If you had peeked into Robert Reinhart’s lab at Boston University during their most recent project, you would have seen researchers gathered around a seated volunteer wearing an unusual head-mounted device; imagine a swimming cap bristling with an array of mazy wires. This strange setup has become key to the growing field of non-invasive brain stimulation (NIBS), a new frontier of neuroscience.
For many decades, brain researchers have jumped at the prospect of being able to peer deeper inside our nervous system. Now, we have imaging techniques to view brain activity in real-time, tools that can reveal the complex genetic architecture of the brain and even computing systems designed to simulate its inner workings. Despite all these incredible advances, our in-depth interrogation of the brain and the nerves it uses to power our bodies has not yet yielded effective therapies for most ailments of the nervous system.
NIBS promises favorable therapeutic outcomes without the need for dangerous surgery, a potential that has seen several players, from Reinhart’s academics to DIY-stimulation enthusiasts on the message boards of Reddit, try their hand at exploring this new frontier.
A hands-off procedure
NIBS techniques generally involve using an energy source – this could be electrical, magnetic or even sonic – to stimulate the brain, as Shrey Grover, a postdoc in the Reinhart lab, explains: “The objective of all of these technologies is basically to change brain activity without having to go inside the brain.”
Preparing for neuromodulation: Reinhart lab member, Breanna Bullard, demonstrating a step during the set-up, confirming the correct placement of electroencephalographic and neuromodulation electrodes on a volunteer and lab member, Eleni Kouvaras. Picture credit: Dr. Robert M. G. Reinhart
There are several different NIBS techniques. The Reinhart lab uses a method called transcranial alternating current stimulation (tACS), which uses electrical currents to alter the rhythms of brain activity inside our skulls. Whilst leveraging electrical devices to heal the brain is an established approach, older techniques, such as deep brain stimulation - a tried and tested therapy for the relief of some symptoms of Parkinson’s disease – usually involve brain surgery. In contrast, Grover’s volunteers are simply required to clean their head briefly and have a gel applied to their scalp, which makes it possible to establish a connection between electrodes mounted in those futuristic swimming caps and the currents of their brain.
The Reinhart team's research investigates the link between distinct brain activity patterns and repetitive behaviors shown by healthy volunteers that are performed to a pathological degree in obsessive compulsive disorder (OCD). With so many NIBS techniques available to researchers (see Box 1) choosing a method might seem complicated. But Grover explains the clear benefits of tACS to this application.
“When we attach electrodes onto the scalp and we measure those electrical brain activity patterns, we find that there are certain rhythmic patterns of activity that tend to repeat themselves after a set time interval. A lot of work over the past few decades has informed us that these frequencies are important for our day-to-day functioning; they contribute to how the brain processes information and then decides what to do with that information. We use tACS to entrain brain activity patterns,” says Grover. The team hoped that by modifying these patterns, they could alter linked repetitive behaviors. This is exactly what they found. Their most recent study showed that patients entrained with NIBS over a five-day period experienced a 28% reduction in OCD-like behaviors.
Their work in OCD is just one of many strands of NIBS research. Researchers around the globe are using techniques like tACS, transcranial magnetic stimulation (TMS) and transcranial focused ultrasound (FUS) to tackle disorders such as depression, addiction and even neurological conditions like stroke.
BOX 1: What are the different types of non-invasive brain stimulation?
Transcranial electrical stimulation – an umbrella term for technologies that alter or excite brain activity without breaking the skin or putting devices inside the body. They typically use electric currents passed through electrodes placed on the skin to achieve this.
Transcranial direct current stimulation (tDCS) – delivers a constant, weak electrical current to the scalp.
Transcranial pulsed current stimulation (tPCS) – a current is applied in short bursts over fixed intervals.
Transcranial alternating current stimulation (tACS) – delivers an oscillating electrical current using a fixed amplitude and frequency. This aims to mimic the natural oscillations of the brain.
Transcranial random noise stimulation (tRNS) – delivers an alternating current, like tACS, but uses a wide range of amplitudes and frequencies to do so, rather than fixed ones.
Transcranial Magnetic Stimulation (TMS) – rather than using direct electrical stimulation, TMS exposes the scalp to a magnetic field. This field, often emanating from a “wand”-style device, can then induce electrical changes to neurons in the region beneath the device.
Transcranial Focused Ultrasound (FUS) – a newer technique than tES or TMS, FUS – like other ultrasound-based medical techniques – releases high-frequency sound waves. Directed at the brain, these waves can alter neuronal activity.
Transcranial Photobiomodulation (PBM) – originally based on a technique trialed on rodents in the 1960s, PBM uses light from the near-infrared area of the electromagnetic spectrum to stimulate tissue. PBM has come back in vogue in the last decade and has been trialed for depression.
