MR-guided high-intensity focused ultrasound for chronic pain: where do we stand?

KEYWORDS:

• Incisionless magnetic resonance-guided focused ultrasound
• chronic pain disorders
• sensory thalamic nuclei
• limbic pain matrix
• objective outcome measures

1. Introduction

Despite tremendous efforts in diagnosis and therapy of chronic pain disorders, a relatively large proportion of chronic pain suffers are classified refractory to pharmacological and behavioral/psychotherapeutic treatments. This therapeutical dilemma is associated with an impaired functional state (sensory alteration, sleep architecture deterioration, cognitive decline, mood disturbance, metabolic deterioration) and impacts the overall quality of life of the affected pain individuals, which in turn leads to a relevant socio-economic burden in order to cover the long-term therapies and public health issue with detrimental effects [1]. Although the incidence of distinct chronic pain disorders may vary, as back pain and headache disorders occur in a high number, adjunctive, and complementary therapeutics using neuromodulation techniques should be considered [2]. These neuromodulation techniques may target superficial or deeper brain structures, the spinal cord, and the peripheral nerve system using noninvasive, less invasive, and invasive surgical approaches. It is noteworthy that the quality of evidence has been classified as minimal to moderate most for most of the clinically used neurostimulation techniques such as noninvasive, non-ablative techniques [transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), transcutaneous vagus nerve stimulation (tVNS)], noninvasive, ablative therapies [Gamma Knife radiosurgery (GKRS), thermal radiofrequency (RFA)] and invasive, non-ablative brain stimulation procedures [deep brain stimulation (DBS), surface/epidural brain stimulation (MCS)]. It is noteworthy that despite central pain modulation, spinal cord stimulation (SCS), peripheral nerve/nerve field stimulation (PNS), and dorsal root ganglia stimulation represent approved and widely used pain interventions. Nevertheless, the need to move more toward high-quality evidence may not limit the worthiness of neurostimulation, which in part alleviated chronic pain levels depending on the applied technique [2–6].

This editorial addresses and discusses current and emerging needs in the field of MR-guided focused ultrasound (MRgFUS) clinical research for the treatment of chronic pain disorders. Furthermore, the author aimed to present and evaluate the most recent advances in MRgFUS as an additional central neurotherapeutics despite other available cerebral modulation technologies. Along these lines, it provides a possibility for potential outcome measures needed to evidently underpin the clinical effects after MRgFUS treatment. The idea to use ultrasound to modulate brain circuits is not new and has been considered for many decades. However, due to several technical limitations such as the need of craniotomy to avoid ultrasound distortion along with the lack of intracranial thermal mapping methodologies (neuroimaging-based thermometry) by MRI, it was not possible to accurately monitor the created brain lesion in real time [7]. Notably, William Fry (1918–1968) and Russels Meyers (1904–1999), pioneers of ultrasound application, published a small-scale study in which the clinical usefulness of ultrasound was evaluated for Parkinson’s patients in 1954 [8,9]. Due to nascent developments, ultrasound operating at higher frequencies between 650 and 720 kHz (MRgFUS) nowadays permits to create small and precisely located brain tissue lesions in an incisionless approach bypassing the cranial vault under guidance of a stereotactic frame and secured through MR-based thermal software, which allows MR-guided focused ultrasound (MRgFUS) to reach deeper brain structures, such as the basal ganglia (globus pallidus) and the thalamus (nucleus ventralis intermedius, VIM/ventroposterolateralis nucleus VPL/central lateral nucleus of the thalamus CLT), which in turn represent well-established targets for the treatment of movement (tremor-dominant Parkinson's disease, essential tremor) and neuropsychiatric disorders (depression, obsessive-compulsive disorder), and chronic pain (neuropathic pain) [8–10]. From the reimbursement perspective, MRgFUS consisting of a helmet-like array with integrated stereotactic frame was approved (FDA and CE) for unilateral thalamotomy in combination with MRI scanners from GE Healthcare Inc. and Siemens Healthineers Inc. and most recently received FDA clearance for staged bilateral thalamotomy awaiting CE soon [10]. Although addressed to tremor, long-term data covering 5 years post-MRgFUS treatment is available, demonstrating the safety and efficacy of MRgFUS, thus fueling its use in additional neurological disorders, such as chronic pain [10]. The differences in acoustic velocities of the cranial vault, brain tissue, the distance between the skull base and the intended target, and the number of sonification elements represent technical challenges, which is of relevance for the created lesioning volume and therefore the therapeutic effect of MRgFUS, as distinct tissue properties may absorb, reflect, and refract ultrasonic waves. Furthermore, different MRgFUS parameters, such as peak temperature, duration, and number of sonication duration, applied energy and the created lesion volume represent relevant issues of ongoing research seeking to implement standardized MRgFUS protocol. Little is known about the underlying cellular and molecular mechanisms that mediate the long-term effects observed after ultrasound ablation, and clinical research is required ahead to decipher the mechanism of action [7,8]. However, the two-stage MRgFUS protocol (reversible lesion at a temperature 45–50°C versus permanent lesioning at higher temperature of 52–60°C) allows for target validation and clinical testing (paresthesia coverage of the painful body area/tremor suppression) in movement disorders of chronic pain depending on the target as CLT lesioning or stimulation for instance does not evoke paresthesia nor is functionally organized as the sensory thalamic nuclei (VPL/VPM) with distinct areas for the head, upper and lower extremities (Figure 1).

