Transient changes in blood-brain barrier permeability after FUS thalamotomy

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Introduction

The blood-brain barrier (BBB) is a complex heterogeneous semipermeable structure of the central nervous system with multiple levels of selective transport, regulatory and protective mechanisms maintaining homeostasis of the central nervous system by controlling passive diffusion and active transport of various substances between the bloodstream and the brain. The main functional and anatomical elements of the BBB are capillary endothelial cells, astrocytes, neurons, and pericytes, which constitute the neurovascular unit (NVU). Within the NVU, the BBB encompasses an extensive system of capillaries and postcapillary venules that regulate the passage of molecules and cells into and out of the brain [1–3]. One of the predictors of altered BBB permeability is the penetration and distribution of gadolinium-containing contrast agents in the intercellular space, which has found greatest application in the diagnosis of tumor lesions [4, 5].

The hybrid magnetic resonance imaging (MRI)-guided focused ultrasound (FUS) system, or MR-guided FUS, is a relatively new technique in Russia. This method of tissue exposure to ultrasound waves involves a hemispherical phased-array transducer consisting of 1,024 individually controlled elements with a diameter of 30 cm, operating at low (200 kHz) and high (650 kHz) frequencies. The device is integrated with a 3.0 T MRI scanner, targeting the thalamic nucleus with submillimeter accuracy using real-time feedback for monitoring and intraoperative image guidance. At high frequencies (> 1,000 W/cm²), FUS is used for ablation of the ventral intermediate nucleus (VIM) of the thalamus in patients with tremor, demonstrating safety and efficacy comparable to other neurosurgical methods (stereotactic surgical treatment: destructive procedures — thalamotomy using gamma knife and pallidotomy; application of low (cryoablation) or high (thermal ablation) temperatures, electrostimulation of deep brain structures) [6–15]. Low-intensity FUS (LIFU) is a non-invasive technique based on acoustic waves of subthermal intensity (≤ 720 mW/cm²), fundamentally different from high-intensity FUS (HIFU). It is designed for reversible modulation of biological processes without tissue damage while avoiding thermal injury due to low radiation intensity. LIFU induces the following biomechanical effects: micro-oscillations activating mechanosensitive ion channels and intracellular signaling pathways; reversible temporary BBB opening; neuromodulation: selective targeting of neural networks to manage abnormal activity in neurological and psychiatric disorders [16–19].

HIFU and LIFU are complementary modalities with distinct biomedical applications. HIFU has revolutionized non-invasive surgery by enabling precise ablation of deep-seated pathological foci. Conversely, LIFU offers promising prospects for targeted therapy of central nervous system disorders, combining safety with the potential for repeated applications. Further development of these methods requires protocol standardization and comprehensive investigation of long-term effects [20–22].

Currently, FUS thalamotomy for tremor treatment represents one of the primary clinical applications of this technology. Standard MRI protocols enable real-time monitoring of sonication during FUS therapy, precise lesion localization, treatment zone adjustment, and evaluation of thermal-induced changes in the target area.

This study presents a clinical case of tremor treatment using FUS, focusing on analyzing BBB permeability changes through imaging phenomena and temporal patterns of contrast medium accumulation in the coagulation necrosis zone.

Materials and methods

The study included observation of a 69-year-old male patient admitted to the Federal Center for Brain and Neurotechnologies of FMBA of Russia for scheduled FUS treatment of Parkinson’s disease tremor. Brain MRI was performed on a Discovery MR750w 3.0T scanner (GE Healthcare) with a 32-channel HNU (Head&Neck Unit) coil and integrated Insightec ExAblate (INSIGHTEC) system for non-invasive FUS ablation.

The MRI contrast agent used was Gadovist (1 mmol/mL concentration) containing gadobutrol (Bayer AG) as the active substance, a paramagnetic low-osmolar cyclic MRI contrast agent (Gadovist osmolality approximately 600 mOsm/kg) representing a neutral (non-ionic) gadolinium (III) complex with a macrocyclic ligand — dihydroxy-hydroxymethylpropyl-tetraazacyclododecanetriacetic acid (butrol), with molecular size approximately 1.5–2.0 nm. Gadobutrol is not metabolized, being eliminated from plasma with a T_1/2 of 1.81 hours (1.33–2.13 hours) and subsequently excreted unchanged by the kidneys.

