Neurons rely on electrochemical processes to communicate, a fundamental mechanism that underpins everything from basic reflexes to complex cognitive functions. These processes are driven by the movement of ions across neuronal membranes, which is tightly regulated by ion channels (Gamper and Ooi, 2015). The flow of ions in response to various stimuli generates action potentials and synaptic signals, facilitating communication between neurons and other cells (Pastor and Attali, 2024; Spekker et al., 2023). Modulating ion channel activity provides a powerful means of influencing neuronal behavior, offering potential therapeutic avenues for a wide range of neurological and psychiatric disorders (Alipour et al., 2023; Chen et al., 2001). A deeper understanding of these principles is essential for exploring how MFs and other neuromodulation techniques can influence brain function, paving the way for innovative treatments and interventions.

Ca^{2 +} ions serve as vital second messengers, regulating key cellular processes such as neurotransmitter release and gene expression (Mitra et al., 2024). However, maintaining calcium homeostasis is essential, as its dysregulation can result in cellular toxicity and neuronal damage (Pikor et al., 2024). Pharmacological agents that target ion channels have been extensively employed to treat a range of medical conditions. For example, calcium channel blockers are particularly notable, they inhibit Ca^{2 +} influx, thereby reducing vascular smooth muscle contraction and cardiac muscle activity (Suzuki et al., 2024). This mechanism makes them highly effective in managing cardiovascular disorders, including hypertension, angina, and arrhythmias, as they lower blood pressure and improve blood flow by preventing excessive calcium-induced constriction of arterial walls (Arfat et al., 2023; Faucon et al., 2023). Additionally, during ischemic events, such as strokes, uncontrolled Ca^{2 +} influx exacerbates neuronal injury and cell death. To counteract these detrimental effects, cells rely on precise regulatory mechanisms to maintain balanced Ca^{2 +} levels, ensuring proper cellular function while minimizing the risk of toxicity (Nava et al., 2020; Ochoa et al., 2021; Qu et al., 2022; Singh et al., 2019).

Furthermore, potassium channel play a critical role in stabilizing neuronal membrane potentials, making them essential for proper cellular function. Blocking these channels can lead to membrane depolarization, increasing neuronal excitability and influencing physiological processes such as vascular smooth muscle contraction and neurotransmitter release (Jackson, 2017). Conversely, activating potassium channels hyperpolarizes neurons, reducing their likelihood of firing. This delicate balance highlights their importance as key regulators of neuronal activity and potential them as promising therapeutic targets for conditions such as depression and epilepsy (Sibille et al., 2015; Sun and Kapur, 2012).

Beyond the nervous system, potassium channels serve diverse roles in other tissues. In the heart, they contribute to the regulation of cardiac rhythm by stabilizing the membrane potential of cardiomyocytes (Grandi et al., 2017). In the brain, they modulate neuronal excitability and synaptic transmission, particularly in regions such as the hippocampus and cortex, which are crucial for memory and learning (Zhang J. et al., 2024). Additionally, in pancreatic β-cells, potassium channels respond to fluctuations in intracellular ATP levels, playing a pivotal role in regulating insulin secretion (Gil-Rivera et al., 2021). These varied functions indicate their importance in maintaining physiological homeostasis and their potential as targets for treating a wide range of disorders.

The gating process of channels is tightly regulated, ensuring that ion flow occurs only under precise conditions, which is essential for maintaining neuronal excitability and proper nervous system function (Alipour et al., 2023).

Ion channels can be categorized based on their gating mechanisms:

Neurons exhibit the remarkable capability to detect and respond to both external and internal stimuli. Signal transmission initiates with the generation of an electrochemical impulse, which propagates rapidly along the axons. Upon reaching the axon terminal, the electrochemical signal triggers the release of neurotransmitters into the synaptic cleft, facilitating communication with adjacent neurons or target cells (Gamper and Ooi, 2015; Yang et al., 2022).

Synapses can be broadly classified into two types:

The membrane potential of a neuron refers to the electrochemical potential difference across its membrane, which is crucial for neuronal excitability and signal transmission. At rest, the neuron maintains a stable baseline known as the resting membrane potential, typically around −70 mV. This potential is primarily sustained by the Na⁺/K⁺ pump, an active transport mechanism that expels Na⁺ from the cell and imports K⁺, creating an electrochemical gradient essential for neuronal function (Garg et al., 2022; Yoo et al., 2023).