Figure 1. Somatosensory and affective nuclei of the thalamus.Schematic diagram depicting the location and composition of the thalamic nuclei relevant for pain transmission. The somatosensory thalamus includes the nuclei ventromedialis (VPM) and ventrolateralis (VPL); (yellow), and the centromedian-parafascicular complex of the thalamus (CmPf), which is located in internal lamina (gray).Reproduced from [9] with permission of Springer Nature.

Published data are derived in the vast majority from uncontrolled observational trials emphasizing the urgent need for randomized-controlled clinical data. Nevertheless, interesting lessons were that bilateral thalamotomy can be performed in a safe manner. Secondly, lesioning of affective brain circuits (CLT) demonstrated a sustained response for neuropathic pain. Thirdly, in those cases, were a larger lesion volume reached other thalamic nuclei, like CmPf, which like the CLT contain rich reciprocal projections to components of the limbic pain matrix, a clinical meaningful responsiveness was present too. These projections included but are not limited to the anterior cingulate cortex (ACC), the anterior limb of the internal capsule (ALIC), and the ventral striatum (VS) [9,11–15]. These findings are of great interest as they may open new avenues to define novel targets for MRgFUS to treat chronic pain. Preliminary data indicate that ACC-DBS and ALIC/VS-DBS promote pain relief; therefore, it appears to be reasonable to discuss and explore ACC and ALIV/VS as novel targets for ultrasound brain modulation. It is well known that CmPf, CLT, ACC, and ALIC/VS account for the limbic domain of cerebral pain processing (Figure 2). These preliminary, uncontrolled results remain to be supported by a growing number of MRgFUS treated pain patients in additional uncontrolled and randomized-controlled studies which are currently on the way. In all ongoing studies, thalamic nuclei are the targets of choice exhibiting distinct response pattern, either the sensory VPL/VPM, or CLT, which is predominantly associated with affective pain transmission. Despite subjective score-based assessment, more and more clinical trials are looking after objective outcome measures like EEG, LEP, and functional/structural neuroimaging relevant for central pain pathways and which might help to better understand these changes in cerebral pain circuits. For instance, an ongoing trial (NCT 04283643) determines MRgFUS effects compared to TMS in acute versus chronic pain versus healthy controls, thus starting to generate comparative data and extending MRgFUS toward acute pain. Another RCT is probing the safety and efficacy of bilateral thalamic ablation proposing a staged protocol, which already has been published for tremor treatment by ultrasound means [10]. Along these lines, sham MRgFUS lesioning is integrated the protocol of another in-human study (NCT 05122403) scoping to unlock clues relevant for the principles of MRgFUS. Despite its approval for thalamotomy for neuropathic pain. MRgFUS received approval for the treatment of facet joint osteoarthritis and is being probed knee osteoarthritis, sacroiliac joint disorders, intervertebral disc nucleolysis, and lesioning of peripheral nerves [16]. Table 1 summarizes current published data and ongoing registered trials.

Figure 2. Projections of the somatosensory and affective pain circuits of the thalamus.Pain processing pathways are highlighted within the cerebral tissue. The somatosensory process and pain memory pathway originate from the brainstem and spinal cord via ascending fibers and project to the thalamic nuclei (CmPf, VPM/VPL, CLT). Signals from the VPL project to the somatosensory cortex, located in the parietal lobe, and these signals are processed in the primary (S1) and secondary (S2) regions. The affective pain processing pathways originate from the CmPF /CLT and project to the insula, the anterior cingulate cortex (ACC) and prefrontal cortex (PFC). Reproduced from [9] with permission of Springer Nature.

Table 1. Clinical trials assessing the efficacy and safety of MRgFUS for chronic pain disorders and appproaching different targets associated with sensory and limbic brain circuits.