Clinical data

In 2017, based on comprehensive examination, the patient was diagnosed with Parkinson’s disease. The disease began with tremor of the left hand followed by subsequent hypokinesia in the left limbs. Pharmacological treatment (dopamine receptor agonists) was initiated, showing positive effect on hypokinesia but no significant impact on tremor. Since 2019 bilateral symptoms were observed. Levodopa and clonazepam were added to the treatment regimen. Despite combination therapy, disabling tremor persisted in the hands, more pronounced on the left. Neurological examination on admission revealed high-amplitude resting tremor of the left hand, resting tremor of the right hand and both legs, jaw tremor, high-amplitude postural tremor in the hands (S > D), mild generalized bradykinesia and hypomimia. Motor tests showed irregular execution, and mild hypokinesia more prominent in the left limbs. Moderate plastic hypertonia was seen in the left hand with cogwheel phenomenon in the distal portion; mild plastic hypertonia was seen in the distal portion of right arm; there was also mild plastic hypertonia in legs (S > D). The patient had slightly stooped posture. He raised himself independently without arm support on first attempt. There were no initial gait disturbances. The left foot shuffled during walking. He had slowed gait tempo with bilateral acheirokinesis more pronounced on the left. Posture was stable. Tendon and periosteal reflexes were moderately brisk in upper extremities (S > D), same as knee reflexes (S > D). No abnormal foot signs were observed. Romberg test was negative. Finger-to-nose test was normal on the right side, with marked intention tremor on the left. The patient reported chronic constipation (bowel movements every 2–3 days) and no dysuria. No hallucinations were present. Cognitive functions were within the normal range for his age. Hypersalivation occurred during nighttime hours. Subjective reports indicate insomnia-type sleep disturbances (frequent nighttime awakenings). Mood baseline was euthymic. Clinical Tremor Rating Scale (CRST/Fahn–Tolosa–Marin Tremor Rating Scale¹) score: 36 points. Given the treatment-resistant nature of tremor significantly limiting patient’s daily activities, high-tech medical care was recommended, i.e. functional neurosurgery (right-sided thalamotomy). The patient provided written informed consent for treatment and required examinations. The MRI study protocol was approved by the Local Ethics Committee.

Brain MRI was performed using the following protocol sequences: T1-WI, T2-WI, SWI, DWI, T2-FLAIR before FUS therapy, at 2 and 24 hours, 1, 3, 6, and 12 months post-treatment. The MR protocol was supplemented with T1-WI after intravenous administration of gadovist contrast agent. Four therapeutic sonications were performed with minimum achieved temperature of 48°C and maximum of 59°C, including 3 therapeutic sonications.

Analysis of mri data changes over time

Abnormal uniform predominantly ring-shaped active accumulation of MRI contrast agent was noted in the sonication zone 2 hours after FUS. After 24 hours, significant decrease in intensity and reduction of contrast accumulation area with petechial pattern were recorded. Clinical Tremor Rating Scale (CRST) score: 14 points.

One month after FUS thalamotomy, pronounced MRI contrast accumulation was again detected at the periphery of the sonication focus forming a rim. In clinical status, the patient reports no tremor in the left hand, with newly emerged periodic tremor in the left leg predominantly in the morning hours. CRST score: 14 points.

At 3 months, reduction in severity and volume of contrast accumulation was observed, changing from a ring pattern to focal areas of enhancement. CRST score: 25 points (Fig. 1). Subsequently, at 6 and 12 months, gradual decrease in contrast agent accumulation activity was noted from discrete petechial patterns at the periphery to complete absence of accumulation in the sonication area, accompanied by reduction in size of the altered MR signal focus on standard MRI sequences.

 

Fig. 1. Variants of pathological accumulation of MRCA in the sonication area on T1-weighted axial image of the brain with contrast enhancement at the level of the basal nuclei after focused ultrasound thalamotomy.
A — after 2 hours, uniform, continuous, ring-shaped accumulation of MRCA is observed; B — after 24 hours, minimal petechial-type accumulation of MRCA; C — after 1 month, moderate, relatively uniform, ring-shaped accumulation of MRCA; D — after 3 months, minimal focal MRCA; E — after 6 months, single, small-caliber focal accumulation of MRCA; F — after 12 months, no MRCA accumulation is observed.

