OVERVIEW OF THE
Molecular Mechanisms Underlying the Action of Electromagnetic Fields
Animal studies have shown that administration of electromagnetic fields may slow or reduce inflammation in the central and peripheral nervous systems through modulation of the microglia-astrocyte crosstalk (Vincenzi et al. 2017, Lameth et al. 2017, Vincenzi et al. 2020, Son et al. 2023, Hyldahl et al. 2023, Zhang et al. 2023). Accordingly, this brought forth numerous clinical trials which have demonstrated the effectiveness of electromagnetic fields in reducing pain (Andrade et al. 2016, Bagnato et al. 2016, Hartard et al. 2023) and improving functional recovery of patients following stroke (Cichon et al. 2018, Weisinger et al. 2022, Saver et al. 2023).
Electromagnetic field (EMF) is a vector field created by the displacement of electrically charged objects where energy interactions with other electric charges or electromagnetic fields occur. As the name suggests, it is the combination of both electric and magnetic fields. Whilst electric field describes the space within which an electric charge exerts an electric force upon another charged body in its vicinity, a magnetic field is a field within which a charge will experience a magnetic influence.
The main property of electromagnetic fields is their ability to influence charged objects in their vicinity. When applied for treatment of neurological disorders, the action of electromagnetic fields can be outlined through five distinct effects:
- Reorientation of molecules and deformation of embedded ion channels with alteration of their activation kinetics and flow of ions (Bertini et al. 2017);
- Modification of ion distribution along the membrane and within the intra- and extra-cellular space in general (Escobar et al. 2020);
- Controlling the opening and closing of voltage-gated ion channels (Bertagna et al. 2021);
- Changing rate of ion and ligand binding and alterations in channel activation kinetics (Kim et al. 2016);
- Electromagnetic induction at targeted brain regions (Sun et al. 2022).
In turn, this action of electromagnetic fields plays a role in regulating:
Microglia-Astrocyte Crosstalk
The main molecular targets for ELF-EMF application on cells of the innate immune system, namely the astroytes and microglia, are extracellular ATP, intracellular Ca2+, and hypoxia inducible factor 1α (HIF1α).
Elevated extracellular adenosine triphosphate (ATP) released by dying or necrotic neurons may be considered as a damage signal that induces inflammatory cytokine release from surrounding cells of the innate immune system (Isakovic et al. 2019). Although released by both astrocytes and neurons, the most significant source of ATP in pathological conditions are astrocytes. Its subsequent uptake takes place through G-protein-coupled adenosine receptors (AR) which are expressed in both astrocytes and microglia (Shinozaki et al. 2017). Whilst A1 and A3 ARs inhibit the activity of adenyl cyclase resulting in decreased cAMP accumulation, A2A and A2B ARs cause an upsurge in cAMP accumulation (Isakovic et al. 2019). In addition to occurring through AR receptors, microglial recognition of ATP also occurs through P2X purinoreceptors 7 (P2RX7), a subgroup of PRRs involved in extracellular ATP-mediated apoptotic cell death and inflammation (Fredholm et al. 2011).
Studies evaluating the role of EMF in mediating extracellular ATP and intracellular Ca2+ signaling in astrocytes and microglia have investigated application of ELF-MF or ELF-EMFs (Golfert et al. 2001, Yang et al. 2010). Furthermore, there have also been attempts to computationally model the influence of fields generated by an electroencephalogram (EEG) on calcium transients. One of such studies has shown that EEG waves can induce an increased frequency and occurrence of Ca2+ momentum waves in Purkinje cells (Ingber et al. 2014). Within the CNS, the calcium momentum waves are a form of Ca2+ signal propagation between neighboring glial cells.
Whilst ELF-MFs increase the cytoplasmic Ca2+ concentration in astrocytes (Golfert et al. 2001), ELF-EMFs appear to possess the ability to impact the rate of calcium influx, therefore changing the total cellular level of Ca2+. The increase of intracellular Ca2+ concentration is usually a consequence of astrocytic induction of diffusion of IP3 through gap junctions and extracellular ATP signaling”, that activates microglial cells within the surrounding area and changes both astrocyte morphology and function (Isakovic et al. 2019).
Hypoxia-inducible factor 1-α (HIF1α) is a subunit of the HIF-1 transcription factor. Within the CNS, HIF1α is expressed mainly by glial cells. Its overexpression in microglia under ischemic conditions leads to induction of A1 reactive astrocytes, recruitment of peripheral T cells and tissue damage.
Numerous studies have demonstrated that application of EMF cases a decreased release of IL-1β, TNF, IL-6, IL-8 and human monocytechemoattractant protein-1 (MCP-1/CCL2) (Rosado et al. 2018, Vincenzi et al. 2017). All these cytokines act as HIF1α inhibitors. Subsequently, the cytokine downregulation decreases neuroinflammation and neuronal death (Rosado et al.2018). Out of those, the most prominent results were obtained in a study investigating the influence of PEMF on microglia (Vincenzi et al. 2017), showing that PEMF has the ability to inhibit HIF1α activation. This inhibition of HIF1α activation, in turn, impairs the microglial induction of A1 reactive phenotype in astrocytes, resulting in a decreased pro-inflammatory response and enabling the initiation of neurorestoration (Vincenzi et al. 2017).
