A Review on Non-Invasive Nanoparticle Interfaces for Brain Stimulation

Aahaan Maini
26 min readJun 25, 2021

Outline of Paper

  1. Abstract
  2. Introduction
  3. Understanding How to Trigger an Action Potential
  4. The Relationship Between Calcium and Action Potentials
  5. The Issues with Deep Brain Stimulation
  6. Principles of Neural Stimulation through Nanoparticles
  7. Quantum-Dot Optogenetic Stimulation
  8. Magneto-Thermal Stimulation
  9. Magneto-Electric Stimulation
  10. Upconverting Nanoparticle Optogenetic Stimulation
  11. Infrared Photo-Thermal Nanorod Stimulation
  12. Magneto-Mechanical Stimulation
  13. Note on Carbon Nanotube Microelectrode Stimulation
  14. Obstacles
  15. Best Method — Personal Opinion
  16. Conclusion

1. Abstract

This review paper conclusively outlines the different approaches for minimally invasive deep brain stimulation through nanoparticles. The common principle involves an external primary stimulus (magnetic field, light or ultrasound) interacting with a specific nanoparticle to generate a localized secondary stimulus (heat, ) to invoke an action potential that continues for the entire neural circuit. Magneto-Electric, Quantum Dot Light, Magneto-Thermal, Ultrasound-Piezoelectric, Optogenetic, Photo-Thermal, Mechano-Magnetic and Carbon Nanotube are the approaches covered, each one comprising of an explanation of each step of the process, a detailed explanation of the nanoparticle-neuron interaction as well as the results of an experiment using that specific approach.

2. Introduction

For decades, the approach to treating neural diseases and disorders has been by stimulating neural circuits in the brain through electrical impulses. That is essentially what deep brain stimulation is.

More specifically though, the affected neurons for these diseases are often located far into the brain, somewhere in the mass of 100 billion neurons. To stimulate these, doctors turned to the only method they knew how: invasive surgery.

All in all, after hundreds of tests and iterations, deep brain stimulation is the process of inserting electrodes into remote parts of the brain, connected by wires or rods, through an open-brain surgery. The electrical signals are generated by a small device called a neurostimulator, which is implanted under the skin of the upper chest.

3. Understanding How to Trigger an Action Potential

Understand that the action potential is not just the peak (at +40 mV), but rather the entire process that follows once the threshold is hit.

Step 5: A neuron has a resting potential (voltage) of -70 millivolts, the interior of the neuron is negatively charged (-70 mV) relative to the outside.

At rest, there are more sodium ions (Na+) outside the cell than inside, and there are more potassium ions (K+) inside the cell than outside. Therefore, when the ion channels open, they move following the natural process of diffusion.

Step 1: Once a local stimulus is activated, it alters the transmembrane potential (the difference between the inside and outside of the cell). If the transmembrane potential reaches -55 or less, the voltage-gated ion channels are opened.

Note: the failed intentions are caused if the stimulus is not strong enough, and the transmembrane potential doesn't reach the threshold.

Step 2: Depolarization is when the transmembrane potential becomes more positive, all the way from -70 to +40 mV. This is caused by the transfer of specifically Na+ ions into the cell.

Note: this includes the 15 mV increase (-70 to -55) that is required to meet the threshold, which is caused by the stimulus, not the transfer of Na+ ions.

Step 3: Repolarization is the inverse of depolarization, or when the transmembrane potential becomes more negative. This in turn is driven by the closing of the Na+ channels, and the opening of the K+ channels, which let K+ ions out of the cell.

Step 4: The K+ channels stay open a little longer than required, which causes a slight dip below the resting potential. However, the sodium-potassium pump (formally known as the Na+/K+-ATPase) transfers both ions until the balance is restored, and the resting potential returns to its default.

4. The Relationship Between Calcium and Action Potentials

Future methods will often discuss the influx of calcium and sodium ions to trigger the action potentials. Calcium isn’t actually responsible for generating the action potential, but rather passing it on to other neurons. Sodium is responsible for depolarization while calcium is responsible for neurotransmitter release.

