MRgFUS for Other Nervous System Diseases

Thermal impact using MRgFUS opens up broad possibilities for treating many other nervous system diseases. The list of such new indications is rapidly growing. For some of these diseases, traditional stereotactic neurosurgery (radiofrequency thermodestruction) was previously successfully applied DBS), and some diseases, on the contrary, became the object of stereotaxis for the first time thanks to MRgFUS. This chapter will present an analysis of some of the most promising applications of MRgFUS in neurology and psychiatry beyond extrapyramidal pathology, for which the first practical results have already been obtained today

Neuropathic pain

Neuropathic pain is pain caused by a disease or injury to the somatosensory nervous system at any level. Neuropathic pain is accompanied by unpleasant distressing sensations and emotional experiences that significantly affect quality of life (Davydov et al., 2018). The prevalence of neuropathic pain in the general population, according to various authors, ranges from 0.9 to 17.9% ( Bouhassira et al., 2008).

Medication treatment for patients with neuropathic pain is not always successful. In cases resistant to pharmacotherapy, surgical treatment methods are recommended, which involve affecting the structures of the CNS and peripheral nervous system involved in the development of pain. These include neuromodulation (chronic neurostimulation of peripheral nerves, spinal cord, DBS and others) and destructive interventions

Among the destructive surgeries used for neuropathic pain, the most common are the destruction of the dorsal root entry zone, less commonly chordotomy, commissural myelotomy, cingulotomy. A well-known and effective method of ablative impact on CNS structures in patients with neuropathic pain is thalamotomy, as some thalamic nuclei (central lateral nucleus – central lateral nucleus of the thalamus CL), medial nuclei) are “relay stations” of the somatosensory pathway. Thalamotomy using radiofrequency thermodestruction and radiosurgery, as well as thalamic DBS proved effective in patients with intractable neuropathic pain ( Jeanmonod et al., 1994; Rasche et al., 2006).

A new approach to treating neuropathic pain is the use of the MRgFUS method ( Brown et al., 2015; Jung et al., 2018). An interesting historical fact is that treatment with focused ultrasound was first conducted specifically to relieve pain in a patient with neuropathic pain—long before the use of ultrasound in extrapyramidal disorders. D. Jean­ monod et al. (2012) were among the first to demonstrate that patients with chronic neuropathic pain experience a 49% pain relief at 3 months and 57% at 1 year after central lateral thalamotomy using MRgFUS. A similar positive effect of MRgFUS is shown in the work D.G. Iacopino et al. (2018) in 11 patients with neuropathic pain. Impact on CL the MRgFUS method was effective in treating trigeminal neuralgia in patients resistant to both medication therapy and other surgical treatments (thermocoagulation, microvascular decompression, gamma knife) Gallay et al., 2020a). It is noteworthy that during ablation CL no deafferentation pain occurs anaesthesia dolorosa), despite the interruption of information flow from pain receptors, which often occurs with other destructive operations on the trigeminal nerve ( Gallay et al., 2020a).

A case is described in the literature of treating and 6-year postoperative observation of a patient with refractory cluster headache – bilateral thalamotomy was performed CL using the MRgFUS method ( Magara et al., 2022). Before the surgery, there were episodes of severe pain with pronounced autonomic symptoms, lasting from 20 to 90 minutes and occurring up to 7 times a day (interictal periods up to 3 months). After the surgery, during the first 3 months, there was a single typical episode lasting 20 minutes, and in the following months, episodes occurred 1–2 times a week without accompanying autonomic symptoms. The patient discontinued basic therapy with ergotamine and caffeine. At the last examination 6 years after the surgery, cluster headache episodes had completely ceased Magara et al., 2022).

In some countries, the use of MRgFUS for chronic pain is officially approved, and currently, in the USA, patients with uncontrolled chronic pain are being recruited to undergo MRgFUS ablation as part of a clinical trial I phases NCT03111277). Other studies are also being conducted in parallel to evaluate the effectiveness and clinical safety of MRgFUS for neuropathic pain.

Presenting our first clinical case of treating neuropathic pain using MRgFUS.

Patient N., 39 years old , visited the clinic with complaints of constant aching pain up to 10 points on the VAS, burning sensation, and lack of sensitivity below the level of the nipples, absence of movement in the legs, and impaired pelvic organ function. Has been suffering from type 2 diabetes since 2011, on insulin therapy since 2020. Disabled I groups.

