A new noninvasive brain stimulation technique that has the potential to help people living with memory loss due to Alzheimer’s disease has been developed by scientists from the UK Dementia Research Institute. We spoke to the first author of the new paper, Dr Ines Violante, Senior Lecturer in Psychological Neuroscience at the University of Surrey, to find out more about the study and what’s next for this research.
The road from idea to laboratory
The technique is called temporal interference (TI), and it was first described by a team at Imperial College London led by Dr Nir Grossman. Back in 2017, they successfully tested it in mice, opening up the possibility of its use in humans. However, there’s a very long way between a proof-of-concept in an animal and trying the technique out on human volunteers.
“There are a number of challenges,” Dr Violante explained to IFLScience. “Let’s just start with the anatomy. If we think about the size of the brain – very different, right? The size of the brain in a mouse is like the tip of my finger and, well, in humans that’s not the case!”
Not only are you dealing with two animals that have very different-looking brains, but the ethical and practical considerations around animal vs. human research are substantially different too. At the end of an experimental period, model animals may be sacrificed so that researchers can extract and examine brain tissues – clearly, this is not an option for human subjects. Safety concerns around human trials are also paramount, so they require careful planning.
Fortunately, TI is not the only noninvasive brain stimulation method that’s been used in humans. We have many years’ worth of safety data about other methods, including transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS). Some of these methods already have medical uses, and scientists have a good understanding of how humans react to them. Using this as a benchmark made designing a trial of TI in 20 healthy participants much easier.
But even with all of this careful planning, nature could still throw a spanner in the works.
“Unfortunately, we also had COVID in between [the mouse study and the human trial],” Dr Violante told IFLScience. “So we had to stop scanning for a year almost.”
Eventually, the team was able to accomplish their experiments in all 20 volunteers. But what does a session of TI actually feel like, and what is it doing to the brain?
How does it feel to have your brain stimulated?
The aim of TI is to replicate the targeted brain stimulation that has, up to now, only been achieved through surgery. Deep brain stimulation (DBS), where electrodes are implanted into the brain in specific areas, comes with some risks – but it does have important uses.
In Parkinson’s disease, it’s the main surgical treatment offered when drugs no longer work to control the symptoms. The electrodes deliver high-frequency stimulation to regions in the brain that help control movement, powered by a battery-operated generator that’s usually inserted under the collarbone (a bit like a pacemaker).
Although treatment for Parkinson’s may be its best-known application, DBS is also approved for use in obsessive-compulsive disorder, some forms of epilepsy, and other movement disorders. A recent study even suggested it could be transformative for people suffering the aftermath of a traumatic brain injury.
But there’s no denying that brain surgery comes with significant risks to the patient.
“Not everyone is a good candidate for DBS,” Dr Violante told IFLScience. “Having brain surgery is not your first port-of-call […] and for many conditions we don’t yet have good targets for DBS.”
By contrast, TI involves applying electrodes to the surface of the skull, in locations that can be carefully mapped and personalized to the individual. The subjects stay awake the whole time and can tell the researcher if something feels off or uncomfortable while the electrodes are delivering overlapping electrical fields over the target region.
"The idea is quite ingenious," Dr Violante said. "The idea is that you have at least two current sources [...] and there is a difference between [the] frequency of those two current sources [...] in the range of something that the brain is going to respond to."
"Because we're using two current sources, they will meet at some point, [where] they generate an interference pattern." It's this overlapping of different frequencies that the research in animals demonstrated had the ability to influence neuronal activity deep within the brain.
With other types of brain stimulation, such as tACS, it’s common for people to experience a tingling sensation, or some more unusual side-effects like the perception of flashing lights (called phosphenes) or a metallic taste in the mouth depending on the frequencies used. With TI, Dr Violante explained, most of the participants hardly felt a thing.
“One advantage of the high frequencies that we’re using with TI is that actually, the perception of the stimulation only occurs for higher intensities. If you would compare tACS and TI directly at an intensity where you’re already feeling the pins and needles and tingling sensations you have with tACS, you don’t feel them with TI, and this is something that we also show in the paper.”
The way that individuals experience brain stimulation differs enormously, but with TI the most common sensation was a slight pressure or heat. “We had one participant that reported it made them laugh!” Dr Violante recalled. An uncontrollable fit of the giggles certainly sounds preferable to complex brain surgery. But the million-dollar question is: does it work?
Does it work, and where do we go from here?
The recent study aimed to see whether TI had the potential to influence the hippocampus, the brain’s memory center, and the team first assessed this possibility using post-mortem brain tissues.
Then they moved to the healthy volunteers, applying the TI stimulation while they were being asked to memorize pairs of faces and names. Functional magnetic resonance imaging (fMRI) was able to show that the stimulation was selectively targeting the hippocampal activity that was being ramped up as the subjects were performing the memory exercise.
A later experiment involved a tougher memory test and longer stimulation sessions. Asking the participants to try to recall the names and faces they’d memorized 30 minutes later revealed that the stimulation led to improved memory accuracy – just as the team had hoped.
The next step, led by Dr Grossman and the team from Imperial College, is a clinical trial in patients with Alzheimer’s disease. Dr Violante explained to IFLScience that the aim is two-fold – clearly, the team needs to understand whether targeting the hippocampus in people who already have impaired memories is possible and beneficial, but they also need to learn more about who the treatment might work best for.
There’s a lot more work to be done before we could see TI being offered as a treatment in the clinic. But these first steps have been promising, and come alongside a separate study from a team in Switzerland who also validated the use of TI to target the human striatum.
The road from hypothesis to validated treatment may be long and winding, but it’s also peppered with lots of little wins.
“You put everything together in the scanner and nothing explodes. You don’t break any equipment, it’s great. When you start seeing that you do have some changes in brain activity, that’s really great,” Dr Violante told us. “And then when we see that we could indeed see changes in behavior by following this line from A to B to C, that was quite exciting.”
The study is published in the journal Nature Neuroscience.