The neuroscience of tomorrow – reaching the brain from the outside

Stimulation of the deepest reaches of the human brain, without cutting the head open, has been a holy grail for many neuroscientist worldwide.

These three words – ‘Deep brain stimulation’ – do not evoke, as a rule, pleasant feelings in us… What does come to your mind in the firstplace when you read or hear about them? Electrodes, electroshock therapy or perhaps the bloody scene of brain surgery? While newest breakthroughs in science have nothing or very little to do with this picture, classical procedures are still based on surgery as the one below.

Currently, Deep Brain Stimulation requires neurosurgery (CC0)

Electric touch

The most fundamental brick of every brain is the neuron, an excitable cell which communicates with others of its kind. Their electro-chemical language is rather a sophisticated one but despite that, curious and bold researchers come up with more and more fine and elegant techniques to influence it. By means of application of electrical or magnetic fields we can induce and then observe various effects. A considerable drawback is that each of the currently available methods has either many limitations, causes complications or is an enormous endeavor (just think about any neurosurgery).

One in particular stands out from the crowd, Deep Brain Stimulation or DBS, as it allows to touch our most intimate part of the brain – innermost subcortical structures (lying under external cortex). Hard to reach and with high risk of potential damage to neighboring areas during surgery, they are neurosurgeon’s nightmare. It is not surprising that development of safer methods is urgently needed.

To make things worse, in many vicious diseases such as Parkinson, problems occur precisely there. As of now, the idea behind DBS is to perform a neurosurgical procedure to plant ultra-thin electrodes in the target areas which will then deliver electrical pulses on site. Afterwards, we are left not only with wiring in our brains but also with a new companion, a neurostimulator connected to it, which we have to carry around all the time with us.

Typical setup for deep brain stimulation; Pacemaker = Neurostimulator (CC0)

Unfortunately, using this technologically advanced electronics does not prevent Parkinson’s disease from spreading further. It does however, prevent some of the worst symptoms, significantly improving  quality of life. Delivering the same treatment without direct intervention would be an ideal situation… but isn’t it still too early for such a  undertaking? Well, one of the recent ideas coming from cutting edge research – Temporal Interference Stimulation might be game changer. Let’s try to understand now what does the future holds in store for us…

Applying well-known tricks from the old-school physics

Successful methods used in science, more often than not are based on effects which are simple in essence and can be easily understood. This is also the case here as the basic principles are not complicated. The underlying concept here is wave interference, occurring when two waves superimpose each other giving birth to the third. Importantly, the new wave oscillates at a completely different frequency. In the context discussed here, electrical currents (our waves) with different yet very high frequencies flow through the brain unable to produce any significant effect. When they collide with each other at a precisely defined location new electrical current emerges activating neurons. The key to success here is difference in frequencies as neurons’ membranes are insensitive to very high frequencies tolerating only electrical current with very low ones.

To visualize it, imagine putting two electrodes on human or animal head, both inducing electrical current flow – each with different yet very high, say 2000 Hz and 2010 Hz, frequencies. Alone, they are unable to affect cells but taken together they are very capable of doing that while creating a so-called electric field envelope which oscillates at ~10 Hz. This is exactly the difference between the two and the only trick used here. What researches can also do, is to determine where does this takes place. In other words, with great accuracy they predict the area of the brain where the electric envelope stimulates neurons due to its low frequency. Isn’t this is beautifully simple?

Sounds great but does it really work?

In recently published interdisciplinary study, researches from MIT combined direct recordings from mice brains, computer modelling, physical experiments and gene analysis to make their point.

By using computer modeling approach they created plausible scenarios and then tested them in anesthetized mice. Signals recorded from the selected neurons in the hippocampus, well-established brain hub for learning and memory, showed that this technique induces the desired effects works as expected. An additional support for their claim came from assessing gene c-fos activation which is rapidly expressed when neurons are activated. Results matched those obtained in electrophysiological recordings. As smart as it sounds it was only a first step.

Knowing that electric field envelope works, they repeated the whole procedure in awake mice in order to prove that stimulation does not affect brain structures lying above the hippocampus. Again, c-fos gene was expressed exactly in the region where stimulation was delivered.  These results were comparable with the previous experiment, indicating high expression in hippocampus and not the cortex.

To probe other potential applications, the authors performed also some exploratory work. Temporal interference was administered to animal’s motor cortex to see if this would be an adequate method to stimulate areas responsible for limb movement. By adjusting the intensity of the current, researchers made paws, ears or whiskers of animals move. For example, stimulation of the specific motor area on the left side resulted in the motion of the limb or whisker on the opposite side. These results speak in favor of the versatility of the method, broadening its use to other areas in the brain.

Safety and potential applications

Side effects and possible unwanted complications haunt great deal of the treatment methods. With clinical applications in mind, scientist also tried to assess the negative impact  which their method might have. One way to assure the safety of the technique was to stain cells in stimulated hippocampi, simply to check for the markers indicating cell death. Additionally, they measured the brain temperature while performing the experiments. Luckily, up until now nothing indicates neither towards neurotoxic side effects nor abnormal temperature rise. Another important point is accidental onset of epileptic-like seizures which might happen during classic deep brain stimulation. So far this problematic aspect did not make itself known but is far too early to make strong claims here as tests in humans have not been carried out yet.

Breakthrough? – Yes, Treatment? – No

While the technique looks very promising, from the medical perspective it is still too early to speak about widespread use. Tests in humans are planned in the near future, therefore soon we might expect further developments here. The word ‘Breakthrough’ is abused and in many contexts distorts the healthy judgment of the scientific news. I would nevertheless argue here, that it is certainly an invention worth this prestigous label. It is truly a thrill to see how different fields of science meet to create and validate a clever technique. It goes without saying that it is equally impressive for lay people and scientist alike. We can only hope that in the course of time we will hear more about temporal interference or related methods and their usefulness in research or clinical settings.

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