A Short Review On The Influence Of Magnetic Fields On Neurological Diseases Part 1

1. Abstract

This study reviews the use of magnetic and electromagnetic fields (EMF), pulsed electromagnetic fields (PEMF), and transcranial magnetic stimulation (TMS) in Parkinson's disease, Alzheimer's disease (AD), or Multiple Sclerosis (MS). 

Parkinson's disease is a neurodegenerative disease that is characterized by stiffness, tremors, and slow movements. However, what many people don't know is that Parkinson's disease can also cause problems with memory and cognitive abilities. However, we shouldn't let this negative news discourage us, especially when we realize that we can take steps to improve our cognitive health.

First, we should understand how Parkinson's disease affects our memory and cognitive abilities. Although everyone's situation is different, some patients may experience memory deterioration, slow thinking, lack of attention, and difficulty with abstract reasoning. These problems can seriously affect daily life, which makes the management of Parkinson's disease more complicated.

However, we should remember that Parkinson's disease does not necessarily mean that all memory and cognitive abilities will be lost. Researchers have found some ways to improve cognitive health, which can also be used by people with Parkinson's disease. These methods include:

1. Perform cognitive training

Cognitive training can help strengthen and challenge the brain's cognitive abilities, including memory, attention, and thinking skills. Studies have also shown that cognitive training can improve cognitive function and quality of life in people with Parkinson's disease.

2. Stay healthy

Physical health has a great impact on cognitive function, so it is very important to maintain a good experience and moderate exercise. Long-term cardiopulmonary exercise, such as running and cycling, has been shown to improve cognitive function.

3. Social interaction

Social interaction is key to cognitive health for many people. Even with Parkinson's disease, we can stay connected with others and strengthen social interactions, thereby reducing the risk of cognitive deterioration.

In short, Parkinson's disease can affect memory and cognitive ability, but we do not necessarily lose memory and cognitive ability. We can improve our cognitive ability through cognitive training, maintaining physical health, and social interaction to maintain a healthy and active life. Let us believe in our abilities, face challenges positively, and keep moving forward. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because Cistanche is a traditional Chinese medicine with many unique effects, one of which is to improve memory. The efficacy of Cistanche comes from the various active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc., which can promote brain health in many ways.

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The Introduction provides a review of EMF, PEMF, and TMS based on clinical observations. This is followed by a description of the basic principles of these treatments and a literature review on possible mechanisms describing the coupling of these treatments with biological responses. 

These response mechanisms include the cell membrane and its embedded receptors, channels, and pumps, as well as signaling cascades within the cell and links to cell organelles. 

We also discuss the magnetic contribution to coupling EMF and the recent finding of cryptochrome as a putative magnetosensor. 

Our conclusion summarizes the complex network of causal factors elicited by EMF such as those arising from the cell membrane via signaling cascades to radical oxygen species, nitric oxide, growth factors, cryptochromes, and other mechanisms involving epigenetic and genetic changes.

2. Introduction

Transcranial magnetic stimulation (TMS) has been recognized as a novel neurological and psychiatric therapeutic tool useful in the treatment of several neurological diseases because it is non-invasive and painless while stimulating specific regions of the brain [1, 2]. 

However, the effects of electromagnetic fields (EMF) on molecular and biological systems are still not completely understood. It is known that "window-effects" are present depending on wavelength and intensity and, because of this, the effects of EMF can range from beneficial to adverse [3]. 

This effect describes the phenomenon in which there are specific amplitudes of frequency values, at which the response of the biological system is activated, whereas other amplitudes or frequencies can inhibit the same biological system [4]. 

In this review, we have studied the impact of magnetic therapy on 3 neurological diseases with a high socioeconomic impact: Parkinson's disease (PD), Alzheimer's disease (AD), and Multiple Sclerosis (MS). 

We cite only those studies that connect these diseases with magnetic therapy. We focused our efforts on those studies involved with coupling (low frequency) electromagnetic fields (EMF), pulsed electromagnetic fields (PEMF), and transcranial magnetic stimulation (TMS) to determine the pathophysiological effects on cell and molecular biology. 

Magnetic therapy used for stroke rehabilitation and its effects on variables such as stroke intensity and regeneration times are also included in this review [5].

3. Technical aspects

In this review, we studied "magnetic field therapy" treatment with EMF, PEMF, or TMS. TMS can be applied in single pulses, multiple pulses, or repetitively (rTMS, applied in low or high frequencies). 