A quick overview of how the process works:

Step 1. The action potential travels down the length of the neuron and reaches the axon terminals.

Step 2. Calcium influx is triggered through separate voltage-gated calcium ion channels

Step 3. Calcium interacts with synapsin, a protein that transports the synaptic vesicles with neurotransmitters inside, to the edge of the cell

Step 4. A series of proteins bind the synaptic vesicles to the cell membrane only if synaptotagmin (protein) detects enough calcium in the cell are high enough

Step 5. The vesicles release the neurotransmitters and are reused, and the process begins again.

Sodium is needed to trigger the action potential and calcium is needed to stimulate more than one neuron.

5. The Issues with Deep Brain Stimulation

It sucks.

It doesn’t take a neuroscientist to know that current deep brain stimulation is inefficient and most importantly, poses dozens of unnecessary health and safety risks for the patient.

Let’s start with the procedure for setting the entire thing up. The most obvious drawback is invasive surgery. Avoiding surgery is something that should always be done due to the risks of human error, especially in an organ as sensitive as the brain. Other surgery risks include:

  • The misplacement of the electrode or issues with the physical electrode (ex. rusted or jagged wire)
  • Infection
  • Brain bleeding and/or brain swelling
  • Stroke or heart problems
  • Accumulation of fluids in the brain
  • Seizures
  • Breathing problems
  • Headache (after surgery)
  • Confusion and difficulty concentrating (after surgery)
  • Long-term biocompatibility of the electrodes
  • Surgery-induced trauma

Non-invasive approaches have been tried in the past but faced challenges of poor spatial resolution, higher power consumption and most importantly the possibility of damage to tissues in between.

6. Principles of Neural Stimulation with Nanoparticles

The ultimate goal is to restore lost function in the brain caused by damaged or disordered neural circuits.

The first step in the process requires wirelessly transmitting the primary stimulus through the brain (at low frequency) onto the specific nanoparticles. Using its unique properties, the nanoparticle converts the broad primary stimulus into a local secondary stimulus. The local stimulus interacts with the specifically targeted neurons, and thus, activates the stimulation.

There are 4 main types of primary (external) stimulus Magnetic, thermal, ultrasound, optogenetic (light) that have been approved safe for in vivo applications. Electrical stimulation technically qualifies as an external stimulus, however that requires surgical implantation, which defeats the purpose of transforming deep brain stimulation. This applies even if nanomaterials are used in conjunction with the electrical stimulus, read more in 12.

As is shown in the image above, the primary stimulus is almost always converted to an electric field or heat, as the secondary (local) stimulus that interacts with the neurons.

Controlling the conversion between the stimuli is dependant on the experiment conducted and the nanoparticle used. Certain experiments require specific properties which can only be achieved with designated nanoparticles. For example, in 4. Magneto-Electric Stimulation magnetic nanoparticles are required to interact with the primary magnetic field stimulus.

The primary benefit of nanoparticles is their potential for targeted drug delivery. They can be very simply injected into the bloodstream, pre-conjugated to target the specific cell. Not to mention the obvious benefit of their size, allowing them to directly interact with neuron membranes and protein/ion channels. Their size also makes them biocompatible (in most cases) overcoming a very important issue.


7. Quantum Dot Optogenetic Stimulation

Light stimulation hasn’t had much of a spotlight when it comes to neurons, however, it is promising because it is non-invasive and its flexibility of targeting various locations —one of the main barriers that traditional deep brain stimulation is stuck behind.

There have been several different approaches of light stimulation tested in the past, each having at least one significant drawback.

  1. Triggering photoactivatable probes by exposure to UV light. Issue: limited temporal resolution and poor selectivity.
  2. Introduce natural light-sensitive channels from single-cell algae, into neurons. Issue: requires genetic editing of the neurons.
  3. Light induces local electric fields to stimulate cell membranes. Issue: not possible in vivo because it requires a conductive substrate.

