Magnetic resonance imaging-guided focused ultrasound and ExAblate Neuro™-emerging technologies in neurology

Structure

Magnetic resonance-guided (ExAblate Neuro; InSightec, Israel), neuronavigation-guided (NaviFUS, Taiwan), and implanted (SonoCloud, CarThera, France) systems are three different types of clinically focused ultrasound (FUS) brain devices currently available on the market.^[6] HIFU and MRI are the two components of the non-invasive surgical technique known as MRgFUS. In MRgFUS neurosurgery , MRI provides precise, real-time images of the brain during the procedure, enabling accurate identification of the target location and reducing the risk of damage to nearby tissue. 1024 ultrasonic rays from the HIFU transducer are sent through the intact skull to a focal point. The target brain tissue is destroyed as the beams converge and become focused. The clinical team can accurately modify the procedure’s location and temperature parameters thanks to continuous, real-time thermal data feedback. The functional effects of the surgery are continuously evaluated clinically while the patient is awake, allowing the multidisciplinary clinical team to fine-tune and confirm the correct target and the suitable number of sonications.^[4]

Mechanism

HIFU works under the principle of sonication, where a minute target in the brain is heated with FUS waves. The primary goal is to increase energy accumulation in the target area, thereby stimulating significant biological reactions without harming the surrounding tissues.^[7] ExAblate MRgFUS system comprises a high-field MRI scanner, a hemispheric 1024-element phased array ultrasonic transducer, and computer systems that employ skull data from a computed tomography scan to direct, align, and operate the transducer array.^[8] Energy attenuation, thermal mechanism, and mechanical mechanism form the overall mechanism.^[7]

Attenuation of energy occurs as HIFU energy is absorbed and scattered from the tissue layer interfaces. Energy loss is the consequence that causes the intensity of the beam to weaken.^[7] Bone has a higher attenuation coefficient than muscle tissue; therefore, it absorbs and reflects a substantial amount of ultrasound (US) energy, primarily within the 3–12 MHz frequency range. As a result, the magnetic resonance–guided high-intensity focused ultrasound (MRgHIFU) becomes defocused, and the cranium overheats. Moreover, we have a skull cooling system for controlling overheating and a piezoelectric transducer, which minimizes the scatter. Hence, it is crucial to consider the attenuation coefficient of a specific medium.^[9]

The primary way that US can be converted to thermal energy is through excessive molecular relaxation processes, which occur after US excitation. These waves induce the tissue’s molecules to vibrate or rotate, creating frictional heat. If temperatures higher than 56°C are maintained for more than 2 seconds, it could lead to coagulative necrosis due to protein denaturation, cellular death, and tissue stiffness. Unplanned cell death results from cellular injury brought on by thermal damage, whereas tissue architecture is normally maintained. As cellular proteins coagulate and their metabolic activity ceases, these targeted cells maintain their shape.^[7]

The mechanical mechanism occurs when US is administered in pulses, causing inertial cavitation that contributes to MRgHIFU ablation. These pulses quickly alter the pressure, which causes the liquid medium found in tissues to form unstable bubbles. These unstable bubbles and their collapse create turbulence, which causes mechanical tissue damage, primarily in the extracellular space. The amplitude of US energy attenuates as it is transformed into thermal energy during its passage through a medium.^[9]

Uses and indications

Application in stroke

The second greatest cause of death and the primary cause of disability globally, respectively, is stroke. The incidence of stroke is rising as the worldwide population over 65 grows faster than all other age groups.^[21] Transcranial US, in combination with tPA, has successfully initiated the first clinical trials, revealing the potential advantage of this combination as a successful vascular recanalization therapy method. However, the availability, cost, and different exclusion criteria of tPA limit its application. The percentage of stroke victims receiving tPA treatment varies between 1.6% (11) and 9% (12) in the literature, with a global average of 3–4%. Therefore, there is a great need for new stroke therapy options.^[22]

Hölscher et al.^[22] were the first to achieve non-invasive, tPA-free, 30-second transcranial clot lysis using HIFU in 2011. A hemispheric phased array transducer (ExAblate 4000, InSightec Inc., Tirat Carmel, Israel) was used, and the study was conducted on cadaveric skulls. Hence, with varying acoustic power output (between 100 and 400 W) and changing flow dynamics, 420 clots were successfully dissolved^[8] [Figure 1].

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Figure 1:

Clinical applications of magnetic resonance imaging-guided focused ultrasound. Vim: Ventral intermediate nucleus of the thalamus, PA: Plasminogen activator, MRgFUS: Magnetic resonance imaging-guided focused ultrasound.