The resting membrane potential can be quantitatively described using the Goldman-Hodgkin-Katz (GHK) equation (Equation 1) (Shirai et al., 2017; Sun, 2019), which accounts for the permeability of the membrane to different ions and their respective intracellular and extracellular concentrations.

Where:

Once the membrane potential is determined, the current flowing across the neuronal membrane can be calculated using Ohm’s law (Equation 2). This equation relates the membrane current (I_m) to the membrane conductance (g_m) and the difference between the membrane potential (V_m) and the equilibrium potential (E_m):

This relationship is fundamental for understanding the dynamics of ion flow across the membrane, which directly influences neuronal signaling. The rate of ion flow, governed by the activity of ion channels, determines changes in membrane potential and, consequently, the initiation and propagation of action potentials. These processes are essential for neuronal communication, as they enable the transmission of electrochemical signals along neural networks.

The interaction of electric, magnetic, and EMFs with biological cells and tissues has been extensively studied. Despite notable progress, the precise mechanisms by which MFs influence living organisms remain incompletely understood, highlighting the need for further research. MFs can interact directly with moving charges, such as ions and proteins, as well as with magnetic materials within tissues, through various physical mechanisms (Hou et al., 2010).

Viewing living cells as electrochemical systems with charged components provides a useful framework for understanding how static MFs and EMFs can influence cellular functions. According to the “window effect” theory, the biological effects of MFs are typically observed within specific frequency or intensity ranges, suggesting that cells respond to physical stimuli in a manner analogous to their response to chemical signals such as hormones (Alipour et al., 2022a; Hajipour Verdom et al., 2018; Latypova et al., 2024; Wu et al., 2022). This theory implies that MFs can act as cellular messengers, eliciting physiological responses such as changes in cell survival, proliferation, apoptosis, differentiation, gene expression, protein synthesis, enzymatic activity, and ion homeostasis (Alipour et al., 2022a; Barati et al., 2021; Hajipour et al., 2017; Hajipour Verdom et al., 2018; Kashani et al., 2023; Krylov and Osipova, 2023; Ouyang, 2019; Wasak et al., 2019). Additionally, MFs have been explored for therapeutic applications, including pain relief and the treatment of certain medical conditions (Paolucci et al., 2020).

The biological effects of MFs depend on several factors, including the type of MF, its strength, frequency, pattern, and duration of exposure, and the specific properties of the target tissue (Hajipour Verdom et al., 2018). MFs interact with metals, ions, and charged or magnetic particles in tissues, potentially increasing the concentration, activity, and lifespan of reactive species such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) (Alipour et al., 2022a; Hajipour Verdom et al., 2018; Schuermann and Mevissen, 2021). For example, paramagnetic metals can participate in ROS production through Fenton or Haber-Weiss reactions, which, at elevated levels, may cause oxidative damage to proteins, nucleic acids, and lipids, leading to cell death (Hajipour Verdom et al., 2018; Shabanpour et al., 2024). However, ROS also play essential roles as signaling molecules, regulating metabolic pathways and the activity of transcription factors such as AP-1 and Nrf-2 (Alipour et al., 2022a; Priya Dharshini et al., 2020).

Moreover, direct interactions between MFs and biological tissues can be described using Maxwell’s equations, though different tissue components exhibit varying responses to MFs (Chi et al., 2020). In the case of ELF-EMFs, the photon energy is insufficient to directly break chemical bonds or damage DNA molecules. For example, at frequencies of 50–60 Hz, the photon energy is approximately 10–12 times smaller than the energy required to break the weakest chemical bonds (Panagopoulos et al., 2021). However, MFs can exert a Lorentz force on moving charged particles, potentially influencing electrochemical currents within cells, particularly in neurons (Yachi et al., 2022). Low-frequency EMFs may induce cellular resonance effects (Tian et al., 2023), while high-frequency MFs can enhance localized energy absorption, modulating neuronal excitability (Moliadze et al., 2010). This dual mechanism indecates the potential of combining photon energy and MF application for targeted neuromodulation.