New devices for the brain
Whilst academic studies remain a slow and deliberate route to medical technology, the demand for immediate therapies for people with conditions such as chronic stress and depression is here right now and the growing potential of non-invasive therapeutics has not gone unnoticed by those outside the academic bubble.
That need is being met through the proliferation of commercial stimulation devices such as Flow Neuroscience’s Flow tDCS headset, marketed in the EU as a medically approved non-invasive device for the treatment of depression, delivered alongside app-based psychotherapy. Flow’s version of tDCS shares some features with that seen in the Reinhart lab. Whilst the device itself is a slick, futuristic headpiece that puts Grover’s wiry swimming cap to aesthetic shame, both use wet pads to ensure a steady connection between electrode and brain and both target regions of the frontal cortex.
Flow Neuroscience's tDCS device. Credit: Flow Neuroscience
Flow’s device has numerous safety features to make sure it can’t be used outside of strict protocols, co-founder, chief technical officer and computational neuroscientist Erik Rehn explains: “Flow is certified according to the medical device directive and all the safety standards which exist for medical devices.” He adds, "We also have safety features around limiting how much you can stimulate, so you have to follow a certain treatment protocol.”
Flow wants to separate its product from DIY tDCS devices that have found an online following through communities such as the 14,000-strong r/tDCS page on Reddit. These devices are entirely unapproved, homemade setups that have caused posters to report skin burns and other adverse side effects.
Flow’s headset has attained a European certification called the CE Mark, which verifies the safety and efficacy of the product for its chosen indication. A key difference between the approval standards for medical devices and pharmaceutical compounds is worth mentioning here. Whilst new drugs must be tested in human trials before being approved for widespread use, to attain the CE mark, Flow’s headset didn’t have to be tested in any published clinical trials. The CE Mark can be attained based on the “principle of action”, meaning that because published studies exist that speak to the efficacy of tDCS in general, a device such as Flow’s that uses tDCS can gain approval. Rehn tells me that whilst no trials have yet been completed using the Flow headset, some are ongoing, with the aim of seeking approval for the stricter US Food and Drug Administration (FDA) device certification soon. “What we are looking for in these upcoming trials is this combination with tDCS and behavioral therapy that, compared to existing studies, will be completely unique,” he says.
Flow’s technology, Rehn tells me, is backed by leading NIBS labs who believe that commercial devices are the way forward. Grover, for one, takes a more cautious view: “We think this is very much in its investigational stages, and it's something which should be pursued only in a laboratory or a clinic or in a clinical setting under the supervision of researchers and clinicians who are purely looking at it from an investigational perspective and not necessarily using this as a treatment option right away," he says.
Departing the brain to stimulate the body
Whether using sound waves or electricity, NIBS techniques stimulate regions of the central nervous system, comprising the brain and spinal cord. Other technologies are looking beyond the brain to the peripheral nerves that carry signals around our body for therapeutic impact. One nerve that has been the target of extensive research is the vagus nerve, the central highway of the parasympathetic nervous system. This network is responsible for a broad range of functions that influence our bodies at rest, including mood, heart rate and digestion.
Proponents of vagus nerve stimulation (VNS) say that targeted activation of the nerve using electrical stimulus could treat not only disorders of the brain, but conditions affecting other regions of the body. Stavros Zanos, a researcher at the Feinstein Institutes for Medical Research, explains: “The vagus nerve innervates a lot of organs in the body. And just by stimulating one nerve, you engage a lot of different organs and functions.”
Stavros Zanos in his lab at the Feinstein Institutes for Medical Research. Credit: FIMR
Stimulating a nerve that ties into so many regions of the body could have unintended side effects if not done in a precise and controlled manner. Zanos’s team have developed several targeted VNS techniques that can exclusively activate selected fibers and signals within the vagus highway. VNS techniques currently in trial include both non-invasive and invasive techniques. Zanos explains that previous studies have backed both approaches, but there remains no consensus on which is superior: “I think the reason that there is no consensus is that we're still discovering what this nerve does to the physiology on one side and to the pathophysiology of diseases from the other side and whether there are significant therapeutic benefits from using it,” he says.
A non-consensus approach?
In the VNS field, whilst some devices have sought certification through mainstream channels for specific conditions such as epilepsy, there are many others that are designed to act non-invasively on the nervous system without making any specific medical claims. These are part of the rapidly growing wellness industry, which seeks to relieve non-clinical symptoms of modern life. One such device is the Sensate, which retails in the UK for £200 ($280). Behind this device is wellness veteran Dr Stefan Chmelik, who tells me he has been teaching meditation and relaxation techniques for nearly three decades. Chmelik had noted a change in people’s ability to gain the space and peace required for effective meditation. “Whereas you would be hard pressed to find somebody these days who would say they don't want to learn to relax more efficiently, it's something which is actually increasingly hard to do,” Chmelik says.
