Introduction
Ultrasound has been “rediscovered” as a method for brain therapy within the last decade. Progressive technologies allow for the focusing of ultrasound through the human skull and enable non-invasive stimulation or ablation of brain tissue. Clinical neuroscientific analyses have indicated that: a) highly focal tissue ablation (e.g., tremor therapy); b) clinical neuromodulatory brain stimulation (e.g., Alzheimer’s therapy); and c) targeted focal blood-brain-barrier opening (e.g., focal drug transfer) are possible. Meanwhile, ultrasound surgery and ultrasound neuromodulation have entered routine clinical therapy. The rapidly ongoing methodological and clinical progress opens completely novel viewpoints for ultrasound brain therapy. This is significant since brain disorders are one of the most urgent problems in our rapidly aging society. Effective medicines are frequently missing (e.g., for dementias), and the application of surgery is limited due to its invasiveness, especially in the elderly.
Methodology of Clinical Ultrasound Neuromodulation
Three technical strategies have been used to modulate human brain activity. The first strategy comprises standard diagnostic systems built for Transcranial Doppler Sonography to monitor and diagnose the intracerebral blood flow situation. The second strategy is highly focused systems, which can target stimulation to very small areas of the brain. The third strategy is highly focused and individually navigated systems which allow us to specifically target individual brain areas on individual magnetic resonance (MR) images. Since every brain is different and pathologies may result in gross morphological brain changes, precise targeting capabilities are crucial. Thus, highly focused navigated systems are state-of-the-art for clinical ultrasound navigation.
For highly focused ultrasound systems, two different classes exist. The first class builds on diagnostic ultrasound and uses sinus tones in the range of several hundred kilohertz. This strategy is characterized as “focused ultrasound” (FUS). For neuromodulatory impacts, such sonication patterns are used for several minutes. The second class of highly focused systems is a new neuromodulation method. It was first published in 2019 after a development period of 10 years.
Figure 1. Treatment setting for one of the current state‐of‐the‐art navigated and highly focused neuromodulation systems (TPS system) Adapted from source
The principle builds on shock wave technologies and consists of ultrasound pulses consisting of different frequencies. The method has been named Transcranial Pulse Stimulation (TPS). TPS pressure pulses are typically repeated at frequencies between 1 and 8 Hz. Both approaches for highly focused ultrasound neuromodulation generate very small stimulation foci. Although the size of the stimulation foci depends on the transducer design and frequency, typical foci are cigar-shaped with a length of about 3-5 I’m and a width of about 4 mm.
The TPS system and some FUS systems represent highly focused and navigated state-of-the-art systems. Their ultrasound focus can be navigated to the cortex and deep brain areas, and this will allow precise modulation of small-scale neuronal networks, including the option to uncover new circuits.
Figure 2. Example for a very small ultrasound neuromodulation focus. A) Acoustic intensity profile of the 0.5 MHz transducer with focus 30 mm measured in free water. The white line in the longitudinal maps (left) indicates the focal plane where the spatial peak pulse average intensity of the acoustic field was measured. Acoustic beam cross‐section of the focal plane is illustrated at right. B) Line plots illustrate the lateral (x, left) and vertical (y, middle) peak normalized acoustic intensity profiles for the acoustic beam in the focal plane. The lateral and vertical dimensions of acoustic beam cross‐sections measured at the intensity full width at half maximum (FWHM) were 5.8 and 5.6 mm. The line plot for the axial (z, right) peak normalized intensity profiles shows a near‐field peak at 12 mm and a far‐field peak at 33 mm (close to the focal length of 30 mm). Adapted from source
Concerning possible mechanisms for ultrasound-mediated neuronal activation changes, complete knowledge is still lacking. Recent data demonstrate direct mechanically induced depolarization effects. Ultrasound can produce very small cell membrane deflections which change membrane voltage and lead to subsequent depolarizations. Hence, it does seem possible to induce plasticity in the brain with transcranial ultrasound.