MFs have demonstrated the capacity to modulate brain activity at both tissue and organ levels, offering promising therapeutic potential for neurological disorders. These effects span multiple scales, from molecular and cellular changes within individual neurons to broader, network-level alterations that influence entire brain regions (Premi et al., 2018).

At the tissue level, MFs can modulate the collective activity of neuronal populations. Techniques such as TMS have shown the ability to non-invasively induce electrochemical currents in specific brain regions, either enhancing or suppressing neural activity depending on the frequency and intensity of the magnetic pulses (Maniglia et al., 2019). For example, repetitive TMS (rTMS) has been shown to induce long-lasting changes in cortical excitability, a phenomenon linked to synaptic plasticity. High-frequency rTMS was applied to the motor cortex has improved motor function in stroke patients by facilitating synaptic connections within motor pathways (de Freitas Zanona et al., 2023; Ni et al., 2023). Conversely, low-frequency rTMS has been used to suppress hyperactive brain regions, such as in patients with tinnitus or depression, where it reduces symptoms by downregulating overactive cortical areas (Adu et al., 2022). These effects are attributed to the ability of MFs to influence the excitability of neuronal circuits, thereby altering information flow within the brain (Asao et al., 2022). By targeting specific regions, MF-based therapies can modulate the balance of excitatory and inhibitory signals, offering therapeutic benefits for a range of neurological and psychiatric disorders (Turner et al., 2014).

At the organ level, MFs can influence larger brain networks, which play a critical role in coordinating functions such as motor control, cognition, and emotion (Cameron et al., 2019). MFs have the potential to reset dysfunctional circuits or enhance communication between brain regions (Dufor et al., 2023), providing therapeutic benefits for conditions such as major depressive disorder (MDD). For instance, rTMS targeting the dorsolateral prefrontal cortex (DLPFC)-a key region in mood regulation-has been shown to enhance connectivity within mood-related networks, leading to sustained improvements in depressive symptoms (Lu et al., 2024; Vida et al., 2023).

Magnetothermal stimulation, which uses MNPs to generate localized heating, represents another innovative approach. This technique allows precise targeting of deep brain structures that are difficult to reach with conventional TMS (Fiocchi et al., 2022; Le et al., 2019). In animal models, magnetothermal stimulation of the hypothalamus has been shown to influence body temperature regulation and metabolic processes, demonstrating the potential of MFs to modulate organ-level functions beyond the brain itself (Jang et al., 2023).

The therapeutic potential of MFs at the tissue and organ levels has been explored in various neurological conditions:

The ability of MFs to modulate brain activity at the tissue and organ levels has significant therapeutic implications. As research continues to elucidate the underlying mechanisms, there is potential for developing more effective and targeted treatments. Combination of MF-based therapies with other modalities, such as pharmacotherapy or behavioral interventions, could further enhance outcomes. Advances in neuroimaging and computational modeling are expected to improve the precision of brain network targeting, leading to more personalized neuromodulation strategies.

MF-based neuromodulation techniques, particularly rTMS, have emerged as powerful tools for treating a range of neurological and psychiatric conditions. Supported by a growing body of research, these non-invasive methods modulate brain activity and have shown efficacy in managing disorders such as depression, schizophrenia, and multiple sclerosis (Alashwal et al., 2023).

rTMS uses rapidly changing MFs to induce electrochemical currents in specific brain regions, modulating neuronal activity through depolarization or hyperpolarization. Depending on the stimulation frequency, rTMS can either enhance or suppress neuronal excitability, making it a versatile tool for treating conditions such as depression, anxiety, and neuropathic pain (Lu et al., 2024).

rTMS involves applying repetitive magnetic pulses through a coil placed on the scalp, which induces electrochemical currents in underlying brain tissue (Tubbs and Vazquez, 2024). The effects of rTMS depend on the frequency, intensity, and duration of stimulation, as well as the specific brain region being exposed (Han et al., 2023). Coil designs, such as figure-of-eight or H-coils, are engineered to optimize MFs strength and focality, ensuring precise stimulation of the desired neural circuits (Deng et al., 2014). Additionally, different pulse types-such as monophasic, biphasic, and burst stimulation-enable frequency-dependent modulation of neuronal activity (Wendt et al., 2023). Stimulation protocols, including conventional rTMS and theta-burst stimulation (TBS), are customized to achieve specific therapeutic outcomes (Liu et al., 2024).