 

A typical manifestation of post-FUS thalamotomy changes in the cerebral white matter is focal signal alteration on MRI. Twenty-four hours after FUS, axial MRI of the brain at the level of the subcortical nuclei in T2-weighted imaging (T2WI) showed minimal enlargement of the coagulative necrosis focus with increasing perifocal edema extending laterally into the posterior limb of the right internal capsule, spreading medially toward the thalamic nuclei and caudally toward the ventrolateral portions of the right cerebral peduncle. T1-weighted imaging (T1WI) and T2-FLAIR sequences also demonstrated characteristic enlargement of the lesion and perifocal edema. SWAN sequence imaging revealed moderate amounts of hemoglobin degradation products within and around the lesion. Post-contrast T1WI showed uneven linear accumulation of contrast agent. Diffusion-weighted imaging (DWI) displayed annular hyperintensity with corresponding ring-shaped hypointensity on the apparent diffusion coefficient map, indicating true restriction of free water molecule diffusion.

Discussion

The term BBB was introduced nearly 100 years ago by L. Stern et al., implying a complex and dynamic structure that severely restricts metabolic exchange between blood and nervous tissue [23]. The BBB consists of endothelial cells lining the microcirculatory bed, and also includes astrocytes, neurons, and pericytes that constitute a functional barrier that prevents lipophobic molecules from being transported from cerebral capillaries to the brain [1, 3]. The brain predominantly contains continuous-type capillaries with tight junctions and a continuous basement membrane. FUS allows reversible disruption of BBB permeability through the creation of spaces between endothelial cells and induction of a perivenular immunological response to reparation in target areas [1, 2]. Observed changes in BBB permeability after HIFU thalamotomy in this study should be interpreted exclusively in the context of secondary effects of HIFU aimed at thalamic VIM nucleus ablation, as opposed to LIFU which is used for reversible BBB modulation through cavitation combined with microbubble agents [18, 24]. One of the key mechanisms by which HIFU affects BBB permeability is the cavitation effect. Under ultrasound exposure, microscopic gas bubbles may form in tissues which then rapidly expand and contract (cavernous behavior), creating local turbulence and microtears in cell membranes that lead to temporary weakening of tight junctions in endothelial cells. Thus, cavitation can disrupt the barrier, providing passage for molecules that normally cannot cross the BBB [10, 11]. During FUS thalamotomy, ultrasound exposure induces localized destruction of brain tissue accompanied by inflammatory reactions, leading to increased expression of pro-inflammatory cytokines and chemokines, and causing alterations in gene transcription [24]. These changes are likely transient, with pro-inflammatory cytokine levels rapidly returning to baseline values, which may contribute to modulation of endocytosis, reduced immunoreactivity of tight junction proteins, and decreased β-amyloid accumulation. Following localized thermal exposure, conformational and functional changes occur in adhesion molecules such as claudin-1, claudin-5, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) — key components of endothelial tight junctions. This reduces their binding capacity with other cells and extracellular matrix due to altered expression of transport proteins and molecules maintaining barrier function, including those regulating pinocytosis (cellular molecule uptake process) [14]. These modifications activate microglia and astrocytes, as reduced adhesion molecule expression may decrease neuroinflammation and immune cell migration to injury sites, suggesting potential long-term effects on neuronal structures and therapeutic applications for neurodegenerative diseases [5, 25, 26]. This is reflected in pathological penetration of various molecules through the BBB. MRI contrast agents with different masses, sizes, and osmolarities can cross the BBB under specific permeability disruption conditions, with these processes being analyzable through MR signal intensity changes in the target area [26].

 

Fig. 2. Axial MRI of the brain at the level of the basal nuclei. Axial MRI of the brain 24 hours after focused ultrasound thalamotomy.
A — T2-WI, a focus of coagulative necrosis with moderate perifocal edema, laterally involving the posterior limb of the internal capsule, extending somewhat medially and caudally towards the cerebral peduncle; B — T1-WI with contrast enhancement, uneven linear accumulation of MRCA; C — SWAN pulse sequence, a significant volume of hemoglobin biodegradation products is determined in the structure and along the periphery of the lesion; D — DWI, annular increase in MR signal; E — ADC, annular decrease in MR signal, indicating a true limitation of diffusion of free water molecules. F — T2-FLAIR, a lesion with moderately pronounced perifocal edema extending laterally to the posterior limb of the internal capsule, as well as medially to the thalamus, caudally towards the cerebral peduncle.