Ultrasound Neuromodulation – Differences Compared to Electromagnetic Stimulation
Clinical neuromodulation has already been performed for decades with electromagnetic techniques. The most important technologies are Transcranial Magnetic Stimulation (TMS), Transcranial Direct Current Stimulation (tDCS), and more recently Transcranial Alternating Current Stimulation (tACS). Thus, the question arises which clinical advantages may be expected from ultrasound. The answer is threefold. First, the narrow focus of ultrasound neuromodulation provides remarkable precision for targeting small brain areas. Second, ultrasound is the first technique that allows for non-invasive, selective, and focal deep brain stimulation. Third, clinical neuromodulation requires stimulation of pathological brains. This includes major changes in the normal conductivity situation inside the brain. Very recent developments now demonstrate that the strengths of ultrasound and electromagnetic techniques may be combined.
Clinical Effects with Ultrasound Neuromodulation
A very recent analysis of uncontrolled TPS data from a treatment series in Parkinsonian (PD) patients found strong improvements in PD clinical scales. In this work, 2 weeks of TPS treatment improved Unified Parkinson’s Disease Rating Scale (UPDRS). Some studies report that brain activation increases in task-specific brain areas, connectivity increases within the diseased brain network, and reduced brain atrophy in disease-specific brain areas.
Safety of Clinical Ultrasound Neuromodulation
Depending on the amount of energy transferred to the brain tissue ultrasound applications may produce local hearing and local cavitations. The consequences may be cell damage and local bleeding. When ultrasound contrast agents are used or local gas bodies exist, the risk for cavitations is largely increased. Thus systems used for clinical ultrasound neuromodulation have been limited in energy output. To achieve ultrasound neuromodulation, effect intensities, mechanical index, and positive/negative peak pressures typically surpass the FDA limits. Current data from healthy subjects and patients demonstrate that ultrasound neuromodulation is safe, and none of the studies has ever described a serious adverse event. Mild to moderate adverse events previously reported with ultrasound neuromodulation is similar to adverse events reported for electromagnetic brain stimulation. Over all human ultrasound neuromodulation studies ever published, the following mild to moderate adverse events have been reported: localized pain at the head or neck, muscle twitches, general headache, heating sensations, itchiness, anxiety, mood deterioration, confusion, tenseness, noise sensitivity, nausea, sleepiness, dizziness, tiredness, and sweating.
Perspectives for Ultrasound Neuromodulation as a New Brain Therapy
Clinical ultrasound neuromodulation with state-of-the-art systems is new but promising brain therapy. Patient data with the navigated focused state-of-the-art technologies are however restricted. Currently, clinical research is rapidly increasing. A search on ClinicalTrials.gov demonstrates at least 17 patient trials are running or intended to be conducted. They concern a large spectrum of diseases: depression, temporal lobe epilepsy, opioid-use disorder, treatment-resistant schizophrenia, anxiety disorders, brain tumors, obsessive-compulsive disorder, and Parkinson’s disease. The major problem is the low sample sizes in the currently published studies. Due to small effect sizes, inter-individual patient variability, and large placebo effects, sample sizes for clinical ultrasound neuromodulation studies need to be considerably increased.
Conclusion
There are various encouraging perspectives for future methodological advances. According to early research, activation and inhibition of neurons differently may be feasible. The fundamental frequency, duty cycle, energy settings, single pulse durations, pulsing structures with primary and secondary pulsing levels, and total sonication timings are just a few of the characteristics that may be altered using FUS technology. Target specificity is crucial, and even little variations in targeting and delivery could lead to differing outcomes. In addition to providing several study possibilities, the broad variables also present numerous interdependencies and challenge effect interpretations. The single pulse energy and single pulse frequency are the only two TPS characteristics that can be altered. As a result, there are fewer alternatives for study, but controlled studies are easier to conduct. In any event, independent measures of neuronal activity, such as functional MRI, EEG, or magnetoencephalography (MEG) measurements, need to be included in future studies on the effects of neuromodulatory drugs in healthy and ill subjects. The potential to combine the benefits of electromagnetic and ultrasound neuromodulation techniques is another promising avenue for future improvements. Based on immediate functional feedback, closed loop electromagnetic methods enable cortical neuromodulation of broader brain regions. Over time, advancements in sonogenetics and freely moving ultrasound devices could pave the way for ultrasonic neuromodulation as a brand-new form of brain therapy.