Nanotech. Neurotech. They both start with Ns and end with tech, but there aren’t many commonalities between them than that. But when these 2 niches merge, what comes out is nothing but mind-blowing. Here’s the story of magnetogenetics, and how it’s set to change the whole concept of neurodegenerative treatments in the next few years.
But first, for the people who live under rocks, let’s cover what both these fields encompass.
Wikipedia: “Neurotechnology is any technology that has a fundamental influence on how people understand the brain and various aspects of consciousness, thought, and higher-order activities in the brain.”
If that sounded like a whole lot of jargon, don’t worry, it’s just Wikipedia. I like to think of neurotech as the field that birthed from your brain asking for more attention to itself, and might I say, it definitely has gotten a ton of people hooked on to it now. Neurotech, at least from my experiences, primarily involves biology and engineering. You got people on one hand of the spectrum mapping the brain by slicing into thin sheets, and digitally reconstructing them using AI. On the other hand, you have people making insane stimulation devices, supposedly increasing working memory by 30%. Neurotech is HUGE.
Wikipedia: Nanotechnology, also shortened to nanotech, is the use of matter on an atomic, molecular, and supramolecular scale for industrial purposes.
Breaking down whatever Wikipedia said, Nanotech just involves any technology set on a nanoscale, which is 1-billionth of a meter. To put it into perspective, your hair is 80,000–100,000 nanometers wide, in diameter. So yeah, nano is really small, and when we go that small, a ton of weird things happen. Materials have new properties, some materials get super strength when on a nanoscale, while some get superconductivity. These properties are what makes this field so attractive, and why it can change neurotech as a whole.
Invasive can be scary, I agree
If you’ve heard of the term brain-computer interface, the first image that may come to mind is a chip getting drilled into your mind, like in the matrix. Turns out, some of the technology in the field really is like that. For neurological diseases and disorders, like Dementia, Dystonia, and epilepsy, implanted neurostimulation devices, like Vagus Nerve Stimulation, Responsive Neurostimulation, and Deep Brain Stimulation, are gaining more adoption from people with refractory(drug-resistant) conditions.
In general, we aren’t super sure how any of the stimulation methods work at a functional level, but we do understand they can be used to modulate certain neurostimulators as well as correct neural oscillations, by the low voltage electrical pulses outputted. Think of these as pacemakers for your brain.
Though the intuition may be up in the air, we know that these devices really do work. If we consider refractory epilepsy, VNS and RNS have yielded amazing results, 75% decrease over ten years and 60% decrease after 3–6 years in seizures respectively. To put this into perspective, some patients can have seizures hundreds of times a month, and a decrease of that proportion can significantly improve a person's quality of life.
DBS perhaps is the most versatile, being able to treat a wide array of neurodegenerative diseases and disorders, from Parkinson’s to major depression. Looking at DBS as a treatment for Parkinson’s(PD) specifically, research has shown a 41% improvement in motor function and an 80% decrease in drug-induced dyskinesia. When the only medication for PD(Levodopa), has serious “wearing-off” side effects, DBS can add a depth of safety for PD patients.
Though we can’t overlook the efficacy of these stimulation therapies, they come with strings attached. For one, they require pretty invasive surgeries, and two, they are hella expensive. Though I praised DBS in the last paragraph, it can actually be the most problematic out of all the other methods; there’s tons of room for error when you’re trying to insert a 1.3 mm in diameter metal rod into your brain.
DBS surgeries usually require reaching the subcortex, which is deeper in your brain; this increases the opportunity for infection and intercerebral hemorrhaging. Outside of physical implications, there can also be psychological repercussions as well. Post-op, patients can experience depression, impulse control disorders, and hypomania, though these a generally short-term. RNS and VNS have less severe side effects, due to less invasive surgeries, but they aren’t free of all(infection is still common).
So, after reviewing these techniques, we can safely say that there is always a tradeoff with the current effective stimulation therapies; put yourself vulnerable to procedural morbidity short term, for long term comfort. What if it didn’t have to be like that? What if we just eliminated the whole surgery aspect out of the mix? This where magnetogenetics comes in.
Magnetics and genetics???
Wikipedia: Magnetogenetics refers to a biological technique that involves the use of magnetic fields to remotely control cell activity.
Eh, Wikipedia didn’t do too bad with this definition. In our case though, magnetogenetics involves the modulation of neuronal cells using magnetic fields.