Noted complaints since 2015 after suffering from purulent epiduritis at the C level VII–ThVI, which developed against the background of septicemia. Since 06/16/2015, the patient experienced severe pain under the left shoulder blade, the pain syndrome progressed, and after 1 week, dysfunction of the pelvic organs and lower paraplegia developed. On 06/24/2015, he underwent emergency surgery – laminectomy was performed ThII–ThIV , removal of a paravertebral abscess at the level of ThV and epidural empyema at the C level VII–ThVI. After the surgery, the neurological status showed persistent lower paraplegia and dysfunction of pelvic organs, along with a stable neuropathic pain syndrome with burning, constricting pain and absence of all types of sensitivity below the level of the nipples. To relieve the pain syndrome, the patient took baclofen 25 mg 3 times a day, gabapentin 400 mg 3 times a day with minimal effect. Periodically, up to 4 times a week, tramadol 50–100 mg was used intramuscularly or orally to manage severe pain. When the dose of gabapentin was increased to 2400 mg/ cthe patient noted a deterioration in overall well-being without a reduction in pain syndrome. Also, for the treatment of neuropathic pain, they took: amitriptyline 50 mg/day for 3–4 months, duloxetine 60 mg/ cut – 6 months, pregabalin 150 mg/day – 3 months, noting poor tolerance to the medications in the form of lethargy, drowsiness, sluggishness without a positive effect on the pain. Increasing the dosages of the medications led to an intensification of the aforementioned side effects. The patient regularly, 2–3 times a year, underwent rehabilitation courses in specialized hospitals; in 2017, an epidural electrode was implanted for 2 weeks for chronic epidural stimulation, in 2018 and 2019 – two-level epidural electrode placement with stimulation for 2 weeks, but the neuromodulation provided only a slight reduction in the pain syndrome, which is why the electrodes were not installed on a permanent basis.

Thus, the patient is diagnosed with pharmacoresistant neuropathic pain according to the following criteria:

1) duration of pain syndrome more than 6 months;
2) pain intensity of at least 4 points on the VAS
3) lack of response to 4 proven effective drugs (gabapentin, pregabalin, amitriptyline, duloxetine),

at the same time, the medications were used for at least 3 months, and increasing the dosages of the medications led to side effects that interfered with taking the medication in adequate dosages (despite treatment, the pain decreased by less than 30%)

Due to the minor positive effect of conservative therapy, the patient turned to the V.S. Buzaev International Medical Centre for the treatment of neuropathic pain using MRgFUS. A consultation was held with the participation of the center’s neurosurgeon, neurologist, and psychiatrist, and a decision was made on the possibility of using MRgFUS therapy for neuropathic pain. Informed consent was obtained from the patient for the procedure.

At the time of admission, the patient was using tramadol 50–100 mg intramuscularly daily, gabapentin 400 mg 3 times a day, and baclofen 25 mg 3 times a day for pain relief. The patient rated the intensity of constant pain at 8 points on the VAS, noting periodic increases in pain to 9–10 points, with the most severe pain in the feet. The pain was accompanied by numbness, tingling or prickling sensations, and burning. Upon admission, the general condition was satisfactory, with no notable features in the somatic status, and the patient was moving with the help of a wheelchair.

Neurological status. Cranial nerves – no pathology. Strength and tone of the neck, shoulder girdle, and upper limb muscles are unchanged. Tendon and periosteal reflexes of the upper limbs are brisk, symmetrical, no pathological reflexes. Active movements in the lower limbs are absent, passive movements are possible in full range. Hypotonia and hypotrophy of the lower limb muscles. Knee reflexes are brisk, Achilles reflexes are absent, pathological plantar signs are elicited on both sides. Below the level of the nipples (level ThIV) absence of superficial, deep, and pain sensitivity on the trunk and lower limbs. Does not control pelvic organ function, requires absorbent underwear. According to the questionnaire PAIN Detect the patient scores 13 points

A neuropsychological study was conducted: according to HADS noted absence of anxiety and depression symptoms (5 and 3 points respectively), according to MADRS – absence of depression symptoms (8 points). No distinct cognitive impairments detected (26 points on the scale MoCA).

Bilateral non-invasive thalamotomy of the central lateral nuclei of the thalamus ( CL) performed without anesthesia, the patient was conscious, which allowed for monitoring the clinical effect and preventing the development of complications in the form of focal neurological symptoms. The destruction sites were projected in the area of the central lateral nuclei of the thalamus ( CL) – on the left measuring 4 × 5 mm, on the right – 4 × 7 mm. No complications or side effects of the surgery were recorded. The duration of the procedure was 3 hours and 15 minutes. After treatment, on the 2nd day, an MRI of the brain was performed: bilateral foci are visualized in the projection CL the specified sizes, no hemorrhages detected, edema around the focus up to 2 mm (Fig. 9.1)

Immediate clinical improvement was achieved after treatment – a reduction in constant pain from 8 to 4 points, and the dosage of gabapentin was reduced to 800 mg/day.

After the treatment, the patient was monitored remotely for 12 months. He kept a pain diary, noting the intensity of the pain syndrome daily. During the first month after surgery, the average pain intensity was 5.9 points on the VAS, and the patient used tramadol 4 times that month. In the second month after treatment, the average pain intensity was 6.3 points on the VAS, with tramadol used 3 times a month. In the third month after treatment, the average pain intensity was 6.7 points on the VAS, with an increased need for tramadol—used 8 times a month. There was a gradual increase in pain intensity: 4th month after surgery—7.2 points on the VAS, 5th month—7.6 points, and 6th month—8.0 points. The need for tramadol gradually increased: in the 4th month after surgery, the patient used it 13 times, in the 5th month—16 times, and in the 6th month—18 times. According to the patient, during the 5th and 6th months after surgery, he used tramadol due to “anxiety, panic, nervousness.” In this regard, venlafaxine was added to the treatment for pain syndrome correction, which the patient took at a dosage of 75 mg/day for 3 months (he refrained from increasing the dosage due to concerns about weight gain, risk of drowsiness, lethargy, sluggishness). Since the pain was mixed (neuropathic and dysfunctional), cognitive-behavioral therapy was recommended by the center’s psychiatrist to reduce pain. After 3 months of cognitive-behavioral therapy, the patient noted a significant reduction in pain syndrome (to 6 points), with tramadol needed only once a month, and this continues to the present. The patient continues to receive cognitive-behavioral therapy with positive effects.

