by Anqi Zhang
figures by Daniel Utter

What do you think of the idea of inserting a long metal wire into your brain? That’s what doctors have done to ease the symptoms of Parkinson’s disease over the past 20 years. Sound scary? A new technique called temporal interference stimulation is exploring the possibility of achieving the same effects by attaching electrical stimulators to the outside of the skull—no brain surgery or metal wires required.

Deep brain stimulation for Parkinson’s disease

Neurons, a type of brain cell, communicate with each other via electrical signals to control functions in the brain and throughout the body. In Parkinson’s disease patients, these signals become abnormal and irregular, leading to major movement disorders, tremors, stiffness, and impairment of balance. About 7 to 10 million people worldwide are living with Parkinson’s disease. Parkinson’s disease cannot be cured, but its symptoms can be controlled by two common treatments: taking medication (such as Levodopa) or having a long metal wire called an electrode surgically implanted into the brain. When the disease cannot be controlled by drugs, as is often the case with late-stage patients, the inserted electrode can effectively mitigate symptoms the moment it’s turned on.

Electrode stimulation treatment, or deep brain stimulation (DBS), requires open-skull surgery to place the electrode into the specific regions deep in the brain that control movement, such as the subthalamic nucleus (Figure 1). After implantation, the electrode is connected to a battery-powered stimulator that can precisely deliver a continuous flow of electricity. Similar to the way that pacemakers regulate heartbeats, this electrical current controls how neurons communicate with each other.

Figure 1: DBS electrode targeting the subthalamic nucleus for Parkinson’s disease treatment. Deep brain stimulation requires a long metal wire to be implanted in a specific part of the brain. This wire, called an electrode, enables the precise manipulation of brain activity via an external source of electricity.

While DBS is effective and has been approved by the U.S. Food and Drug Administration (FDA) for two decades, it comes with risks. Most notably, the electrodes are implanted via invasive open-skull surgery that can lead to various complications. For example, the rate of DBS-related infection has been reported to range from 3.8% to 12.6%. Also, the rigid electrodes might move out of place and cause further damage to the brain. Lastly, scar tissue accumulated around the electrodes can decrease the efficacy of stimulation treatment over time. To avoid these complications, MIT researchers recently published a study in the scientific journal, Cell, titled “Noninvasive Deep Brain Stimulation via Temporally Interfering Electric Fields,” which describes a non-surgical technique that achieves an effect similar to that of DBS in mice.

How does noninvasive deep brain stimulation work?

Neurons have the ability to send signals to other neurons repetitively. The rate at which the signals are repeated in one second is called the frequency, which is measured in hertz (Hz; Figure 2A). For example, a frequency of 2 Hz means that the signal occurs twice per second. In practice, when electrodes placed on the skull apply current at a certain frequency, neurons close to the electrodes can “sense” the stimulation and send signals at that same frequency. This method, however, cannot easily target a specific region deep inside the brain because the neurons near the skull will sense a much stronger stimulation. The MIT researchers circumvented this problem by strategically placing two pairs of electrodes on the skulls of mice and exploiting how their electrical signals interacted or “interfered” with each other.

This method relies upon two key scientific insights: 1) neurons do not respond to stimulations of very high frequency (>1,000 Hz = 1 kHz), and 2) stimulation waves interfere with one another (the stimulation travels in the form of an oscillation that resembles a wave). Interference occurs when two waves meet and form a combined wave of increased or decreased strength, depending on the properties and relative locations of the two original waves. Additionally, when two waves with slightly different frequencies meet, they will form an envelope wave whose frequency equals the difference of the frequencies of the two original waves (Figure 2B). This phenomenon is known as temporal interference.

The MIT researchers exploited these concepts to achieve noninvasive deep brain stimulation. In brief, they attached two pairs of electrodes to the mouse skull (without surgery) that applied current stimulation at slightly different frequencies. The frequencies of these two original electric fields—2.00 kHz and 2.01 kHz—were too fast for the neurons to follow, but an envelope field with a frequency of 10 Hz (the difference of the two high-frequency fields) was produced where the two electric fields intersected. Only the neurons in this region, therefore, were affected by the low-frequency envelope field (Figure 2C). Even though the researchers haven’t yet targeted the parts of the brain that are reached by DBS, they can easily alter the size and location of the targeted brain region by changing the electrodes’ positions and current intensity.

Figure 2: Schematic of temporal interference stimulation. A) Frequency is defined as the number of times a signal is repeated in one second, measured by Hz. B) When two waves with different frequencies interact, they form an envelope wave with a frequency equal to that of the difference of the original waves’ frequencies: 2.01 kHz – 2.00 kHz = 10 Hz. C) Two pairs of electrodes attached to a mouse’s skull apply current stimulation at slightly different frequencies (2.00 kHz, red; 2.01 kHz, orange). The resulting envelope field (10 Hz, blue) can trigger responses from the neurons located where the two electric fields intersect.


Precision of temporal interference stimulation

One important requirement of DBS is high spatial precision (i.e., the accuracy of targeting a specific region). Stimulating brain regions unrelated to the disease might reduce the effectiveness of treatment or cause undesired side effects. In their study, the authors both built computer models to simulate the stimulation effects and demonstrated their spatial precision via two sets of experiments in anaesthetised mice.

In the first set of experiments, the researchers selectively targeted a small region found deep in the brain called the hippocampus, and they proved that stimulation of this area does not affect an overlaying brain region called the cortex. The stimulation effect was validated with two laboratory techniques. The first method was an electrical recording technique called in vivo whole cell patch clamp, which uses a glass tube called a patch pipette to acquire signals from neurons in the brains of live animals. This method requires open-skull surgery on mice to place the patch pipette deep into the stimulated brain region, and it demonstrated the stimulation effect with single-cell precision. The second method was a technique called c-fos labeling, which can reveal neurons that have recently been stimulated. After the noninvasive stimulation experiment, the authors dissected the mouse’s brain and found that the only neurons that had been activated resided in the hippocampus region and not in the overlaying cortex region.

In the second set of experiments, the researchers showed that they could selectively stimulate the parts of the brain that are responsible for forepaw and whisker motion by observing body movements that correlated to the stimulation frequency. Taken together, these experiments prove that specific brain regions can be selectively targeted.

Promises and challenges

For the first time, this work demonstrated the possibility of noninvasive stimulation of deep brain regions. One can thus envision achieving DBS without open-skull surgery, which would benefit many Parkinson’s disease patients.

Many challenges must be overcome, however, before these findings can be applied in the clinic. First, the stimulation’s precision is still much lower than the level required by DBS treatment. The authors hypothesize that larger numbers of electrodes and multiple sets of interfering fields may be able to target smaller regions of the brain, such as the subthalamic nucleus, which is the region that’s targeted when treating Parkinson’s disease. The absolute limit of this spatial precision, however, remains unknown. Second, the volume of the human brain is about 1,400 times larger than that of a mouse, so it’s still unclear whether this temporal interference technique can target regions located deep inside of the human brain. Third, validating the stimulation in a human brain will be challenging because the two validation methods used in this work are both highly invasive and cannot be used on human patients. But once these challenges are solved, noninvasive DBS holds the promise to revolutionize the treatment of Parkinson’s disease and benefit millions of patients.

Anqi Zhang is a Ph.D. student in the Department of Chemistry & Chemical Biology at Harvard University.

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