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Contraindications

Despite having many applications, ExAblate Neuro has certain contraindications. Certain conditions, such as cardiac disorders (including unstable angina, myocardial infarction, congestive heart failure, and arrhythmia on medication), renal dysfunction, bleeding disorders, hypertension that is not under control, other systemic diseases, and infection, are some of the absolute contraindications for ExAblate Neuro.^[15]

Other contraindications include patients with metal implants, such as pacemakers, neurostimulators, or metal clips, as well as patients with a history of cerebral lesions (tumor, hemorrhage, and infarction), intracranial surgery, and those who have experienced seizures in the past year.^[15,23] A skull density ratio (SDR) of <0.4 was formerly thought to be adverse for MRgFUS therapy; however, recent studies have shown that SDR alone cannot be considered to be an absolute contraindication; other skull characteristics should also be considered.^[24] Finally, pregnant and lactating women also cannot undergo MRgFUS therapy.^[15]

Outcome and efficacy

MRgFUS efficacy has been well-documented in conditions such as ET, PD, and GBM, which is further elaborated below. MrgFUS is a viable surgical option for the treatment of ET, as all studies reported favorable post-operative outcomes. The non-invasiveness of MRgFUS over DBS is one of its advantages.^[25] According to Maesawa et al.^[26] (2021), at 6 months, the CRST improved by approximately 68.5%. In clinical practice, we observe a recurrence of tremor during the first year after treatment, but it then stabilizes in effectiveness. They reported a significant reduction in the motor score of the UPDRS of 60.9% postoperatively and also reported that even after 4 years, a 56% improvement in CRST was maintained.^[26]

PD and its correlation to MRgFUS have demonstrated the feasibility, safety, and accuracy of PTT-MRgFUS in a study with the following results: At the 3-month follow-up after surgical treatment, the clinical outcomes, as measured by the UPDRS score and global symptom relief, improved by 60.9% and 56.7%, respectively. In another study, it was noted that at the 1-year follow-up, clinical studies using bilateral PTT-MRgFUS ablation for the treatment of PD reported significant improvements in tremor, rigidity, distal hypokinesia, and dystonia.^[13]

While several pre-clinical studies for GBM treatment are conducted, the data required for clinicians to make informed decisions in clinical trials are insufficient. Such FUS applications must be studied for their safety, efficacy, optimization, reproducibility, and outcomes when combined with other therapies to help improve treatment outcomes^[20] [Figure 2].

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Figure 2:

Complications and contraindications of magnetic resonance imaging-guided focused ultrasound.

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Challenges and limitations of the technique

MRgFUS still has a number of drawbacks despite having important advantages in treating neurological illness using thermal ablation-based treatment. It is important to note that the very high percentage of post-operative recurrence is the most significant limitation. For instance, tremors were recurring during the post-operative follow-up in patients with PD and ETs who underwent MRgFUS thalamotomy.^[13] Expanding the treatment envelope is another challenge of MRgFUS. The amount of brain tissue within the skull cavity that can be successfully targeted and treated is referred to as the treatment envelope. The efficiency of sonication is higher for central targets (such as thalamotomy) than for peripheral targets (such as capsulotomy ) using the current MRgFUS technology, and this variation is patient-specific. The sonication efficiency can decline over time within a single session, according to data from early MRgFUS thalamotomy patients. This could be due to changes in the acoustic characteristics of the skull and brain tissue resulting from the heating process. This restriction will affect whether conducting bilateral procedures in a single session is feasible. Other difficulties with MRgFUS thermoablation include increasing the number of MRgFUS candidates, optimizing the process workflow, and incorporating more patient-centered outcome metrics.^[6]

The primary challenge with MRgHIFU is the attenuation of energy in thick tissues. Inappropriate heating, skin damage from reflecting tissue, and the dissipation of US energy can occur in areas with high attenuation coefficients, such as the skull. Another technological difficulty presented by MRgHIFU is correctly focusing US beams to prevent undesirable biological reactions.^[9] Although both of these issues have been resolved to some extent using multiple sources of US waves or by adjusting the temporality of US waves from different transducers in the case of focusing energy beams and by the use of external cooling systems in the case of energy attenuation, it is still necessary to try and modify the MRgFUS further to obtain better results.

Complications

The idea that MRgFUS is non-invasive is a common misconception. Although this is accurate in terms of open surgery, intracranial edema typically causes temporary balance and/or sensory side effects. Lesion extension outside the target zone may be the cause of their continued presence.^[27] Head pain and dizziness were the most frequent sonication-related problems, occurring in more than one-third of patients. This appears to be the patient’s primary source of discomfort.^[25] It is regarded as best practice and is reflected in the current guidelines, which recommend excluding patients with a history of balance and/or gait disorders. This could lead to the exclusion of many patients with severe ET who exhibit gait problems, a frequent “soft” ET symptom. Younger ET patients who refuse to consent to the challenges of DBS also need to be taken into account for the possibility of permanent gait impairment.^[27]

The most frequent neurological side effect was ataxia, followed by sensory impairments and gait abnormalities. Ataxia’s immediate collected proportion was 50%, compared to 20% for sensory problems, which is a considerable difference. Further evidence showed that the region linked to clinical improvement and post-operative ataxia shared a considerable amount of tissue.^[25] The primary objective of MRgFUS is to reduce limb tremor, which is often the dominant type. Patients whose axial tremor symptom burden is higher may be more suitable for DBS since head and vocal tremors do not respond to unilateral therapy. When doing bilateral MRgFUS thalamotomy, there is a lot of consideration taken due to previous concerns about the possibility of dysarthria from traditional thalamotomy.^[27] The high dropout rate is a significant obstacle to determining the long-term side effects of MRgFUS patients. As a result, it is hard to assess the full extent of the complications. Finally, MRgFUS for ET has never been associated with bleeding, seizures, or trajectory-related problems, making it a uniquely safe technique compared to DBS or Radio-frequency ablation (RFA) [Figure 2].^[25]