In this case, the target was chosen as the thalamic nucleus CL, since this structure is the main one in transmitting afferent information from the spinothalamic pathways to the subcortical and cortical somatosensory domains, and the posterior part CL (CLp) regulates the cognitive, sensory, and affective aspects of chronic neuropathic pain ( Nüssel et al., 2022). In addition CLp is a convenient surgical target due to its anatomical location and is characterized by low individual variability. According to the literature, ablation specifically CL provided a good lasting effect in the form of reducing neuropathic pain syndrome by an average of 50% in early studies ( Allam et al., 2022).

The effect of treatment was significantly influenced by the patient’s psychological state. By the 6th month, the patient’s sensation of pain increased, yet there was no need for narcotic drugs. During consultations, he noted that he took medications in advance, out of anxiety and fear that “acute pain would start again.” However, the patient categorically refused antidepressants. Due to these characteristics, cognitive-behavioral therapy was proposed, which proved to be quite effective.

Thus, bilateral non-invasive thalamotomy using MRgFUS can be considered a potentially effective method for treating refractory neuropathic pain. To achieve optimal results, it is necessary to consider the psycho-emotional state of patients selected for such treatment. The final decision to include MRgFUS in the list of recommended methods for neuropathic pain requires randomized controlled trials.

Hypothalamic Hamartoma

Hypothalamic hamartoma (HH) is a rare benign tumor, with a prevalence estimated at 1 in 200,000 children ( Bernasconi et al., 2019). From a morphological perspective, it represents a gangliocytoma—a benign tumor of the sympathetic nerve ganglia with low proliferative potential and minimal nuclear atypia ( Susheela et al., 2013; Louis et al., 2021). The first symptoms of GG can be observed as early as the 1st year of life, although many cases with onset in adulthood have been described ( Beggs et al., 2008).

Hypothalamic hamartoma is characterized by various manifestations, the most common of which are gelastic (laughter-associated) seizures, cognitive impairments, and precocious puberty ( Beggs et al., 2008). In 0.5% of patients with HH, dacrystic seizures are described, characterized by pathological stereotypical crying, tearing, grimacing, sobbing, a sad facial expression, or a subjective feeling of sadness ( Cohen et al., 2021). According to data L.H. Castro et al. (2007), the presence or absence of epilepsy in patients with HH is more determined by the location of the tumor and its connection with the temporal lobe (epilepsy is more common when located in the posterior part of the hypothalamus and the mammillary bodies area) than by the tumor volume

In practice, the classification most commonly used for GG is O. Delalande, M. Fohlen (2003), which classifies GG into 4 types based on MRI data: I type – small formations on a stalk, characterized by a horizontal plane of attachment to tuber cinereum; II type – predominantly intraventricular formations with a vertical attachment plane; III type – spreading in III ventricle and interpeduncular cistern (combination I и II types with both horizontal and vertical attachment planes) IV type is defined as GG, completely located within III ventricle (these are usually very large tumors with a wide attachment to both the mammillary bodies and the hypothalamus, and they invade the interpeduncular cistern). Dynamic observation of patients showed that hamartomas do not progress, but increase in size as the brain develops.

Approaches to the treatment of HH in recent years have undergone significant changes, with a shift in focus from medication therapy towards innovative minimally invasive surgical methods. Anticonvulsants are generally unable to completely control seizures and are considered an important but only symptomatic treatment (Mikhailov et al., 2017). Open neurosurgical resection or disconnection of the hamartoma through pterional, transcallosal, or transventricular access leads to good seizure control but is accompanied by a high rate of complications (neurological, endocrine, cognitive, behavioral) – up to 50%, which limits the use of this method ( Alvarez-Garijo et al., 1983; Machado et al., 1991). A number of studies have been published on stereotactic thermocoagulation of the GG with positive effects: in 84% of cases, seizure control was achieved, and complications were observed in 3–5% of patients without the development of neuroendocrine disorders ( Kameyama et al., 2016).

As a new approach to ensure safe and complete disconnection of the attachment zone of the GG from surrounding structures, the use of laser and radiofrequency thermocoagulation with the help of robotic stereoendoscopy was proposed Kameyama et al., 2016). The effectiveness of this approach was evaluated as high (especially in patients with isolated gelastic seizures and intraventricular hamartomas), with a favorable outcome rate of 78% and a complication rate of 8%. The use of stereotactic laser interstitial thermotherapy demonstrated effectiveness similar to open microsurgery (absence of seizures in 76–81% of operated patients), but with the development of a number of irreversible complications in up to 20% of cases ( Xu et al., 2018). Stereotactic radiosurgery has proven to be effective and safe, with seizure control rates ranging from 60 to 71% and a very low complication rate (2%) (Savateev et al., 2022)

Analysis of available literature data indicates that the success of treating HH is determined not so much by technical capabilities as by understanding the mechanism of epileptic seizure formation, including within the hamartoma, and proper planning of the disconnection of the formation from surrounding structures while preserving adjacent brain formations. In this regard, an innovative treatment method such as MRgFUS may become a successful alternative minimally invasive method for affecting HH to dissect the formation from adjacent tissues. Currently, only 2 articles have been published in the available literature describing 5 clinical observations of patients with HH who underwent treatment using MRgFUS with good results and without the development of side effects ( Yamaguchi et al., 2020; Tierney et al., 2022).