In theta-burst stimulation (TBS), there are three 50-Hz pulses applied at 5 Hz for 20– 40 sec as continuous TBS (cTBS) or as intermittent TBS (iTBS) [6, 7]. A magnetic field is produced with a coil, either single or butterfly-shaped. 

The lines of flux pass perpendicular to the plane of the coil which is normally placed tangential to the scalp. The intensity of the magnetic field can reach up to approximately 2 Tesla and typically lasts for approximately 100 ms. 

The magnetic field induces an electric field which is perpendicular to this plane. This electric field excites neurons and currents are induced leading to motor-evoked potentials [8]. Paired pulses lead to short intracortical inhibition and facilitation which reflects cortical interneuron action [9].

4. Diseases and magnetic fields

Positive clinical effects of TMS in Parkinson's disease have been reported in several reviews [10–15]. Treatment with TMS was superior to placebo [14] in patients with mild disease who have a greater potential for neural rehabilitation [15]. 

Treatment with TMS improved mobility and activities of daily living scores in the more active patient group [12]. Furthermore, weekly TMS (pico tesla flux density) reduced the frequency of freezing and falling [16]. 

Not only can clinical symptoms of Parkinson's be relieved by TMS [11], but also the concentration of dopamine and homovanillic acid in the lumbar cerebrospinal fluid also tended to return to normal values [17, 18]. 

The enhancement of reduced smell perception after only 7 Hz EMF represents EMF's window effect, specifically, the release of dopamine and the subsequent activation of dopamine D2 receptors within the olfactory bulb [19]. 

In Parkinson's disease, there are two proposed mechanisms for coupling electromagnetic fields: radical oxygen species (ROS), and the effect of ROS on membrane potential (see Main Section) [20, 21]. 

The influence of electromagnetic fields on membrane potential and cortical excitability is also mentioned in clinical studies of AD by Lopez et al. [22]. TMS therapy has been associated with "cortical rewiring" or "synaptic plasticity". These phenomena are also reviewed in this manuscript in combination with treatment of the aging brain [23–25]. 

Clinically, it was found in AD patients that the application of repetitive TMS can transiently restore or compensate for damaged cognitive functions [26]. It has also been reported that in AD patients, the application of three-dimensional (3D)-pulsed magnetic fields reduces inflammation and produces vasodilatory effects which, in turn, improve blood circulation most likely due to the release of nitric oxide (NO) [27]. 

In the peripheral blood mononuclear cells of AD patients, Capelli et al. [28] tested the ability of low frequency-PEMF to modulate gene expression in cell functions that are dysregulated in AD (i.e., beta-site amyloid precursor protein cleaving enzyme 1 or BACE1). 

These investigators observed that LF-PEMF can stimulate epigenetic regulation mediated by miRNAs, which may lead to a rebalancing of dysregulated pathways. 

The expression of typical AD proteins, such as tau, showed the positive effects of rTMS with low and higher frequencies in studies in AD mouse models [24]. MS is not a typical neurodegenerative disease because of the immune system's involvement, which attacks the nerve fibers' myelin sheath [29]. 

It is reported that in MS, EMF exerts therapeutic effects through modulation of immune-relevant cells [30]. Another characteristic found in MS patients is reduced blood oxygen, reduced blood circulation, and impaired cell metabolism. 

Sakamoto and co-workers found that the application of magnetic fields with low frequency and intensity improves these parameters and reduces symptoms of MS [31]. Low levels of NO were also found in the brains of MS patients [32, 33]. 

Following the application of magnetic fields, this parameter is normalized in cell models [34, 35]. 

The dual role of NO is discussed for pain transmission [35] as NO inhibits nociception in the peripheral and the central nervous system, as well as mediating the analgesic effect of opioids and other analgesic substances. Hochsprung et al. [36] found that treatment with PEMF may be effective in reducing pain in patients with MS, using monopolar dielectric transmission of pulsed electromagnetic fields. 

In summary, several clinical parameters are positively altered after electromagnetic therapy in patients with neurodegenerative diseases.

5. Basic principles

Time-varying magnetic fields produce forces on charges and are more effective than static magnetic fields [37]. Time dependence of the magnetic field (B(t)) induces an electric field (E) according to Faraday's law: CurlE = – 1/c dB/dt. 

In this equation, the vector E stands for the electric field, the vector B represents the magnetic induction and B = H + 4πM. In the present case, there is no magnetization (M), and therefore the induced electric field (E) is generated completely by the time-dependent magnetic field H(t). 

The symbol c is the velocity of light. Time-oscillatory magnetic fields induce intracellular eddy currents, which, according to the Lentz rule, counteract the change of the external magnetic field. Eddy currents appear in materials which are electrically conduct-ing, especially on cell membranes. 

