The Neuromodulation Revolution
Stimulating the brain — it’s an old idea that’s time has come (again)
Do you recall the phrase “everything that’s old is new again?” It feels particularly accurate for neuroscience these days. If you’ve read our blog series on psychedelics, you know we’re in the midst of re-discovering the healing powers of some very old medicines for mental health. The same thing is happening with the science of neuromodulation. Neuromodulation is “the alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation or chemical agents, to specific neurological sites in the body.” For this post, I will mainly focus on the application of non-invasive stimulation directly to the brain, but non-invasive stimulation to the peripheral nervous system is equally fascinating and a great follow-on topic. These exciting developments are allowing us to modulate the state of the brain, for both short and long term benefits.
A Historical Perspective
The ancients knew something about neuromodulation, the early Romans and Egyptians who had access to electric fish (a fascinating neuroscience subject all on its own) and used the creatures to treat headaches and pain. These fish are pretty strong electrical sources, generating between 8–200 volts! According to historical records, the earliest recorded use of these treatments was from CE 46 detailing the work of a healer and court physician Scribonius Largus. His work for the emperor Claudius described several uses for the torpedo fish, but mainly focused on pain relief throughout the body, including headaches and gout. Imagine putting one of these on your head when you’ve got a migraine!
These practices continued into the 1700’s and then things got really exciting with the work of Galvani and Volta convincingly demonstrating the electrical properties of nerves, and then later the brain. Understanding the signalling mechanisms of the nervous system lead to great advancements and opened the way for both scientific findings and novel treatments. While the 1800’s saw a proliferation of electrical medicine quackery, (including the invention of the vibrator for those so inclined!), it also ushered in a period of experimentation surrounding the nervous system that still bears fruit today. I’ll get to the advancements, however if you are not from the neuroscience community then all of this discussion about brain stimulation might bring up some disturbing scenes of electroconvulsive (electroshock) therapy (ECT) from the 1970’s. First used in the 1930’s, ECT, while sensationalized in the media, is actually an accepted, effective treatment for major depressive disorder (MDD), mania and catatonia. At the time (and here we see a similar story to psychedelics) the physicians who used it didn’t know why it worked, they just knew that it DID work on their most refractory patients. ECT seemed to serve as a reset for the brain, which is truly an electrical organ in it’s own right. The stimulating pulses used in ECT cause a temporary seizure in the brain. Through that mechanism, the stimulation appears to modulate both neurochemistry and potential neurotrophic effects in the brain causing long term relief from MDD and other difficult mental health conditions. While it’s not the most elegant solution, and has since been completely redesigned by modern science, it still works. However, we now have even more precise and elegant solutions that are bringing new energy to this field
We’ve come a long way baby!
It’s electric….
I’m not covering implantable stimulators in this blog, but there has also been an emergence of novel and life-changing treatments using these techniques in both the spinal cord and central nervous system. Tremors, pain, incontinence can all be modulated by the right “dose” of electrical stimulation, giving patients unable to be treated by a drug relief after much suffering. More on these in a later blog!
For now, I will focus on the non-invasive stimulation methods, meaning that the apparatus remains entirely outside of the body and typically sits on or near the head to cause its effects.
Like our old friend the electric fish, a more controlled but substantially lower dose electrical stimulation to the brain can have a host of benefits. I first encountered this type of neuromodulation during my Accelerated Learning program at DARPA, when researchers at the University of New Mexico proposed using transcranial direct current stimulation (tDCS) as a method of priming the brain for faster learning and detecting stimuli. The most amazing thing was, it worked! And that seminal work has ushered in a wave of experimentation regarding both tDCS and its close cousin transcranial alternating current stimulation (tACS). Transcranial electrical stimulation (tES), the general term for the tech, does not penetrate deeply into the cortical surface of the brain and it is hypothesized that the current spread is shallow and diffuse. Back in the “early days”, the device was really two sponges with saline solution hooked up to a nine volt battery (I’m not kidding), but now it has evolved into much more sophisticated form factors. Researchers are beginning to combine tES with electroencephalography (EEG) to better understand how the brain is responding to this stimulation. Additionally a host of companies are now offering this technology for commercial purchase (way too many to list here) — primarily for personal performance improvement, but in some cases more aligned with medical treatments. While the jury is still out on whether or not it’s something that you should do on your own from home(!), there is certainly no shortage of ongoing research and work in this area. Even the US Air Force is pushing this research forward and expanding the learning and training applications started so many years ago. A few years after the Accelerated Learning program, DARPA launched the RAM Replay program which was specifically looking at closed loop non-invasive stimulation for memory enhancement. I’m planning a later blog on sleep, so I won’t steal my own thunder — but the researchers found some incredible memory enhancements from stimulating the brain during sleep — both with transcranial electrical stimulation and with something as simple auditory stimulation during the appropriate phase of sleep. Other groups have gone on to show similar results as well. Now that’s accelerated learning!