Presenting our clinical case of treating ET using MRgFUS.

Patient, 32 years, disease onset at the age of 4, when rare episodes of unnatural laughter first appeared. Parents sought help from a pediatrician at their place of residence, and the condition was considered behavioral traits related to the girl’s character, with no diagnostic studies or treatment recommended. At 16, there was an increase in gelastic seizures with the addition of dacrystic ones, and the development of bilateral tonic-clonic seizures. Anticonvulsant therapy was selected, but seizures persisted for many years without a positive response to medications. At the beginning of treatment, 3 types of seizures were observed: 1) isolated gelastic and dacrystic seizures with preserved consciousness; 2) focal hypomotor with loss of consciousness, accompanied by tearing, oroalimentary and bimanual automatisms, speech perseverations, ambulatory automatisms; 3) focal, evolving into bilateral tonic-clonic. Every 2 years, the patient underwent brain MRI: retrospective evaluation of all images showed a formation in the hypothalamus projection, but it was not timely recognized and described.

Since the age of 16, treatment was conducted with oxcarbazepine, levetiracetam, lamotrigine. At the time of admission to the V.S. Buzaev International Medical Centre, the patient was receiving oxcarbazepine 1200 mg/day, levetiracetam 500 mg/day, carbamazepine 400 mg/day. Despite the ongoing therapy, the frequency of seizures remained high, with gelastic seizures occurring 5–6 times a day, focal hypomotor seizures 2–4 times a month, and bilateral tonic-clonic seizures once every 2 months. Fig. 9.2. MRI of the patient with HH (arrows) before surgery. Fig. 9.3. Electroencephalogram of the same patient before treatment. Ovals indicate sharp-slow wave complexes.

Family history: A paternal cousin is under the care of an epileptologist, receiving anticonvulsant therapy. MRI (Fig. 9.2) reveals a T2 hyperintense lesion that does not accumulate contrast agent, along the anterior and right wall III ventricle, measuring 8 × 8 × 8 mm, corresponding to GG II Fig. 9.4. Intraoperative monitoring of the temperature regime in the projection of the optic tract and the right mammillary body (pink line). Fig. 9.5. MRI of the same patient during the MRgFUS procedure (GG indicated by arrows)

Video-EEG monitoring was conducted without sleep deprivation for 94 hours during active and passive wakefulness, sleep, and post-awakening with functional tests (13.10.2022). During passive wakefulness, the main rhythm is represented by regular, stable, modulated a-a rhythm with a frequency of about 9.5–10 Hz and an amplitude of up to 75 µV is recorded in the occipital leads with spreading to the posterior temporal and parietal areas of the hemispheres. Zonal differences are clearly expressed. In the posterior frontal-central regions, a regular stable sensorimotor rhythm of arc-shaped configuration with a frequency of 8.5–9.5 Hz and an amplitude of 60 µV is recorded (Fig. 9.3). During sleep and wakefulness, regional epileptiform activity is recorded in the right posterior frontal and temporal areas in the form of single sharp waves, sharp-slow wave complexes, with a low representation index during wakefulness, and an increase in the index to medium during sleep. Also, during sleep, regional epileptiform activity is recorded in the left temporal area in the form of single sharp-slow wave complexes with a low representation index

Treatment using MRgFUS was aimed at dissecting the tumor from surrounding tissues. The operation was performed on 12/05/2022. During the treatment, the MRI T2 mode was used to assess the impact FSE in the axial, sagittal, and coronal planes. Additional temperature control was performed in the projection of the optic tract and the mammillary body during each ultrasound exposure (Fig. 9.4). Nine therapeutic ultrasound exposures were conducted with a gradual increase from 10,000 to 22,000 J, lasting from 15 to 25 seconds, reaching temperatures from 52 to 58°C.

In Fig. 9.5, an MRI study during treatment with MRgFUS is presented. Intraoperative imaging did not reveal signs of hemorrhage or off-target heating. Fig. 9.7. MRI of the brain of the same patient 3 months after treatment.

There were no serious complications during the procedure. One gelastic seizure occurred during the first therapeutic ultrasound treatment. A combination of modes was used to monitor changes after MRgFUS T2 cube и T2 FSE using a 32-channel head coil. Three hours after treatment, two necrosis zones with cytotoxic edema measuring 3 mm each were identified in the projection of the aforementioned hamartoma, surrounded by vasogenic edema up to 4 mm thick (Fig. 9.6)

The patient returned to professional activities 10 days later. She noted increased confidence at work due to the absence of seizures. Currently, she has been under observation at the Center for more than 12 months, with no gelastic or dacrystic seizures detected after treatment, which corresponds to IA class according to the scale of surgical treatment outcomes for epilepsy by J. Engel (1993).