 

Almost no MRI contrast agent penetration observed 24 hours after FUS thalamotomy may indicate partial normalization of BBB permeability following initial disruption of its integrity. The cells appear to actively restore their functions and structure, leading to normalization of the BBB’s primary functions. FUS exposure activates pro-inflammatory agents and cascade processes that also affect permeability; over time, with the initiation of reparation, the inflammatory response diminishes, resulting in restoration of the barrier function. Changes in cellular metabolism and their microenvironment, along with accompanying edema, may influence intercellular junction functionality and extracellular matrix levels, explaining the absence of agent penetration. Local changes in blood supply and microcirculation in the target area also impede agent penetration, as natural vasoconstriction and reduced blood flow occur in the coagulation necrosis zone, limiting the agent delivery. These processes may additionally be influenced by patient-specific factors: age, vascular system status, comorbidities, and concurrent or prior medication use [24, 26, 27].

The key question requiring in-depth investigation involves determining the interval for reactive restoration of BBB permeability following FUS exposure, as well as establishing the duration of this effect. In our study, we observed restoration of active agent accumulation within 1 month, indicating a temporal window during which the BBB returns to its baseline state. Further studies are required for more precise understanding of these processes [18, 26].

Conclusion

FUS opens unique prospects for temporary modulation of BBB permeability and could serve as a promising method for targeted delivery of therapeutic agents or elimination of pathological molecules from cerebral parenchyma.

Observed multidirectional changes in pathological accumulation of MR contrast agents in sonication areas provide crucial information for assessing the extent and nature of BBB dysfunction, and may also serve as treatment efficacy indicators.

Despite the method’s potential, further research is required to understand long-term effects, safety, and efficacy of repeated FUS procedures, as well as potentially develop more specific MRI contrast agents with defined molecular sizes for precise assessment of BBB changes.

The initial results obtained open new opportunities for studying BBB integrity management under various physical or chemical exposures.

The presented clinical case highlights the importance of integrating novel technologies like FUS with traditional imaging methods such as MRI to enhance diagnosis and treatment of tremor and other neurological disorders.

About the authors

Mikhail B. Dolgushin

Federal Center of Brain Research and Neurotechnologies

Author for correspondence.
Email: mdolgushin@mail.ru
ORCID iD: 0000-0003-3930-5998

D. Sci. (Med.), Professor, Head, Department of X-ray and radionuclide diagnostic methods

Russian Federation, Moscow

Christina A. Prishchepina

Federal Center of Brain Research and Neurotechnologies

Email: kprishchepina@mail.ru
ORCID iD: 0009-0009-4522-161X

radiologist

Russian Federation, Moscow

Ivan S. Gumin

Federal Center of Brain Research and Neurotechnologies; Moscow State University

Email: mdolgushin@mail.ru
ORCID iD: 0000-0003-2360-3261

radiologist, radiologist, Research and educational center

Russian Federation, Moscow; Moscow

Elena A. Katunina

Federal Center of Brain Research and Neurotechnologies; Pirogov Russian National Medical Research University

Email: mdolgushin@mail.ru
ORCID iD: 0000-0001-5805-486X

D. Sci. (Med.), Professor, Head, Department of neurodegenerative diseases

Russian Federation, Moscow; Moscow

Ilya V. Senko

Federal Center of Brain Research and Neurotechnologies

Email: mdolgushin@mail.ru
ORCID iD: 0000-0002-5743-8279

D. Sci. (Med.), Head, Neurosurgical department, Federal Center for Brain and Neurotechnology

Russian Federation, Moscow

Raisa T. Tairova

Federal Center of Brain Research and Neurotechnologies; Pirogov Russian National Medical Research University

Email: mdolgushin@mail.ru
ORCID iD: 0000-0002-4174-7114

D. Sci. (Med.), Professor, сhief physician, Medical Director, Associate Professor, Department of neurology, neurosurgery and medical genetics

Russian Federation, Moscow; Moscow

Andrey V. Dvoryanchikov

Federal Center of Brain Research and Neurotechnologies

Email: mdolgushin@mail.ru
ORCID iD: 0009-0009-0678-7821

engineer

Russian Federation, Moscow

References

Supplementary files