“So, Anush, you're telling me that if I put a magnet next to my head I can control my neurons?”
Technically, yes. Transcranial Magnetic Stimulation is the device we’re looking for in this case. TMS is used as a treatment and recreational therapeutic for the patient and average consumer. It usually involves an electromagnetic coil emitting low-frequency waves that SOMEHOW manipulate the neuronal oscillations in your brain.
This seems like our golden solution, right? Nope! TMS is actually flawed in the sense that we can't actually modulate exact and specific neural pathways if we wanted to. For example, DBS in Parkinson's is generally used to stimulate the sub-thalamic nucleus(STN), which is involved in moderating and validating motor movements. If we tried to use TMS, the EM field generated would fail to penetrate the initial, within the safe amplitudes mandated. Even if the EM radiation did reach the STN using higher power levels, the focal area would be too great to have any substantial effects. The problem with TMS is precision.
Considering that TMS is one of the most precise non-invasive stimulation therapies on the market, it seems like our dream of one-upping on DBS is a lost cause. Thank you for reading this article and- haha you thought. You forgot about the NANO.
Ultrasmall Superparamagnetic Nanoparticles- What the heck?
TMS methods fail to reach depths greater than 3cm with significant energy, but that doesn’t mean there is no presence of the EM field at all within the deeper brain structures. What if we were able to use whatever is left of the EM field to create a local electrical charge, something similar to what a rectifier does in an electrical circuit?
That’s exactly what we can do using ultrasmall superparamagnetic nanoparticles(USPION).
Sadly, there’s no Wikipedia definition for this one so I’ll dissect it myself.
- Ultrasmall: this is in a literal context, these particles are under 20 nanometres, size is a big factor in why these are the most effective
- Superparamagnetic: Essentially any material that is able to magnetize under the presence of an EM field, and can return back to its net-zero magnetization once the EM field has been removed
- Iron Oxide: nanoparticles consist of maghemite (γ-Fe2O3) and/or magnetite (Fe3O4) particles
- Nanoparticles: General term to mean ultrafine particle between the range of 1–100nm in diameter.
The superparamagnetic part is THE property of the USPION that makes it so useful; we can basically induce electrical currents through these nanoparticles at targeted locations, frequencies, and powers. USPIONs provide literally nano-level tuning for magnetogenetics therapies.
But firstly, how would we get these nanoparticles to the parts of the brain we want them to be in in the first place?
We can first suspend these nanoparticles in a solution and inject them intravenously. Since USPIONs are just a special type of magnetic nanoparticle, we can use magnetic fields generated outside of the body to steer the nanoparticles into the general brain region. These nanoparticles are engineered to be under 20 nm to allow for superparamagnetism, the size also allows for the particles to passively pass through the blood-brain barrier.
Once these particles reside in the brain, we can rely on targeting ligands on the surface of the nanoparticle to chemically bind to specific neurons. Targeting ligands are basically just molecules that are engineered to bind to certain receptors, in the case of neurons, these molecules would bind to the ion channels of the target neuron.
Converting magnetic to electric to fire neurons
Now the fun part, actually stimulating your neurons! We can use the same coils used in TMS to produce stimulating electromagnetic waves. These external EM waves are capable of generating strong electric charge oscillations inside of the USPION.
This oscillation generates an electric field, an alternating current(AC), local to the target neuron. According to Faraday’s law, the change in magnetic flux through a loop induces a current. Think of an induction motor, the rotor is able to spin because the magnetic field is constantly rotating, generating a current in its closed conductor.
A similar phenomenon occurs in the nanoparticle since the TMS coil is just copper wiring looped together with a pulsed current flowing through it. The magnetic flux(vectors of the magnetic field) is constantly changing as the current flows through the coil.
Now, the AC fields induced in the USPION alter the transmembrane potential, or the charge on the surface of the neuron, causing the voltage-gated ion channels of neurons to open or close.
Simply put, these voltage-gated ion channels control the excitability of neurons by restricting the flow of cations into the cell. These specific ion channels change states when there is an electric charge present on the surface of the cell membrane, called the membrane potential.
Once these ion channels open, positively charged ions flood cell, creating a voltage difference between the outside and inside of the cell, forming the action potential. The change from a net negative charge inside of a neuron cell to a net positive charge is what causes a neuron to fire, the action potential.