On the follow-up MRI of the brain 3 months after the treatment (Fig. 9.7), there is a complete regression of vasogenic edema. In the projection of the hamartoma, two hyperintense foci in T2 mode measuring 3 × 2 × 3 and 2 × 3 × 4 mm are determined, corresponding to the sonication points performed at the visible edge of the formation.

In Fig. 9.8, an electroencephalogram is presented 3 months after treatment during sleep and wakefulness, showing regional epileptiform activity in the right temporal region as single sharp-slow wave complexes. Compared to Fig. 9.8. Electroencephalogram of the same patient 3 months after treatment with MRI-guided focused ultrasound. A single sharp-slow wave complex is marked with an oval. There is a positive trend in the form of a significant decrease in the index of epileptiform activity in the right hemisphere of the brain compared to the preoperative electroencephalogram.

The described clinical case shows that dissection of the hamartoma using the MRgFUS method was effective in controlling epileptic seizures without any side effects. For a surgically inaccessible HH, this technology allowed the patient to be completely free from epileptic seizures, forced laughter, and crying (during more than a year of observation). Effectiveness may depend on the accuracy of targeting, the extent of thermal damage to the selected target area, and the size of the HH.

Epilepsy

More than 50 million people worldwide suffer from epilepsy, with drug resistance observed in 25-30% of cases. The method of choice in such situations is surgical correction, which, however, does not always lead to the complete elimination of the epileptogenic focus.

Currently, clinical trials of MRgFUS are ongoing in patients with therapy-resistant focal epilepsy NCT02804230, NCT03417297). The results of pilot studies demonstrate the clinical effectiveness of thermal impact on the anterior nuclei of the thalamus using the MRgFUS method to prevent the generalization of seizure activity in focal epilepsy ( Parker et al., 2019). In the research V. Krishna et al. (2023) the application of the method in 2 patients with therapy-resistant epilepsy followed by an evaluation of clinical outcomes at 3, 6, and 12 months contributed to a reduction in seizure syndrome manifestations: one patient experienced no seizures throughout the observation period, while the second achieved a reduction in the number of seizures from 90–100 to 3–6 per month. One of the patients experienced changes in attention and memory in the postoperative period.

Treatment of patients with resistant forms of epilepsy using MRgFUS may become a routine approach in the coming years, just as this technology is currently used for the correction of movement disorders.

Hydrocephalus

Hydrocephalus remains a condition that in many cases is associated with an unfavorable clinical outcome. In occlusive hydrocephalus, the separation of spaces for cerebrospinal fluid may require surgical interventions (often repeated) to restore CSF circulation, which increases the risk of intra- and postoperative complications. In the study S. Monteith et al. (2013) on cadaveric material, the potential possibility of creating openings using septum pellucidum ablation and ventriculostomy at the floor projection has been demonstrated III ventricle under MRI-guided focused ultrasound for optimal cerebrospinal fluid dynamics. The principle of the method is based on creating cavitation-induced tissue damage to ensure free circulation of cerebrospinal fluid under dynamic MRI control

To conclude the possibility of using the MRgFUS method for treating patients with hydrocephalus, further experimental and clinical research is necessary.

Depression and Obsessive-Compulsive Disorder

Therapeutic efficacy and safety of high-intensity MRgFUS in the treatment of depression were evaluated in studies NCT02348411 и NCT03421574. Bilateral ablation of the anterior limb of the internal capsule using MRgFUS ( NCT02348411), conducted on a 56-year-old patient diagnosed with “major depressive disorder with a course refractory to psychotherapy and electroconvulsive therapy” (more than 6 sessions conducted), demonstrates significant and sustained (over 1 year of observation) improvement in Hamilton scale scores (decrease from 26 to 8 points after 1 week and to 7 points after 12 months), Beck scale (decrease from 26 to 12 points after 1 week and after 12 months), and the Global Assessment of Functioning scale (increase from 40 to 85 points after 12 months). The patient’s quality of life was assessed using the questionnaire SF-36: an increase in mental health scale scores from 20.5 to 45.6 was identified ( Kim M. et al., 2018).

In 2015, a team of specialists from South Korea performed anterior capsulotomy using MRgFUS in a pilot study on 4 patients with medication-resistant obsessive-compulsive disorder (OCD) Jung et al., 2015). The procedure proved to be not only safe (without hemorrhages or infarctions) and tolerable (without deterioration of neurocognitive functions) but also effective: all patients showed significant improvement on the Yale-Brown Obsessive-Compulsive Scale. Subsequently, this same group increased their cohort to 11 patients with OCD, reporting improvement in 6 of them ( Kim S.J. et al., 2018).