Static magnetic fields produce forces on charged particles in motion. Because cellular plasma membranes are constantly moving, even static magnetic fields produce time-varying forces on the charged particles in the brain [38, 39].

6. Sites at the cellular and molecular levels for EMF coupling

Charged ions such as sodium, potassium, calcium, and magnesium are present in all tissues of the body. Most of the biomolecules possess charges and therefore they can be directly influenced by electric fields [40, 41]. 

In general, there are multiple methods for coupling electrical fields, for example, by voltage-gated calcium channels, nonspecific charged moieties like Ca2+ or other receptors, coupling by Larmor precession, etc. [40]. 

The cell membrane and its embedded molecules are the most relevant candidates for EMF-coupling because of the very high gradient of electric field at this location [40]. The cell membrane generates a resting potential which comes from the segregation of charged ion concentrations by molecular machines such as pumps, transporters, and ion channels largely situated within the plasma membrane [41]. 

Levin and coworkers showed that artificial depolarization holds the cells in an undifferentiated and proliferative state, while artificial hyperpolarization accelerates differentiation [42]. A switch between pathological (e.g., inflamed) and normal states can be elicited by external changes in the membrane potential [43, 44]. EMF, PEMF, and TMS [45] can each influence this resting potential. 

Microdomains of ion channels and transporters are distributed in patterns across the entire two-dimensional surface of the cell membrane [41, 42]. Within the membrane, PEMF can activate voltage-gated calcium channels (VGCC) [46] (Fig. 1). 

From these channels, specific signal amplification processes carry membrane-mediated effects into the interior of the cell [47, 48]. During TMS stimulation of the cortex, neurons are most excitable when their membrane potential is just below the threshold but not discharging [45]. 

It has been shown that TMS directly acts more on the surface layers of the cortex, where an electric field will induce a change in the resting transmembrane potential by superimposing an electrically induced transmembrane potential [25]. 

When the electric current penetrates the membrane, a neuronal membrane may be depolarized and/or hyperpolarized from its resting value, which causes excitation or inhibition of the cell. This can lead to secondary training effects of the neurons evoking new synaptic wiring also via long-term potentiation and activating a family of tyrosine kinases (e.g., Fyn) [49, 50] (Fig. 1). 

Training effects are especially important for the aging brain. TMS-enhanced synaptic markers activate the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) pathway (Fig. 1) as well as the downstream kinase Fyn, enhancing glutamatergic synaptic transmission and increasing phosphorylation of the subunits of N-methyl-D-aspartate (NMDA) receptors in the hippocampus [23]. 

This suggests that these events lead to changes in structural plasticity in the aged hippocampus and improve cognitive function. In the cortex of the rat brain, TMS fields stimulate other neurons that inhibit the activity of dendrites from neurons within the deeper cortex layers [51]. 

This inhibition process depends on a type of receptor protein in the dendrites termed GABAB (gamma-aminobutyric acid) receptors. Blocking these receptors prevents transcranial magnetic stimulation from altering the activity of stimulated brain regions. 

The topographical pattern of the cell membrane can encode additional information [42, 45]. For example, time-varying patterns of molecular fluctuation and specific rhythms can enhance such information [52] and, accordingly, the signal-noise ratio can be lowered significantly. 

For coupling EMF, a discontinuous cell geometry with clustered receptors favors EF detection [53]. Specifically, if macrophage-operated Ca2+ channels are clustered within lamellipodia, inhibition of these channels abolishes their migration response. Regarding cell geometry and protrusions as microvilli, the formation of such structures can be induced by EMF (e.g., at 1 Hz and 2-V/cm field in macrophages [54]). 

In rat osteoblasts, the pathways elicited by PEMF can be abolished with the knockdown of the primary cilia by RNA interference [55]. In contrast, microvilli-like structures can be damaged by PEMF frequencies between 50 and 70 Hz (0.6-V/cm field). Of note, a loss of such structures and a collapse of the apical membrane is found in the endoderm cells of the embryonic yolk sack [56]. 

In mitochondria, a very high membrane potential is normally present as the outer membrane potential measures 180–220 mV compared to the maximal 70–90 mV resting potential of the cell's plasma membrane [57]. 

Using "nano pebble" sensors, Tyner et al. [58] and Lee and Kopelman [59] found that the membrane potential of mitochondria spreads to a wider distance than was predicted using the parameters for shielding and damping by stochastic Brownian movement of random water molecules. 

Thus, magnetic therapy can also affect mitochondrial function, and this can lead to changes in ROS and NO production (see below).

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