And magnetic…
The last two technologies I want to touch on have made incredible strides in the last few decades and I will address them in sequence. Transcranial magnetic stimulation (TMS) has been around for many decades. If you remember anything about high school physics, you will remember that where there’s electricity moving around, there’s also magnetism — the good old “right hand rule.” So not only does the brain generate magnetic fields (and this is what magnetoencephalography (MEG) measures) its firing can be augmented via electromagnetic induction caused by the TMS pulses. The strength of the magnetic fields generated in TMS are on the order of 0.5–1 Telsa, although researchers have worked with stronger fields. Accurate use of the device — which looks kind of like a big figure 8 shaped paddle — requires the precise placement of the coil over the region of the brain being targeted. This is often accomplished through the patient undergoing a structural MRI to ensure that their unique brain structure is being taken into account. One of the most interesting things about TMS, sometimes also referred to as rTMS when the stimulation is a repetitive pulse, is that the signalling in the brain can be either enhanced or turned down by the magnetic pulses. The work of Dr. Mark George at the Medical University of South Carolina has been fundamental in proving out this technology, both in the lab and the clinic. TMS is now both a useful diagnostic/research tool and FDA approved as a treatment for depression. While TMS can also be quite shallow in terms of its penetration in the brain, deep TMS can be used at up to depths of 6 cm in the brain. Not deep enough for a structure at the center of the brain, but certainly deeper than tES. This is an exciting tool in the neuromodulation arsenal, and now with FDA approval for treatment of depression these research tools are leaving the lab and entering the clinic.
And sound too!
I have saved the most exciting concept (to me) for last. Ultrasound has been used in medical imaging for decades, coming into use first in the 1940’s and then into popular clinical use in the 1960’s. The principal behind the imaging capabilities of ultrasound is that these undetectable-by-human-ear sound pulses (on the order of 1 to 18 MHz) are sent into the body through transducers. The density of different tissues in the path of the sound waves reflects back to the sensor, an echo, that can be processed into an “image” of the soft tissue beneath. The common pregnancy ultrasound is a perfect example of this — and is a treasured item for many a first-time parent. However, some clever neuroscientists and physicists teamed up to see if ultrasound, instead of imaging, could be used to stimulate the brain at greater depths than all of the previous technologies discussed. The technology is sometimes referred to as transcranial focused ultrasound (tFUS). This is really ground-breaking and important, since many deeper brain structures are vital to brain function, but are typically outside of the reach of any non-invasive stimulation tools. While the transducer and receiver are a bit different than those used to check your carotid artery, the physics is extremely well understood and advancements are being made very rapidly. This work absolutely requires precise alignment of the stimulation with a structural MRI, and the technology isn’t quite super portable yet . . . but it’s getting there! My friend and colleague Dr. Jamie Tyler has been at the forefront of this technology, and I’m always excited to connect with him and hear about the latest developments and where the field is heading. This technology portends exciting implications for mental health, sleep, and a whole host of NEW methods of altering states in the brain never before possible. Some of the most thrilling work I’ve seen is from my colleague Dr. Jay Sanguinetti, who is working on not ONLY mood, but mindfulness and consciousness. The idea that these tools could be used not just for medical purposes, but even much deeper — even spiritual applications is inspiring. I encourage you to check out their work as I can’t capture all of the details here.
I hope you’ve enjoyed this brief glimpse into the ongoing neuromodulation revolution. It’s an amazing time in scientific history to be able to work with the brain and its states in these increasingly precise and non-invasive ways. I believe we are on the cusp of not only being able to understand the functioning of the brain in new ways, but to engage with our own brain states in non-pharmacological ways. I’m truly excited about what’s next and can’t wait to see the entrepreneurial prime movers who create new technologies and solutions in this emerging domain.
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