From July 2017 to November 2019, in 2 clinical studies NCT03156335, NCT03421574) 16 patients with treatment-resistant OCD or major depressive disorder underwent capsulotomy using MRgFUS (University of Toronto, Ontario, Canada). In 4 patients, it was not possible to reach the target temperature for lesioning the intended nuclei, and they were excluded from the study. A detailed clinical report on the first 12 patients (6 patients with major depressive disorder and 6 patients with OCD) who were observed for at least 6 months shows that 4 patients with OCD achieved the planned response criteria—a reduction of ≥35% in the Yale-Brown Obsessive-Compulsive Scale score, and 2 patients with a major depressive episode achieved response criteria with a reduction of ≥50% in the Hamilton Depression Rating Scale score Davidson et al., 2020a, b) Mild side effects (headache, scalp sensory disturbance, etc.) occurred in 7 patients.

Currently, there is a significant historical experience in treating patients with depression and OCD using the method of radiofrequency ablation. Extrapolating the obtained data to the MRgFUS technology may provide a new impetus in improving the treatment of patients with this profile.

Thrombolysis in Ischemic Stroke

To date, there remains a problem with the inefficiency or impossibility of timely thrombolytic therapy in patients with ischemic stroke. The anterior and posterior cerebral arteries, distal branches of the middle cerebral artery are difficult to access for endovascular intervention and are at high risk of perforation during mechanical manipulations. It has been hypothesized that MRgFUS may improve clinical outcomes of thrombolysis. Since 2011, this method has demonstrated in animals and cadaveric material the fundamental possibility of affecting thrombotic masses in the vessel lumen, as well as suppressing the growth of atherosclerotic plaques by reducing the level of oxidized low-density lipoprotein cholesterol and increasing macrophage apoptosis ( Brahmandam et al., 2022).

In ischemia models, MRgFUS facilitated thrombolysis and angiogenesis by enhancing the expression of angiogenic/anti-apoptotic factors ( Brahmandam et al., 2022). Pilot clinical studies have demonstrated positive results of using high-intensity MRgFUS in the form of artery recanalization after thrombotic stroke, reduction in the number of atherosclerotic plaques in carotid arteries, increased tissue perfusion, and reduced stenosis diameter in patients with atherosclerotic lesions of cerebral arteries ( Zhang et al., 2015; Sun et al., 2019). Thrombus fragmentation was achieved using MRgFUS within 2 to 24 hours after its formation ( Brahmandam et al., 2022). The use of MRgFUS in the occlusion of small brain vessels has advantages over endovascular techniques due to lower invasiveness and higher accuracy in thrombus visualization. These studies are currently ongoing in several stroke clinics worldwide.

Opening of the Blood-Brain Barrier

All the ablation techniques discussed above fall into the category of high-intensity MRgFUS (power impact around 1000 W/cm²). A standalone non-invasive method for affecting the brain has become low-intensity MRgFUS (most often in the range from 2 to 20 V/ cThis method already has several applications in clinical neurology today.

Low-intensity MRgFUS combined with intravenously administered microbubbles of contrast agent reversibly opens the BBB with high temporal and spatial precision. The combined action of ultrasound and microbubbles promotes the formation of microstreams of tissue fluid, causing the separation of tight intercellular contacts of endothelial cells. It should be added that the direct mechanical impact of the ultrasound wave impulse on biological tissue leads to areas of mechanical tension and compression, which also play a role in the temporary opening of the BBB. The restoration of the BBB after low-intensity MRgFUS exposure occurs approximately within 1 day without any damaging tissue effect (Kholyavin, 2019; Kobus et al., 2016).

The idea of using low-intensity MRgFUS to open the BBB is particularly appealing for the treatment of neurodegenerative diseases. The essence is, firstly, to achieve the penetration of endogenous antibodies (immunoglobulin G (IgG) и IgM) к b-amyloid and other pathological proteins accumulating in the brain as the disease progresses, and secondly, in the activation (in response to ultrasound exposure and opening of the BBB) of astrocytes and microglial cells to break down protein aggregates and enhance neurogenesis ( Mainprize et al., 2016; Baek et al., 2022; Ma et al., 2023). The same approach can be used for other diseases to deliver high-molecular therapeutic complexes or cells to the brain (e.g., viral vector genetic constructs, stem cells, etc.), as well as in neuro-oncology for targeted delivery of chemotherapeutic agents to tumor tissue ( Mainprize et al., 2016).

Alzheimer’s Disease

Alzheimer’s Disease (AD) is the most common neurodegenerative disease and the leading cause of dementia in modern society. Alzheimer’s Disease is characterized by a progressive decline in memory and other cognitive functions in the elderly. In 2019, there were over 55 million people with dementia worldwide, and according to some forecasts, this number could increase to 150 million by 2050. Nichols et al., 2022). Such alarming epidemiological data determine the exceptional medical and social significance of developing effective treatments for BA

The classic histomorphological features of Alzheimer’s disease are amyloid plaques in the brain parenchyma, which are aggregates of pathologically altered neuronal protein b-amyloid, and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein of neurofilaments (Illarioshkin, 2003). These changes and the accompanying neuroinflammation trigger a large cascade of molecular events, ultimately leading to the death of hippocampal neurons (the main target of neurodegeneration in AD) and other parts of the CNS. Currently, the exact role b-amyloid burden in the development and progression of clinical symptoms of AD remains controversial and is under active study, however, overall the leading therapeutic approach in most studies is the development of methods for eliminating aggregates b-amyloid from brain tissue. This is the focus of innovative drugs developed in recent years based on monoclonal antibodies to various “maturity” forms b-amyloid and different parts of the molecule ( Mintun et al., 2021; van Dyck et al., 2023). However, the clinical results of treating Alzheimer’s disease with these drugs lead only to a moderate slowing of the rate of neurodegeneration (by approximately 30%) and are associated with serious complications. Therefore, it is important to continue the search for alternative anti-amyloid strategies.