One of the most well-established and clinically validated applications of rTMS is in the treatment of MDD, particularly for patients who have not responded to conventional therapies such as antidepressant medications or psychotherapy (Lu et al., 2024). The non-invasive nature of rTMS, coupled with its relatively mild and transient side effects-such as scalp discomfort or mild headaches-makes it a compelling alternative for individuals with treatment-resistant depression (Lanza et al., 2023). Standard rTMS therapy for MDD typically involves daily sessions administered over a period of four to six weeks, with each session lasting approximately 30 to 40 min (Al-Ruhaili et al., 2023). This structured regimen has been shown to significantly improve depressive symptoms in many patients, offering hope for those who have struggled to find relief through other treatment modalities.

rTMS has also shown promise in treating bipolar disorder, particularly for depressive episodes. Preliminary studies suggest it could serve as an effective adjunctive therapy, though further research is needed to establish its efficacy (Nguyen et al., 2021). In schizophrenia, rTMS has been used to target the temporoparietal cortex, a region associated with auditory hallucinations. Low-frequency rTMS (1 Hz) applied to this area has reduced the frequency and severity of hallucinations in some patients (van Lutterveld et al., 2012). Additionally, rTMS targeting the prefrontal cortex has been explored for improving cognitive function and alleviating negative symptoms such as social withdrawal and apathy (Kos et al., 2024). While not yet a first-line treatment, rTMS is increasingly used as an adjunctive therapy for medication-resistant symptoms (Wagner et al., 2021; Xie et al., 2023).

rTMS has been investigated for alleviating symptoms of multiple sclerosis (MS), a neurodegenerative disorder characterized by motor dysfunction, fatigue, and cognitive impairment (Ahmadpanah et al., 2023). High-frequency rTMS targeting the motor cortex has shown potential in improving motor performance and reducing spasticity by enhancing cortical excitability and promoting neuroplasticity (Hassan et al., 2021). Studies have also explored its use for fatigue and cognitive symptoms, though results have been mixed (Gaede et al., 2017; Iglesias, 2020). Despite variability in outcomes, rTMS offers a non-invasive and well-tolerated option for managing certain MS symptoms, particularly in patients unresponsive to conventional therapies.

Beyond rTMS, other MF-based techniques are being explored for their therapeutic potential:

Unlike DBS, which is a highly targeted, tCS provides non-specific stimulation across cortical areas. This distinction highlights the need for advanced techniques such as magnetothermal stimulation, which combines the precision of targeted interventions with the non-invasive nature of methods such as tCS (Zhang E. et al., 2024).

While MF-based neuromodulation holds great promise, several challenges remain. Precise targeting of ion channels without affecting surrounding tissues requires further technological refinement. Additionally, the long-term effects of MF exposure on brain function and structure are not yet fully understood, necessitating comprehensive safety studies (Borrione et al., 2020; Singh et al., 2020).

Standard non-invasive techniques such as tDCS and TMS are limited in their ability to reach deep brain regions effectively (Luigjes et al., 2019). These methods typically influence on superficial cortical areas, making it challenging to modulate deeper neural circuits that are critical in conditions such as epilepsy, Parkinson’s disease, and treatment-resistant depression. Magnetothermal stimulation overcomes this challenge by using MFs and nanoparticles to enable precise and targeted neuromodulation deep within the brain (Yuan et al., 2022). This innovative approach not only expands the range of treatable neurological and psychiatric conditions but also holds the potential to enhance therapeutic outcomes significantly.

As research progresses, there is growing interest in personalized approaches to neuromodulation. By tailoring stimulation parameters to individual neurophysiological profiles, clinicians can optimize treatment efficacy and patient outcomes. Furthermore, combining MF-based therapies with complementary modalities, such as pharmacotherapy or behavioral interventions, may further enhance therapeutic results.