Quantum dots can be used to eliminate all the above issues through their unique optoelectrical properties and ability to selectively attach to biological channels.

All you need to know about quantum dots (QDs) is that they are semiconducting nanoparticles that absorb light and release it as a different colour. They can range from 2–10nm and the colour varies with their size.

This approach proposes a new method of using CdSe Quantum Dots to stimulate neurons through light excitation of ion channels.

Remember in the previous approach how the neuron was stimulated through disturbance of the transmembrane potential, the same principle applies here.

The electric dipole moment created when the external light shines on the QD creates a local electric field (a secondary stimulus). This field near the cell membrane disturbs the electrochemical potential, causing the voltage-gated ion channels to activate and begin diffusion.

The stimulation of the entire cell will occur if the QD disturbance can activate enough ion channels.

Using QDs propose several benefits over other approaches:

  • Near-instant activation or deactivation by switching the external light or on off
  • Control of Spatio-temporal resolution through selective binding to specific particles
  • Benefits in sensitivity, stability, and biocompatibility
  • Target specific cells

One overlooked aspect is the QDs' ability to bind to very specific cells in a fashion similar to targeted drug delivery. Altering the surface chemistry, specifically by customizing the binding proteins.

How the Stimulation Works

As you know, for the action potential to be triggered the transmembrane potential must increase to -55 mV. The local electric field induces a voltage change in the neuron.

The voltage of the local electric field (that induces the depolarization) depends on the proximity of the QD to the cell membrane.

Experiment and Results

The approach taken to illuminate the QDs and record the changes in the cell’s voltage was the patch-clamp technique. Specifically, for interaction with cortical neurons, CdTe QD films and CdTe QD probes were employed.

The experiment was conducted on cortical neurons on newborn mice, about 30,000 QD films per well in 12-well plates. Just to clarify this was in vitro, not in vivo.

Both the films and probes have an emission peak at 640nm and an absorption below 630nm wavelengths.

Once the neurons were cultured on the QD films, the QDs were bound together because of the Van der Waals force (attraction of neutral molecules).

Excitation of the QD films with 550nm wavelength light successfully caused the cell membrane to depolarize, crossing the threshold and invoking several action potentials, or in other words “stimulating” the neuron. (Fig. a)

The variability of this approach was staggering. In certain tests, the neuron didn’t invoke any response and in other tests, almost all of the neurons were successfully stimulated. The presumed cause behind the variability was the proximity of the neurons to the QD substrate and how healthy the cells were, since through testing it was revealed that the neuron health would be compromised through this method of stimulation.

To eliminate the need to culture the neurons with the QD films, QD probes were used — glass instruments with 5–10 micrometre tips coated with QDs. The stimulation could be carried out in the neurons’ natural environment, beneficial for the long-term goal of applying this in vivo.

Figure a shows the disturbance of the current on the neuron when the illuminated QDs interact with the cell membrane and alter its transmembrane potential.

One thing to note is that using the QD probes removed the variability and the cells were often able to respond to the QD stimulation for up to 5 minutes.

Quantum-Dot Light stimulation has successfully been proven in vitro to achieve action potentials through depolarization, which is primarily through interaction with the K+ and Na+ channels.


8. Magneto-Thermal Stimulation

Employing magnetic fields as the primary stimulus is a promising approach because of their ability to not harm (or even interact with) tissue in the brain and their strength is not affected by the depth, allowing for deep penetration.

Similar to Magneto-Electric Stimulation, the magnetic field must be converted into a secondary stimulus to interact with the neurons, through the use of superparamagnetic nanoparticles. Specifically 12nm Manganese ferrite nanoparticles (MFNPs).

The MFNPs are heated by a radio frequency magnetic field targeted to neurons with the TRPV1 ion channels since they are activated by heat and pain. The local temperature increase by the MFNPs activates the TRPV1 channel, opening it and causing an influx of sodium and calcium ions into the neuron, thus depolarizing it (refer back to Understanding how to trigger an action potential). TRPV channels transport sodium, calcium and capsaicin.