Attempts to use low-intensity MRgFUS with the introduction of microbubbles into the bloodstream to study the possibility of modulating the BBB, effects on cognitive functions, level b-amyloid and tau protein in the brain began 15 years ago in experimental studies on transgenic mice with AD models. It was shown that such exposure can promote “washing out” b-amyloid from the brain parenchyma into the cerebrospinal fluid and lymphatic system, enhance uptake b-amyloid by microglial cells, reduce the level of phosphorylated tau protein, improve memory and behavior in animals, and slow the progression of the disease ( Ma et al., 2023). In experiments with intravenous administration IgG in AD models, the use of low-intensity MRgFUS led to a 39-fold increase in uptake IgG hippocampal cells and a 4-fold increase in neurogenesis in the hippocampus ( Dubey, 2020).

The success of these works led to the initiation of a similar approach in clinical trials for patients with AD. In 2022, the results of a multicenter study were presented NCT03671889 (Rezai et al., 2022). The authors assessed the safety, clinical, and neuroimaging effects of low-intensity MRgFUS targeting the hippocampus, frontal, and parietal lobes in patients with mild AD. Ten participants aged 55–76 underwent 30 separate MRgFUS procedures with follow-up for 6–12 months. All patients experienced immediate BBB opening after MRgFUS exposure and subsequent closure within 24–48 hours. The treatment was well tolerated, with no serious procedure-related side effects. Changes in cognitive functions assessed by various scales after MRgFUS exposure were comparable to those in the control group, but PET scanning demonstrated a noticeable reduction in the average level b-amyloid in the regions of the brain exposed to ultrasound. Thus, it was confirmed that the use of low-intensity MRgFUS on several areas of the brain with temporary opening of the BBB is accompanied by a reduction b-amyloid load and does not negatively affect the progression of AD ( Rezai et al., 2022).

In 2023, the results of an open study were published NCT04118764: 9 patients (average age 70.2 ± 7.2 years, average score on the Mini-Mental State Examination 21.9 points) underwent 3 low-intensity MRgFUS procedures once every 2 weeks with subsequent follow-up for 6 months. The permeability of the BBB in the hippocampus, anterior cingulate gyrus, and precuneus temporarily increased without adverse events. PET image analysis demonstrated moderate reduction b-amyloid load in the right parahippocampal and inferior temporal lobes. However, there was no recorded change in cognitive functions and the level of AD biomarkers in cerebrospinal fluid and blood (p- tau181, b-amyloid 42/40) Meng et al., 2023).

Expanding research in this area will help determine the real clinical significance of MRgFUS in AD and the long-term effects of the treatment conducted.

Other Neurodegenerative Diseases

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons, neurogenic paresis of skeletal and bulbar muscles, amyotrophies, fasciculations, muscle spasticity, and early fatal outcome (usually due to respiratory failure) (Illarioshkin, 2003). The mechanisms of neurodegenerative process development in patients with ALS remain not fully understood. In experiments on transgenic animals with an ALS model Eisen et al., 2017) and in clinical studies using transcranial magnetic stimulation, neuroimaging, and electrophysiological methods ( Menon et al., 2015) it has been demonstrated that signs of cortical neuronal and glial dysfunction are observed in the early stages of ALS and may precede the degeneration of spinal motor neurons. This indicates the key role of upper motor neurons in the pathophysiology of the disease, so interventions targeting the motor cortex area may be important for slowing or stopping disease progression

In the research A. Abrahao et al. (2019) Four patients with ALS and clinical signs of upper motor neuron dysfunction were included to assess the feasibility of non-invasive access to the motor cortex by opening the BBB using low-intensity MRgFUS. Ultrasound treatment targets were individualized according to fMRI activation of the hand or foot in the primary motor cortex. The average duration of the MRgFUS procedure was 66 minutes (ranging from 43 to 173 minutes), which included obtaining planning sequences, targeting, and the ultrasound exposure itself. Patients tolerated the procedure and intravenous microbubble injections without any side effects; no changes in neurological status were recorded during ultrasound therapy. Follow-up MRI studies in all participants did not reveal parenchymal or subarachnoid hemorrhages, ischemia, gliosis, or worsening of cortical atrophy of the precentral gyrus within 30 days post-intervention. Thus, this study represents an important first step towards creating a platform for the non-invasive delivery of potential neuroprotective agents to the motor cortex area in patients with ALS.

