, often improve the fatigue of MS suggest that depletion of neurotransmitter stores in damaged neurons may contribute significantly to the development of fatigue in these patients. The present report concerns three MS patients who experienced over several years continuous and debilitating fatigue throughout the course of the day. Fatigue was exacerbated by increased physical activity and was not improved by rest. After receiving a course of treatments with picotesla flux electromagnetic fields (EMFs), which were applied extracranially, all patients experienced improvement in fatigue. Remarkably, patients noted that several months after initiation of treatment with EMFs they were able to recover, after a short period of rest, from fatigue which followed increased physical activity. These observations suggest that replenishment of monoamine stores in neurons damaged by demyelination in the brainstem reticular formation by periodic applications of picotesla flux intensity EMFs may lead to more effective impulse conduction and thus to improvement in fatigue including rapid recovery of fatigue after rest.

Int J Neurosci. 1998 Jul;95(1-2):107-13.

Yawning and stretching–a behavioral syndrome associated with transcranial application of electromagnetic fields in multiple sclerosis.

Sandyk R.

Department of Neuroscience at the Institute for Biomedical Engineering and Rehabilitation Services of Touro College, Dix Hills, NY 11746, USA.

Intracerebral administration of adrenocorticotropic hormone (ACTH) elicits in experimental animals a yawning stretching behavior which is believed to reflect an arousal response mediated through the septohippocampal cholinergic neurons. A surge in plasma ACTH levels at night and just prior to awakening from sleep is also associated in humans with yawning and stretching behavior. Recurrent episodes of uncontrollable yawning and body stretching, identical to those observed upon awakening from physiological sleep, occur in a subset of patients with multiple sclerosis (MS) during transcranial therapeutic application of AC pulsed electromagnetic fields of picotesla flux density. This behavioral response has been observed exclusively in young female patients who are fully ambulatory with a relapsing remitting course of the disease who also demonstrate a distinctly favorable therapeutic response to magnetic stimulation. ACTH is employed for the treatment of MS due to its immunomodulatory effects and a surge in its release in response to AC pulsed magnetic stimulation could explain some of the mechanism by which these fields improve symptoms of the disease.

Int J Neurosci. 1997 Jan;89(1-2):39-51.

Progressive cognitive improvement in multiple sclerosis from treatment with electromagnetic fields.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

It has long been recognized that cognitive impairment occurs in patients with multiple sclerosis (MS) particularly among patients with a chronic progressive course. MS is considered a type of “subcortical dementia” in which cognitive and behavioral abnormalities resemble those observed in patients with a frontal lobe syndrome. The Bicycle Drawing Test is employed for the neuropsychological assessment of cognitive impairment specifically that of mechanical reasoning and visuographic functioning. It also provides clues concerning the patient’s organizational skills which are subserved by the frontal lobes. Extracerebral pulsed applications of picotesla flux intensity electromagnetic fields (EMFs) have been shown to improve cognitive functions in patients with MS. I present three patients with long standing symptoms of MS who, on the initial baseline, pretreatment Bicycle Drawing Test, exhibited cognitive impairment manifested by omissions of essential details and deficient organizational skills. All patients demonstrated progressive improvement in their performance during treatment with EMFs lasting from 6-18 months. The improvement in cognitive functions, which occurred during the initial phases of the treatment, was striking for the changes in organizational skills reflecting frontal lobe functions. These findings demonstrate that progressive recovery of cognitive functions in MS patients are observed over time through continued administration of picotesla flux intensity EMFs. It is believed that the beneficial cognitive effects of these EMFs are related to increased synaptic neurotransmission and that the progressive cognitive improvement noted in these patients is associated with slow recovery of synaptic functions in monoaminergic neurons of the frontal lobe or its projections from subcortical areas.

Wiad Lek. 2003;56(9-10):434-41.

Application of variable magnetic fields in medicine–15 years experience.

[Article in Polish]

Sieron A, Cieslar G.

Katedra i Klinika Chorob Wewnetrznych, Angiologii i Medycyny Fizykalnej SAM, ul. Batorego 15, 41-902 Bytom. sieron@mediclub.pl

The results of 15-year own experimental and clinical research on application of variable magnetic fields in medicine were presented. In experimental studies analgesic effect (related to endogenous opioid system and nitrogen oxide activity) and regenerative effect of variable magnetic fields with therapeutical parameters was observed. The influence of this fields on enzymatic and hormonal activity, free oxygen radicals, carbohydrates, protein and lipid metabolism, dielectric and rheological properties of blood as well as behavioural reactions and activity of central dopamine receptor in experimental animals was proved. In clinical studies high therapeutic efficacy of magnetotherapy and magnetostimulation in the treatment of osteoarthrosis, abnormal ossification, osteoporosis, nasosinusitis, multiple sclerosis, Parkinson’s disease, spastic paresis, diabetic polyneuropathy and retinopathy, vegetative neurosis, peptic ulcers, colon irritable and trophic ulcers was confirmed.