MNPs represent a cutting-edge approach in neuromodulation, offering a highly targeted method to influence neuronal ion channels and modulate brain activity. These nanoparticles can be introduced into the body and precisely directed to specific brain regions using external MFs (Latypova et al., 2024; Signorelli et al., 2022). The physical mechanisms of MNPs in neuromodulation can be broadly categorized into three hypotheses:

While these hypotheses provide a framework for understanding MNP-based neuromodulation, several challenges remain. For instance, the extent of localized heating and its specificity to target neurons need further investigation (Roet et al., 2019). Similarly, the magnitude of mechanical effects and their impact on neuronal membranes require quantification to establish thresholds for therapeutic efficacy (Romero et al., 2022). Moreover, advances in imaging and simulation techniques are essential to bridge these gaps and validate the proposed mechanisms in vivo (Ge et al., 2024). To overcome these challenges, researchers are exploring the use of high-resolution imaging modalities, such as MRI and optogenetic tools, to visualize MNP behavior in real-time. Additionally, computational models that simulate MNP-neuron interactions under various field conditions can provide insights into optimizing neuromodulation protocols (Alipour and Zali, 2022; Alipour et al., 2022b; Kamkar et al., 2022).

One of the most promising aspects of MNPs is their ability to achieve precise targeting of specific brain regions. By functionalizing the surface of MNPs with ligands, antibodies, or peptides, these particles can be engineered to selectively bind to specific neuronal populations or ion channels. This specificity allows for the modulation of distinct neural circuits, offering highly selective therapeutic interventions (Dominguez-Paredes et al., 2021; Liu et al., 2020).

For example, MNPs can be directed to regions such as the basal ganglia in Parkinson’s disease, where they modulate voltage-gated ion channels in affected neurons, potentially restoring normal function and alleviating symptoms (Xu et al., 2023). Delivery methods for MNPs include systemic administration (e.g., intravenous injection) or localized application (e.g., intracranial infusion), with external MFs guiding the nanoparticles to the desired site to enhance precision and minimize off-target effects (Ashoori et al., 2023; Kazemi-Ashtiyani et al., 2022; Satari et al., 2024).

The interaction of MNPs with ion channels is grounded in neurobiophysical principles. Localized heating alters ion permeability coefficients, as described by the Goldman-Hodgkin-Katz (GHK) equation (Equation 1), influencing membrane potential (Vm) and neuronal excitability. Changes in membrane conductance (gm) and equilibrium potential (Em) can be quantified using Ohm’s law, illustrating the direct impact of magnetothermal stimulation on neural activity (Alvarez and Latorre, 2017).

The thermal energy generated by MNPs can also influence the surrounding cellular environment, affecting membrane fluidity, enzyme activity, and metabolic processes. These indirect effects further modulate ion channel function and neuronal signaling, demonstrating the multifaceted nature of MNP-based neuromodulation (Evtushenko et al., 2023; Li et al., 2021; Montalbetti et al., 2021).

Preclinical studies have demonstrated the promising potential of MNPs for neuromodulation in animal models. For example, MNPs have been successfully used to modulate activity in the motor cortex of rodents, resulting in changes in motor behavior and electrophysiological responses (Hescham et al., 2021; Romero et al., 2022; Wu et al., 2021). Similarly, MNPs targeting circuits associated with pain have shown efficacy in alleviating chronic pain in mouse models, with minimal off-target effects (Wu et al., 2017).

A key advantage of MNPs is their capacity for repeated and adjustable interventions. The same population of nanoparticles can be activated multiple times through the reapplication of a MF, offering a flexible, reversible, and non-invasive approach to neuromodulation (Roet et al., 2019). However, the clinical translation of MNPs for magnetothermal stimulation in humans faces several safety challenges that must be addressed:

To overcome these challenges, future studies should focus on developing advanced imaging techniques, such as MRI, to track the real time biodistribution of MNPs (Ebrahimpour et al., 2022; Remmo et al., 2024). Computational modeling of MF interactions with biological tissues can also help optimize parameters to minimize risks (Singh et al., 2024). Collaboration between materials scientists, biophysicists, and clinicians will be essential to design and test biocompatible MNPs that meet regulatory standards for human use.