Drawn to scale diagram of coated (orange) superparamagnetic nanoparticles (grey) in a magnetic field (B~) and heat (red) activated opening of the TRPV1 channel (labelled).

How the Stimulation Works

20 mg/ml is the aqueous dispersion of the MFNPs and the strength of the magnetic field is 40 MHz, complying with the FDA regulations for RF fields and heating the nanoparticle at an initial rate of 0.62 degrees per second. To trigger an action potential, theoretically, it should only take 8 seconds because the out-of-cell temperature required to cross the depolarization threshold is 42 degrees Celcius. This is very close to the average body temperature of 37 degrees, allowing for rapid TRPV1 opening and closing. One thing to note is that the generated heat is limited to the cell membrane and does not continue into the cytoplasm.

A significant challenge for effective neuron stimulation in vivo is achieving a high density of MFNPs (needed for the regional heating on the cell membrane). Magneto-thermal stimulation exploiting the advantage of nanoparticles and targets the MFNPs to desired neurons resulting in effective and less-nanoparticle-consuming stimulation.

Experiment and Results

All the experiments were carried out in vitro with precultured HEK 293 cells (kidney cells). The tests proved that it would be applicable for neurons in vivo.

Within the first 15 seconds of turning on the magnetic field, the calcium concentration inside the cell increased 160x. The influx was activated by the TRVP1 channels, since cells without nanoparticles but with TRVP1 channels, and cells with nanoparticles but without TRVP1 channels exhibited no calcium influx when under the same magnetic field.

The above experiment proved that the 40 Mhz magnetic field-induced heating of the MFNPs can activate the opening of the TRVP1 channels in seconds, which then induces a sodium and calcium influx sufficient to trigger an action potential. All of this without causing any damage to the targeted cells or surrounding tissue.

The data displays similar conclusions, initially registering small increases in transmembrane potential followed by the precursor depolarization to the action potential.

This technique was also adapted and successfully tested in vivo to trigger behavioural responses in worms.


9. Magneto-Electric Stimulation

Magneto-electric nanoparticles are a specific type that can be influenced and controlled by an external magnetic field. They have caught the eye of researchers due to their ability to couple a magnetic or electric field at room temperature.

This approach involves using magneto-electric, or ME, nanoparticles in the brain of an unhealthy patient to stimulate the neurons to fire at the level of a healthy one.

An externally generated very low-intensity external magnetic is sent into the brain, which then induces electric charge oscillations in the nanoparticles, which can interact with the neurons and stimulate the neural pathway.

The field interacts with the ME nanoparticles, inside the brain, which causes it to repeatedly move back and forth (oscillating), which then causes the neurons to fire.

ME nanoparticles are first injected into the body in an aqueous solution, and then the targeted drug delivery into the brain takes over. The nanoparticles must be below 20 nanometers to passively diffuse over the Blood-Brain Barrier.

How the Stimulation Works

The low-intensity field generates AC signals at the same frequency of healthy neural charge activity. When the nanoparticle oscillates, it causes all the neurons around it to fire at the same frequency, stimulating them non-invasively.

Localized electric fields produced converted by the ME nanoparticles stimulate an individual neuron, which then uses neurotransmitters to stimulate other neurons and so on until the entire targeted circuit is activated.

The field disturbs the neuron’s transmembrane potential, the difference in electric potential between the inside and outside of a cell, which activates the voltage-gated ion channels.

Experiment and Results

The principle is to regulate the electric pulses to compensate for any malfunctions caused by illnesses or lapses in the electric signals, by applying AC magnetic current at matching frequencies to the nanoparticles.

The key is that the frequency of the magnetic field had to be matching frequency as that of a healthy person to regulate the electric signals.

After the nanoparticles were injected, the procedure was applied in these four regions of the brain:

  • Thalmic Area
  • Subthalamic Nucleus
  • Globus Pallidus
  • Medial Globus Pallidus

The technique was applied to a patient with Parkinson’s Disease to compare the effects versus traditional deep brain stimulation.