Electromagnetic Field Action Summary
Figure 1. An example of the influence of extremely low frequency electromagnetic fields on the microglia-astrocyte crosstalk and their role in tissue regeneration (© EMHANCE)
Through the downregulation of HIF1α, ATP release, and intracellular Ca2+ concentration, external electromagnetic fields instigate a reduction in the expression of pro-inflammatory factors within microglia. This, in turn, fosters their potential shift towards the M2 phenotype, leading to the initiation of A2 reactive astrocytosis and subsequent neurorestoration (Fig. 1). The emergent A2 phenotype serves a dual role, contributing to the formation of glial scars and concurrently enhancing the suppression of the immune response. This cascade of events triggers a consequential transformation in microglia,transitioning from the M1 to the M2 phenotype through the intricate microglia-astrocyte crosstalk. The net result is a marked attenuation of the immune response, effectively mirroring the advantageous outcomes observed in various comprehensive research studies upon the application of ELF-EMFs (Cichon et al. 2017, Arneja et al. 2016).
Action Potential Propagation
Action potentials are the electrical signals that neurons use to communicate with each other. These signals are crucial for the transmission of information within the nervous system and are fundamental to various brain functions, including sensory perception, motor control, and cognitive processes. The propagation of action potentials relies on the coordinated opening and closing of ion channels in the neuronal cell membrane, leading to changes in membrane potential and the generation of electrical impulses.
Electromagnetic field therapy introduces external electromagnetic fields to the brain tissue, which can interact with neuronal activity and modulate action potential propagation. The effects of EMFs on action potential propagation are complex and can vary based on several factors, including the frequency, intensity, and duration of the electromagnetic fields applied.
In general, by influencing ion channels, neuronal excitability, network synchronization, neurotransmitter release, and neurovascular coupling, EMFs modulate brain function and contribute to treatment of neurological disorders.
Electromagnetic Field Action Summary
Ion channel modulation – Electromagnetic fields could influence the opening and closing of ion channels in the neuronal cell membrane, affecting the flow of ions across the membrane and consequently altering action potential generation and propagation (Bertagna et al. 2021).
Neuronal excitability – EMFs might alter the excitability of neurons, making them more or less likely to fire action potentials in response to stimuli (Echchgadda et al. 2022).
Synchronization of neuronal networks – Electromagnetic fields could synchronize the activity of neuronal networks, leading to more coordinated and efficient propagation of action potentials.
Neurotransmitter release – EMFs may impact the release of neurotransmitters,which are crucial for transmitting signals between neurons. This could influence the strength and efficiency of synaptic communication and, in turn, affect action potential propagation (Afrasiabi et al. 2014).
Neurovascular coupling – Electromagnetic fields might influence the coupling between neuronal activity and cerebral blood flow, which could indirectly affect action potential propagation by altering the supply of oxygen and nutrients to active brain regions (Arendash et al. 2012).
Neural Stem Cell Differentiation
Neural stem cells (NSCs) are self-renewing and undifferentiated cells that can give rise to neurons, astrocytes, and oligodendrocytes — the building blocks of the nervous system. As such, they hold immense potential for regenerative medicine and the treatment of neurological disorders due to their ability to differentiate into various neural cell types. Their regenerative potential makes them a valuable target for therapeutic applications in neurodegenerative diseases, spinal cord injuries, and brain trauma. Recent research has explored innovative approaches to control NSC differentiation, and one promising avenue involves the use of external electromagnetic fields (EMFs) (Cui et al.2017).
Electromagnetic fields can impact NSC differentiation through multiple mechanisms. Firstly, they can influence intracellular calcium levels, a key regulator of NSC differentiation (Ma et al.2023). As a result, this calcium influx can activate calcium-dependent signaling pathways that direct cells towards specific lineages. Additionally, EMFs might induce epigenetic changes,altering gene expression profiles and influencing NSC fate determination (Maet al. 2016, Capelli et al. 2017). On top of this, EMFs have also been shown to upregulate the Cav-1 channel activity (Lisi et al. 2006, Piacentini et al. 2007, Ma et al. 2013), β-III-tubulin, MAP2 (D’Ascenzo et al. 2006), and the brain-derived neurotrophic factor (BDNF) (DiLoreto et al. 2009). With that, ELF-EMF stimulation significantly supports adult hippocampal neurogenesis (Cuccurazzuet al. 2010, Sakhaie et al. 2017). By exerting modulatory effects on key molecular factors, such as BDNF and its downstream cascades, ELF-EMF not only bolsters the survival and integration of nascent neurons but also augments synaptic plasticity and network connectivity. This orchestrated symphony of cellular events precipitated by ELF-EMF stimulation substantively contributes to the maintenance of cognitive acuity and potentially counteracts the detrimental effects of neurodegenerative processes.
Electromagnetic Field Action Summary
Any ability to manipulate NSC differentiation through application of external electromagnetic fields opens new avenues for regenerative medicine. Herewith, EMF-based approaches could be harnessed to generate specific neural cell types for transplantation, enhance endogenous repair mechanisms, or modulate neural circuits to treat neurological disorders.
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