Furthermore, optimizing the size, composition, and surface chemistry of MNPs is essential for maximizing their efficacy while minimizing adverse effects (Dehghani et al., 2024; Shamsipur et al., 2024). Advance in nanotechnology and materials science are expected to drive the development of more sophisticated MNPs capable of precise and controlled modulation of ion channels. These innovations could pave the way for novel treatments for a range of neurological disorders, including chronic pain, epilepsy, and neurodegenerative diseases.

Magnetothermal stimulation uses the unique properties of MNPs to achieve precise and localized neuromodulation. This technique is based on the ability of MNPs to convert energy from an AMF into heat (Castillo-Torres and Páez-Maggio, 2022; Chen et al., 2015). The amount of heat generated depends on several factors, including the magnetic susceptibility of the nanoparticles, their size, the strength of the applied MF, and the frequency of the AMF (Kuppe et al., 2020; Ovejero et al., 2021). Typically, magnetothermal stimulation utilizes AMFs with field strengths ranging of 10–100 mT and frequencies between 100 kHz and 1 MHz (Kim et al., 2024; Kuckla et al., 2023). These parameters are carefully optimized to ensure efficient energy transfer to the MNPs while minimizing off-target heating and potential tissue damage. The MFs are generated using specialized devices such as Helmholtz coils or solenoids, which create uniform AMFs around the target region. For clinical applications, wearable or implantable MF generators are being developed to facilitate localized and patient-specific neuromodulation (Davidson et al., 2024; Oh et al., 2024; Sarica et al., 2021).

Generally, magnetothermal stimulation offers several advantages over established MFs-based neuromodulation methods:

The development of remote neuromodulation techniques, particularly those utilizing MFs, represents a transformative advancement in neuroscience. These methods combine precision, safety, and versatility, offering significant advantages for both research and clinical applications (Zhi et al., 2025). By enabling non-invasive modulation of neuronal activity, remote neuromodulation introduces a new paradigm in the treatment of neurological and psychiatric disorders.

One of the most compelling advantages of remote neuromodulation is its non-invasive nature. Techniques such as DBS require surgical implantation of electrodes, which carries risks such as infection, bleeding, and complications from anesthesia (Shoshiashvili et al., 2023). In contrast, MF-based methods, such as TMS and magnetothermal stimulation, modulate brain activity without penetrating the skull or brain tissue. This eliminates the need for surgery, reducing the risk of adverse effects and avoiding the recovery time associated with invasive procedures (Radyte et al., 2022). Indeed, remote neuromodulation offers a high degree of precision in targeting specific neuronal circuits. This precision is achieved by carefully calibrating MF parameters, such as strength, frequency, and focus, allowing for the modulation of neural pathways implicated in various (Park et al., 2020; Zhang et al., 2023).

The non-invasive nature of these techniques enhances the accessibility of neuromodulation to a broader range of patients, including those who are ineligible for surgery due to underlying health conditions. Furthermore, the ability to administer these treatments repeatedly without surgical intervention makes them ideal for managing chronic conditions that require ongoing therapy (Lv et al., 2023). This approach is especially beneficial for populations traditionally underserved by surgical interventions, such as pediatric patients, the elderly, and individuals with comorbidities that increase surgical risks (Ege et al., 2023). Additionally, the reversibility of remote neuromodulation allows treatments to be adjusted or discontinued without the long-term consequences associated with implanted devices, expanding therapeutic possibilities without the need for invasive procedures (Zanos, 2019).

The use of functionalized MNPs further enhances specificity, as they can be engineered to bind selectively to specific neuron types or ion channels, enabling highly targeted neuromodulation. This precision is particularly beneficial for treating conditions such as epilepsy, chronic pain, and depression, where dysregulation neural circuits plays a key role (Yu et al., 2021). Additionally, the ability to modify treatments based on patient response improves therapeutic outcomes and minimizes side effects. This flexibility supports the advancement of precision medicine, where treatments are customized to the unique characteristics of each patient.

As remote neuromodulation technologies continue to advance, their potential applications are poised to expand significantly. Innovations in imaging, computational modeling, and nanotechnology will further refine the precision and efficacy of these techniques. For example, integrating real-time neuroimaging with MF-based neuromodulation could allow for dynamic treatment adjustments, optimizing outcomes for patients with complex neurological conditions.