Below are the electric signals in the four regions of a healthy person.

Below are the electric signals of a patient diagnosed with Parkinson’s Disease. The main lapse in signals occurs in the Thalmic region with minor errors in the other three regions.

Below are the electric signals of the same patient with Parkinson’s Disease, after receiving the non-invasive ME nanoparticle treatment.

We can see that the major fix was in the regulation of the signals in the thalamic region, with minor fixes in the other regions.

Just for comparison, below are the electric signals of a patient with Parkinson’s Disease after traditional deep brain stimulation treatment. I know, crazy!


10. Upconverting Nanoparticle Optogenetic Stimulation

Optical stimulation is another popular option however existing methods employ visible wavelengths of light, which are absorbed and scattered by brain tissue, significantly decreasing spatial resolution and maximum simulation depth.

Instead, in this approach micro-lightbulbs are injected and remain in the brain through its micromotions. The micro-lightbulbs are made of lanthanide-doped upconverting nanoparticles (UCNPs) encapsulated in a biocompatible Parylene C polymer.

UCNPs absorb near-infrared light (NIR) as the primary stimulus and emit visible light locally to stimulate neurons. Conversion to lower wavelengths is required because the proteins responsible for stimulation respond primarily to visible light.

NIR as the primary stimulus mitigates both issues of optical stimulation by making use of the decreasing cross-section of tissue and the optical windows (certain wavelengths where tissue absorption is at its minimum). The UCNPs are evidently able to be imaged through thick slices of the brain.

Photon Upconversion is the process of emitting light at lower wavelengths than what was absorbed. UCNPs upconvert from NIR light to visible light.

To understand how photon upconversion works, click the link below. The example used is our specific used case as well.

How the Stimulation Works

The micro-lightbulbs would be dispersed in artificial cerebrospinal fluid and injected into the brain tissue. This makes this approach minimally invasive, not completely non-invasive, however, all the issues with traditional deep brain stimulation are still mitigated due to the lightbulbs’ nanometre size. Additionally, possibilities of cell targeting mechanisms may be explored in the future.

Channelrhodopsins are exclusively light-gated ion channels. Channelrhodopsin-2 (ChR-2) is activated at 480 nm wavelengths of visible light. Therefore, the UCNPs are built to upconvert and emit visible light at wavelengths of 450–500nm.

However, ChR-2 requires at least 1 mW/mm² to invoke an action potential, which needs a high concentration of UCNPs at the target neurons as well as an enhancement to the emission light flux. This can be achieved by turning the micro-lightbulb into a microresonator that resonates at the emission wavelength. A microresonator is a structure that traps light through reflective surfaces. A high Q factor microresonator can enhance the emission to surpass the intensity needed for activation.

Another approach could be to increase the intensity of the near-infrared light stimulus, but that would damage layers of brain tissue it passes through.

Once these channels are activated, they allow the movement of Na+ and K+ ions, the default method of depolarization.

There are a variety of factors that determine the efficiency of this approach: the propagation loss of the primary stimulus, the coupling efficiency of light to the micro-lightbulbs, the conversion efficiency by the UCNPs, the concentration of UCNPs as well as any enhancement mechanisms applied.

Experiment and Results

To test the efficacy of this approach, in vitro experiments were conducted on thick brain slices from adult mice. UCNP micropillars were placed on top of the brain tissue for measurement, as an alternative to the internal UCNPs that would be injected for in vivo applications.

NaYF₄ UCNPs composed of 40% Yb³+, 20% Gd³+, and 2% Tm³+ were employed as they produced the brightest emissions following the photon upconversion. The UCNPs are 24nm long and encapsulated in 4nm NaYF₄ shells to prevent quenching (a decrease in fluorescence) and to increase their emissions up to UCNPs 5 times their size.

The NIR light was applied at wavelengths of 980nm and the upconversion by the external micropillars resulted in the second stimulus of 800nm. The reasons for the change being so minimal are the modified conditions, especially the concentration of the UCNP pillars and the major fact that they were external.