If the USPION are able to create electric charges, you can see how we can use these nanoparticles to manipulate the ion channels of specific neurons. The frequency of this AC field will be the same as the frequency of the external EM field, therefore we can induce very specific rates of neuron firing.
The biggest difference between the EM waves generated during TMS therapy, and the EM waves required for USPION-based therapy is that the magnetoelectric nanoparticles require much lower energy to generate the local electrical field. This is also how we ensure that we are only stimulating the parts of the brain with the USPIONs. Since brain tissue requires much higher energy magnetic fields to produce electrical charges, we now that only the specific neurons coupled to a USPION are being modulated by the EM field.
“The nanoparticles can be considered as finely controlled deep brain local stimulation switches that can enable high-precision (with nanoscale localization) and high-throughput (energy-efficient) non-invasive medical procedures.”
This is a HUGE upgrade from conventional TMS, where we could only stimulate brain areas no smaller than the diameter of a dime. We are now able to get 10 million times more precise with our therapies, ANYWHERE in the brain. In any depths, in any crevices we want.
Is this the invasive stimulation killer?
If we relate USPION-based therapy back to parkinsons, epilepsy, and alzheimers, we can now treat all of these from outside the body. Where these disorders would have previously required highly invasive procedures, we can now treat them externally.
Let’s consider a potential epileptic patient who would be taking an USPION based therapy path:
- First, they would be administered the USPIO nanoparticles, which would be dispersed throughout the brain
- Post-seizure, physicians can diagnose the exact type of epilepsy and where in the brain using magnetic particle imaging or magnetic resonance imaging, USPIONs are great contrast agents
- Patients could be provided a personal TMS device that they would use in the case that they notice signs of a seizure
- In the case of a seizure, patients would administer TMS using their device, which would have preset parameters for frequency and amplitude of the EM wave based on their diagnosis
This is only a hypothetical use-case, but there are many real world studies being conducted using USPIONs.
Yue et al., 2012 simulated the brain activity of a Parkinson’s patient and the usage of magnetic nanoparticles to correct the abnormal firing of neurons in the STN, and a few other brain regions that attribute to Parkinson’s tremors. They found that the nanoparticle-based therapy outperformed DBS, both in recovering normal periodicity of neuronal activity(frequency at which neurons fire), and amplitude of the activity(voltage). Though this isn’t hard proof that USPIONs are better than DBS, this shows promising results for future applications.
Another interesting and recent study leveraging USPION was Lu et al., 2020, where scientists treated depressive-like symptoms using nanoparticles in the prelimbic cortex in mice. They saw significant improvements in depressive-behaviour after 5 days, 2x5 minutes of 10hz TMS with the nanoparticles each day. This in-vivo study is a major stepping stone for future studies using USPION-assisted TMS, which will probably be the biggest application of these nanoparticles.
Why isn’t being used in humans right now?
Though USPIONs may seem like a godsend for the magnetogenetics field, there’re a few drawbacks to the tech that's preventing them from being used in humans right now.
- The rapid oscillation and electrical charge in the USPION can cause overheating, which wouldn’t be very pleasant to brain tissue
- Biocompatibility: oscillation could potentially form free radicals, which are harmful to cells and tissue
- We still don’t understand the effects of chronic exposure to these particles, more studies are needed
- Synthesiszing USPIONs is still unscalable
- There has yet to be a practical method to record neural activity using the USPIONs(Magnetic particle imaging is promising, but portability is a problem)
- USPIONs a metabolized after a few weeks, we need to identify a way for these nanoparticles to persist for a much longer time
My final thoughts
Globally, there are over 50 million people with Alzheimers globally, another 50 million have epilepsy globally , and then another 10 million people globally suffer from Parkinsons. With these 3 neurological disorders alone, people affected total more than the population of the Phillippines.
As I’ve discussed above, these patients have therapies and procedures available to them, but most of them are expensive or unsafe. Imagine being in a position where you have to decide between a life of pain or potentially dying because of a surgery.
Magnetogentics provides a new pathway for millions of people suffering from neurological diseases, and suffering the pain of deciding between life and risking death from surgery. Non-invasive therapeutics is the future, and will continue to be the future for years to come. Magnetogenetics is the next step in the safer treatment of neurological diseases, it’s only a matter of time before we see a world free of these diseases.
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