This observation led to Chmelik’s founding of BioSelf Technology and creation of the Sensate, a rubber-coated device roughly the size and shape of a wireless mouse. It connects to a lanyard and is designed to sit on your chest bone. When I first became aware of the Sensate midway through 2020, it was marketed as a VNS device that could cut stress and anxiety. By the time I speak to Chmelik in early 2021, something has fundamentally changed. “We're definitely not a VNS technology. We refer to self-regulation, to increasing resiliency, that by mimicking certain natural practices, you can increase vagal efficiency,” says Chmelik. This pivot, according to Chmelik, was to avoid any confusion with the medically approved VNS approach. However this distinction has, somehow, been lost in just about all coverage of the Sensate. It remains easy to find Sensate-branded adverts promoting the device as a VNS product, although Chmelik tells me the team are trying to remove these.
Unlike for VNS or tDCS, there is no published evidence that increasing “vagal efficiency” alone can help reduce stress. Sensate’s website nonetheless features many case studies from satisfied customers. Pitching the Sensate to Zanos, I get the following reply: “There may be some mechanism that this device taps into, but I cannot imagine what it would be.”
BioSelf Technology's pebble-shaped Sensate device. Credit: Bioself Technology
Chmelik explains that the Sensate’s proposed mechanism of action on the autonomic nervous system, called infrasonic bone conduction, is not dissimilar to that attained through religious chanting or humming. Chmelik is the first to admit that we have fully departed the realm of mainstream medical research at this point: “The fact is that Sensate is a non-consensus technology. We're saying something that doesn't yet form part of general mainstream medical science,” he says. The BioSelf team, nevertheless, have a roadmap for clinical approval, and Chmelik tells me that his team have half a dozen pilot studies underway.
What’s the best way forward for brain stimulation?
It feels like there are limitations inherent to all these approaches to stimulate the nervous system. Academic research will undoubtedly produce the most robust findings but moves at a glacial pace. Using these nascent findings to jump straight to producing medical devices is faster but sacrifices accuracy – whilst Grover’s lab designs each experiment so that they can verify that targeted brain areas are in fact being activated using electroencephalography (EEG) mapping, there’s no way to check that the Flow device, for example, is definitively activating the frontal brain areas it is aimed at. With a “non-consensus” approach like Sensate’s, the technology becomes easier to use, but at the significant cost of a scientific evidence base.
Is there a right way forward for brain stimulation technologies? Zanos and Grover come down on different sides of the debate here. Grover is reluctant to draw any firm conclusions about the potential of NIBS, just yet. “These kinds of neuromodulation technologies are very much in their infancy. Even something like transcranial alternating current stimulation has been around for just over a little over a decade and there's a lot of debate in the community as to just how effective this technique is.” Zanos, on the other hand, sees the potential in letting industry try out different concepts, as long as they are targeted at a healthy population: “I think there is something to be learned from pretty much any honest scientific endeavor, even if it fails,” he says. “I think we will learn things about how our body works. In that sense, I wouldn’t discourage this type of investment or this type of commercial or scientific endeavor.”
Zanos reminds me that he isn’t an expert in the moral balances of these technologies. Luckily, Laura Cabrera, assistant professor at the Center for Ethics and Humanities in the Life Sciences at Michigan State University*, is just that. From Cabrera’s perspective, a delicate balance must be struck. "The main point is to not overhype, because that is dangerous, and creates a misinformation bubble. There's also no need to create fear. We should be transparent about what we know, what we don't know and the type of things that are dangerous for people to be doing with these types of technologies.”
But Cabrera, like Zanos, accepts that these kinds of devices, regardless of any input from academia, will have a niche if they promise a fast route to a better life. “That also speaks to the to the type of culture we're living in. People feel there is this need for "wellness", for getting back with your own self. The market for wellness devices is just huge, because these people want to find a way to be able to calm themselves, to feel more at ease, to be less stressed,” says Cabrera.
She adds, “And they think “I'm going to use a device that you can just quickly connect and get results. There's less and less people inclined to learn meditation the hard way. I'm not saying that is best way, but it really speaks to the culture we are currently living in.”
Whether the slow and thorough academic route or an expedited commercial approach wins out, brain stimulation remains a frontier that will be explored by neuroscientists for decades to come. For Grover, the potential to improve people’s lives through NIBS and other stimulation techniques is hugely exciting: “We would like to examine how this intervention would fare in individuals who are clinically diagnosed with OCD and potentially even in other disorders of compulsivity, such as substance use disorders, addiction, gambling disorder or individuals who might be experiencing compulsive behaviors of different kinds, such as compulsive eating, compulsive shopping and compulsive internet use. There are lots of opportunities.”
*Cabrera is now associate professor and Dorothy Foehr Huck and J. Lloyd Huck early career chair in Neuroethics at The Pennsylvania State University.