However, this is still promising as it shows that photon upconversion by UCNPs is possible through thick brain tissue from NIR light applied externally.


11. Infrared Photo-Thermal Nanorod Stimulation

The infrared neural stimulation approach is unique, it relies on the absorption of infrared light by gold nanorods, which then convert it into heat or an electrical stimulus to stimulate the neurons.

Gold nanomaterials as a whole are more efficient than magnetic nanoparticles generating heat meaning they require fewer materials to enter the body, which is always a positive. Out of all the gold nanomaterials, the ones used in this approach, gold nanorods (Au NRs) are the most applicable for LSPR with infrared light (explained below) and can be optically tuned to a high degree of specificity. They have become increasingly popular for biomedical applications, particularly in conjunction with light due to their unique optical properties.

Au NRs do not require any genetic changes or physical interaction with the cells to activate the stimulation. Their surface chemistry can be altered to increase biocompatibility and to target specific neurons, commonly carried out through a polymer and/or silica coating.

A: Visualization of gold nanorods under a TEM microscope. B: Visualisation of gold nanorods with silica coatings under a TEM microscope.

Infrared neural stimulation is much more applicable than traditional due to more accurate spatial resolution, no electrical communication between the nanoparticle and the neuron (minimizing risk) and of course, it is completely wireless. The most significant benefit is the absence of modification to the target neuron, which will be explained in more depth in Expert Opinion on the Best Method.

Before understanding the stimulation, an understanding of the interaction between gold nanorods and infrared light is required. When near-infrared light is applied, the electrons in the nanorod becoming disturbed and oscillate away from their equilibrium.

The oscillating electric field causes coherent oscillations of all the electrons, known as localized surface plasmon resonance (LSPR). LSPR is exclusively generated when light interacts with nanoparticles smaller than their wavelength. Keep in mind that the LSPR is at a specific frequency and wavelength, which is dependant on the shape, size, etc. of the nanoparticle.

How the Stimulation Works

When the infrared light interacts with the gold nanorods, if the light wavelength matches the LSPR wavelength, the absorption process begins. Free electrons are excited and collide with one another, converting it to heat and sending it to the crystal lattice. From there it is dissipated into the environment outside the cell.

The heating from the LSPRs of the Au NRs can now invoke either one or both of the following stimulation techniques, depending on the cell and various specifications.

In technique A, the heating changes the cell membrane capacitance (same principle as electrical capacitance) which can open voltage-gated ion channels, generating an influx of ions and depolarizing the neuron.

In technique B, this is similar to 6. Magneto-Thermal Nanoparticle Stimulation because it uses the LSPR heating to activate the temperature-sensitive TRPV ion channels, which then let in sodium and calcium ions, and so on. Remember that TRPV channels transport sodium, calcium and capsaicin.

Experiment and Results

The first out of two experiments is an in vitro application of infrared laser-illumination of gold nanorods to stimulate spiral ganglion neurons from postnatal rats.

Infrared laser interacted with the Au NRs, invoking photothermal stimulation which caused inwards transmembrane currents, which were proportional to the laser pulse length. If the pulse length was longer than 25 microseconds, action potentials in the neurons are successfully triggered.

Data displaying action potentials fired in response to this stimulation.

The change in local temperature was in the range of 0.5 to 6° C, once again in accordance with the 37 to 42° C threshold in 6. Magneto-Thermal Nanoparticle Stimulation. The specific change was in conjunction with the laser pulse lengths.

Average temperature increase in relation to pulse length of the lasers.

A fun fact is that the above experiment was repeated using gold nanospheres but resulted in much weaker electrical activity of the neurons.

The second experiment is an in vivo application employing 80nm Au NRs and 980nm infrared laster wavelength. The Au NRs are bound to the cell membrane of a rat nerve, onto which lasers between 0.32 and 2.3 Joules per cm squared were applied.

Historical data states that thermal damage does not occur for levels lower than 1 Joule per cm squared, and although the previous value is above this range, the actual energy that gets transmitted is significantly lower (due to the intensity of the infrared diode) and the power is almost exclusively absorbed by the Au NRs.