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of trinucleotide CAG-repeats in the gene HTT, what leads to the synthesis of a pathologically elongated neurotoxic polyglutamine-containing protein huntingtin (Illarioshkin, 2003). Currently, there is only symptomatic therapy for this disease. In the study C.Y. Lin et al. (2019) on a transgenic model of BG low-intensity MRgFUS c the introduction of microbubbles into the bloodstream was used to open the BBB to deliver liposomes containing plasmid DNA of the glial cell line-derived neurotrophic factor gene into the brain GDNF). Such MRgFUS-based therapy significantly improved motor characteristics in mice with a BG model, with the achieved hyperexpression in the brain GDNF led to a significant reduction in the formation of polyglutamine protein aggregates, a decrease in oxidative stress and apoptosis, and improved neuronal survival

It is evident that further research related to the opening of the BBB in neurodegenerative diseases is of great importance for experimental and clinical neurology and will actively develop in the coming years.

Neuromodulation

Low-intensity MRgFUS induces reversible changes in neuronal excitability and activity of neural networks exposed to ultrasound. Despite significant interest in this promising new area of non-invasive, highly targeted neuromodulation, the mechanisms of the modulatory effect of MRgFUS remain poorly understood. It is suggested that the ultrasonic flow, when interacting with cell membranes, influences the functioning of mechanosensitive ion channels (Kholyavin, 2019). The neuromodulatory potential of low-intensity MRgFUS is also explained by various non-destructive thermal effects (the influence of even small changes in local temperature on transmembrane currents, activity of cellular enzymes, and other parameters determining the pattern of neuronal discharges), as well as cavitation effects caused by ultrasound within the lipid bilayer of neuronal membranes Darrow, 2019).

Experimental studies on various animal species and clinical studies in humans have shown that low-intensity MRgFUS can be used safely and effectively for cortical and subcortical neuromodulation ( Legon et al., 2020). In humans, such ultrasound exposure has been applied to the temporal cortex, primary and secondary somatosensory cortex, primary motor cortex, primary visual cortex, and thalamus. It has been shown that low-intensity MRgFUS affects the amplitude of evoked potentials, power, phase, and frequency of the electroencephalogram, resting-state functional MRI parameters, reaction time ( Lee et al., 2016; Legon et al., 2018, 2020). There are isolated reports on the use of low-intensity MRgFUS in the treatment of serious CNS diseases, such as thalamic ultrasound stimulation in patients with consciousness disorders after severe traumatic brain injury ( Monti et al., 2016).

W. Legon et al. (2020) compared the results of neuromodulation using MRgFUS in humans with well-known stimulation methods such as transcranial magnetic stimulation and transcranial electrical stimulation. In a series of experiments using various protocols and levels of ultrasound energy, it was found that in terms of overall effectiveness, as well as the frequency and severity of side effects, low-intensity MRgFUS is comparable to the other aforementioned non-invasive neuromodulation methods, which have a long history and are recognized as safe for humans

The emergence of the low-intensity MRgFUS method not only opens new therapeutic opportunities in neurology but also allows for the integration of non-invasive innovative neuromodulation technologies into broader practice for use in healthy individuals of various ages and professions (memory and attention modulation, sleep normalization, various training, relaxation techniques, etc.). The experience gained in recent years with MRgFUS in extrapyramidal and other nervous system diseases shows that this technology represents more than just a new method of functional therapeutic impact on the brain based on a stereotactic approach. Essentially, thanks to MRgFUS, we are talking about erasing the boundary between conservative and surgical neurology. This significantly expands the possibilities of providing effective assistance to various categories of patients with severe, often disabling movement, sensory, and behavioral disorders. As discussed in the monograph, MRgFUS represents, on one hand, a certain alternative DBS (taking into account the existing limitations for macroelectrode brain stimulation due to its invasive nature, surgical risks, the need for constant monitoring of the stimulator’s operation mode, etc.), and on the other hand, a qualitatively new level of ablative stereotactic neurosurgery. For example, trial reversible ultrasound interventions allow modeling the effect on a specific area of the brain and finding the most effective target for a particular patient VIM, PTT, VO, ZI and others – in isolation or in combinations). Positive experiences have been gained worldwide and in our clinic with effective two-stage treatment, i.e., safely performing repeat surgeries when symptoms return in patients with ET, PD, and dystonias. The use of several developed methodological techniques (asymmetry of created lesions, timely cessation of impact on the second side with sufficient anti-tremor effect, symptom control during trial sonications) has breathed new life into the idea of bilateral stereotactic ablations in ET and potentially in other movement disorders. Our results indicate that such operations using MRgFUS can be safe both in staged and simultaneous execution, but this requires strict adherence to all requirements and adequate consideration of existing risks, indications, and contraindications. It can be expected that the use of MRgFUS for treating various movement disorders will gradually expand. Simultaneously, methodological foundations and indications for using ablative high-intensity MRgFUS modes will be clarified, even in non-motor neurological disorders – pain syndromes, epilepsy, affective disorders resistant to conservative therapy, hydrocephalus, thrombotic ischemic stroke for arterial recanalization, etc. The initial results of such interventions look promising, although significant additional experimental and multicenter randomized clinical studies are still needed here. A promising variety of MRgFUS is the use of low-intensity ultrasound exposure. It allows for temporary opening of the BBB for the treatment of neurodegenerative and other CNS diseases, and also lays the foundation for implementing a fundamentally new neuromodulation mode in practice. This demonstrates the significance of MRgFUS not only for clinical practice but also for fundamental neurology and neurophysiology. Thus, despite its youth, the MRgFUS method has already firmly established itself and confidently looks to the future.