12. Magneto-Mechanical Nanoparticle Stimulation

Mechanical interactions with neurons are very uncommon but follow the same principles as each of the other methods, and when paired with magnetic can be very effective.

This approach works by using magnetic nanoparticles (MNPs) to mediate magnetic forces being converted into the mechanical opening of N-type mechano-sensitive calcium channels.

Overall the approach is mediocre, with a suitable spatial-temporal resolution, deep tissue penetration, controllable stimulation and of course binding to specific cells. This mediocrity can also be viewed as a benefit as the entire process is fairly straightforward, eliminating unnecessary complications and issues.

The secondary mechanical stimulus is different than the previous approaches because the MNP does not convert the magnetic forces (primary stimulus) into mechanical (secondary stimulus), but rather the nanoparticle itself becomes the secondary stimulus and exerts the mechanical force.

Mechanical force is exerted through the magnetostrictive property of the MNPs, allowing them to change shape and/or size when they are being magnetized.

How the Stimulation Works

The first step is performed by the binding of the MNPs to the cell membrane, remaining localized. The specificity of the binding can be improved by coating the MNP with antibodies targeting the N-type calcium channels, although this may hamper the performance of said channels.

Once the MNPs are localized on the cell membrane and the magnetic field is applied, through the process of magnetization of the nanoparticles, their magnetostrictive property allows them to change their physical form/

These changes in shape and/or size, regardless of what they are specifically, stretch the cell membrane. Mechano-sensitive channels are activated by the increase in membrane tension and allow calcium ions into the cell.

Experiment and Results

A series of experiments were performed on human neurons cultured in vitro to understand which ion channels specifically were being activated by the stretching of the cell membrane.

The inhibiting of the N-type mechano-sensitive channels resulted in the complete termination of stimulatory effects.

Testing the magnetic stimulation at different temperatures resulted in no significant difference, concluding that temperature-sensitive TRP ion channels (which are a major part of mechano-sensitive channels) are not being activated.

Another possibility is the activation of the PIEZO2 channels, but even if this were true, their transport of calcium ions would be insignificant in total.

It was proven that even though other mechano-sensitive channels (TRPV4, PIEZO1 and NMDA) might have been activated through the stretching, the N-type calcium channels are the largest and are responsible for the majority of the calcium ion influx.

Although physical stimulation was not tested, the proof of ion influx can be inferred as successful stimulation by the process described in How to Trigger an Action Potential.


13. Note on Carbon Nanotube Microelectrode Stimulation

Carbon Nanotubes show promising approaches for improving deep brain stimulation however, they are slight improvements that still fall victim to the overhanging problem with traditional deep brain stimulation.

Carbon Nanotube fibre microelectrodes can be used in place of large, metal electrodes. They have a dramatically lower tissue impedance and can be used without any additional surface instruments. They have been tested and can stimulate neurons in a 10 times larger area with equal effectiveness and their nanometre size causes a significantly smaller immune response.

In vivo testing in rodents with Parkinson’s disease has proven all of the above benefits successful.

However, the two major pitfalls with deep brain stimulation are still prevalent: the need for invasive surgery as well as an invasive rod transmitting electrical signals in the brain. While all the improvements cannot be discounted, it is still an electrode, which still needs to be invasively placed in remote parts of the brain and connected with a metal wire.

This is the same reason why this section is shorter and only gives a brief overview of the topic. While this approach does significantly improve traditional deep brain stimulation and it might be a required middle step before the transition is made to the stage of non-invasive stimulation, the impact isn't at the same calibre as the other methods.


14. Obstacles

The burning question — which approach is the best? A better question is which approach is the best at maximizing output while minimizing procedures and health issues. Also, this is the section where I get to drop my two cents and predictions for which method will win out.

The most effective approach is the balance between the primary and secondary stimuli. Primary stimuli need to be able to pass through several layers of the brain without causing damage, have the capabilities for high spatial-temporal resolution and be safe for long-term exposure. Secondary stimuli are selected based on their conjunction with the ion channels of the targeted neurons.

Regardless of the specific approach, several issues need to be addressed before non-invasive nanoparticle stimulation is widely adopted. Biocompatibility, stability during interactions, tissue accumulation, body clearance and long-term effects are the major issues. The lack of information about neurotoxicity and the interactions between nanoparticles and the brain poses the most significant challenges for widespread adoption. Nanoparticles have vastly different physical and chemical properties than their average-sized counterparts of the same material.

Optogenetics (primary stimulus) is challenging because the light waves weaken the more tissue they pass through, almost becoming ineffective for stimulation at remote parts of the brain. Scientists have observed random behavioural changes in rats and fish following optogenetic stimulation.

Thermal interaction with neurons (secondary stimulus) can damage neurons long-term, especially with the very high temperature of 42 degrees Celcius interacting directly with the neurons. To put it in perspective, a fever is qualified as severe if the body temperature is 38 degrees or higher.

While using quantum dots, the stimulation was unable to invoke a standard response, making it extremely unreliable.

As noted by the scientists carrying out experiments involving this, long-term biocompatibility for specifically gold nanorods is an important issue.


15. Best Method — Personal Opinion

Chart evaluating each aspect of the different approaches of nanoparticle neural stimulation

After my research, I have concluded that Magneto-Electric Stimulation is the most effective. Specifically employing magnetic nanoparticles. I believe this approach will be the first

#1: Effectiveness for Targeted Drug Delivery. Magnetic nanoparticles, such as Iron-oxide nanoparticles, have already been heavily tested for targeted drug delivery into the brain. They can be manufactured under 20nm to passively diffuse over the blood-brain barrier and they can be navigated using an external magnetic field. To understand more about using magnetic nanoparticles for targeted drug delivery, check out this paper by

#2: Range of Applicable Neurons. As you know, magneto-electric stimulation works by generating a local electric field and activating the voltage-gated ion channels. Unlike several other approaches, these voltage-gated channels are prevalent on all neurons, allowing for stimulation of a much wider range of neurons and therefore treatment of dozens of more diseases.

#3: No Damage to Tissue. Traditional deep brain stimulation that has been used for several decades, been successful thousands of times and it works by using a local electric field. The electric field doesn’t cause any damage to the targeted neurons or surrounding tissue. Therefore, magneto-electric stimulation employs the same approach as a local electric field, causing no damage. Evidently, this has proven true, not just theoretical.

#4: Proven Results. Magneto-electric stimulation is by far the furthest along towards adoption, due to past in vivo testing in humans. Guduru et al. (2012) is a perfect example, in which their testing in humans proved successful.

#5: Efficacy. While reliability and efficiency is a major issue in other approaches, it doesn’t apply to magneto-electric stimulation due to the high coupling efficiency of magnetic nanoparticles and the use of electric stimulation. Guduru et al. (2012) have once again proven this, where their experiment using magneto-electric stimulation proved more effective than traditional deep brain stimulation (explained in more detail in Magneto-Electric Nanoparticle Stimulation).


16. Conclusion

For so long we have accepted that the best way to stimulate neural circuits in the brain is through physically sending electrical signals into the brain. However, the discovery and advancement of nanoparticles have enabled a revolution.

These nanoparticles enable high-precision, high-throughput wireless medical procedures.

Currently, the only approach remotely similar to using this technology elsewhere is targeted drug delivery using nanoparticles that are controlled ), which are controlled externally.

Future moonshot ideas could leverage this concept for defibrillators or pacemakers, possibly even brain-computer interfaces. Dare I even say, nanobots?

The bottom line is that the work done with using nanoparticles is proof that we can use nanoparticles inside the body to connect and communicate with devices in the external environment. It may just be in the form of magnetic fields and electric signals right now, but it lays the foundation for future breakthroughs.



Aahaan Maini

16-year-old ML dev currently building Circulate to tackle the blood shortage in India