Reference	PN	Design	Target	Indication	FU	Outcome	SAE/AE
Gallay, 2020 [15]	8	OT	MRgFUS CLT (peak 51–64°C)	TN	53 m	51% pain relief/3 m 71% pain relief/12 m 78% pain relief/53 m	None
Jeanmonod, 2012 [14]	12	OT	MRgFUS CLT (peak 51–64°C)	NP	12 m	49% pain relief/3 m 57% pain relief/12 m	1 ICH
Gallay, 2018 [13]	180 (treatments)	OT	MRgFUS CLT (peak 51–64°C)	NP	3 m	na	None
Martin, 2009 [12]	9	OT	MRgFUS VPL (Peak temperature 51–60°C)	NP	N.a.	Mean pain relief 68% after 2 d	None
NCT03111277	10	OT	MRgFUS CLT	NP PP	12 m	NRS/BPI SAE	—
NCT04579692	10	OT	MRgFUS CLT	TN	6 m	NRS/BPI/PGIC/BNI	—-
NCT03100474	500XX	OT/PR	MRgFUS thalamic nuclei/na	NP	5y	——	—–
NCT04485208	40	OT	MRgFUS VPL/VPM	NP	8w	NRS/BPI/PHQ-9	—-
NCT04649554	30	OT	MRgFUS na	NP	3-12 m	NRS/PDI/PCS/PROMIS GHQ/PROMIS SDQ/AE/QST/LEP/PGIC	—-
NCT04283643	149	RT	MRgFUS/(na) TMS	AP/CP/HS	1d	NRS/EEG/MRI	—-
NCT05122403	12	RCT	MRgFUS CLT	NP	12 m	NRS/MRI/AE	—-
NCT03309813	10	RCT	MRgFUS medial thalamus bilateral	TN	3 m	NRS/PROMIS PI/AE/PGIC

Abbreviation: MRgFUS – magnet resonance guided focused ultrasound; TMS – transcranial magnetic stimulation; OT – observation trial; RCT – randomized controlled trial; RT – randomized trial; PR – patient register; y – year; m – months; w – week; d – day; FU – follow up; m – months; AE – serious adverse event; ICH – intracranial hemorrhage; NP – neuropathic pain; TN – trigeminal neuralgia; AP/CP – acute/chronic pain; PP – phantom pain; HS – healthy subjects; CLT – posterior part of the central lateral thalamic nucleus; VPL/VPM – ventroposterolateral/ventropostero-medial nucleus of the thalamus; NRS – numbering rating scale; PDI – pain disability inventor; PCS – pain catastrophizing scale; PROMIS – patient reported outcomes measurement information system; PROMIS GHQ – general health questionnaire; PROMIS SDQ – sleep disturbance questionnaire; PROMIS PI – pain inventory; QST – quantitative sensory testing; LEP – laser evoked potential; PGIC – patient´s global impression of change; BPI – British pain inventory; BNI – Barrow neurological institute; C – degree centigrade; EEG – electroencephalogram; MRI – magnet resonance tomography; XX movement disorder/pain/psychiatric cohort, NCT – ongoing trials (results not published).

Several confounding variables deserve enhanced attention when interpreting these preliminary data as there was no control of data collection bias along with missing placebo control, which could have been easily achieved by reversible ultrasound temperature between 40°C and 42°C, thus helping to control for the influence of possible confounding factors and satisfy the needs for more robust data. The level of evidence for the usefulness of MRgFUS will certainly rise soon once results are available of the several ongoing RCT but remains moderate yet. This holds true as a broad variety of brain modulation technologies are available and the accessibility for chronic pain patients depends on the structural resources of the treating site. Despite well-developed expert-guided recommendations balancing the pros and cons of the different brain stimulation therapies (invasive versus noninvasive; ablative versus non-ablative), evidence derived data comparing the different techniques is lacking, and further clinical research might be useful to categorize the suitable brain modulation treatment on a personalized level.

However, prior to the transition of MRgFUS into clinical routinely use further unmet issues need to be addressed. Along with the lack of long-term data provided by robust study protocols with standardized and objective outcome measures to provide high-class evidence and pre-clinical investigations to shed light into mechanism of action impacting central pain circuits, point-of-care MRgFUS requires interdisciplinary structural and personal resources and should be performed under the umbrella of appropriately equipped clinical research institutions with the capability to carry out such studies and care of these individuals.

2. Expert opinion

In the past years, MRgFUS proved to be an additional therapeutical tool for interventional pain therapy. Although most of the existing literature appears to be premature to finally classify the usefulness and safety guards of ultrasound ablation that do not allow generalization, this remarkable and fascinating neurotherapeutic has the potential to shape pain therapy. Various lines of clinical research and the number of treated pain patients are steadily increasing and extends indication from chronic to acute pain accompanied by objective measures such as neuroimaging and electrophysiological data aiming to elaborate the clinical effects observed so far. Given these efforts, MRgFUS has gained notoriety in the pain community. Taken the multidimensional character of pain into account, there has been an extension toward alternative and suitable brain targets within the realm of the limbic pain matrix of the brain. These developments may further promote an increasing interest for health-care professionals dedicated to pain medicine in order to learn more and be aware of the practical aspects of MRgFUS. This stratification process cannot be achieved without robust scientific background and high-class evidence leading to reproducible high-class publications. To address these gaps, an increasing number of in-human studies is currently under investigation indicating that MRgFUS is on the right track to achieve these goals. Saying so, findings derived from MRgFUS studies for tremor are helpful to characterize the efficacy and safety profile of unilateral and bilateral thalamotomy/lesioning in the long term.

A broad variety of brain modulation [TMS, tDCS, tACS, tVNS, SRS, GKRS, RFA, DBS, MCS, SCS, PNS] and ultrasound technologies have been probed to treat chronic pain disorders, each of them having distinct advantages and disadvantages with no evidently proven superiority or inferiority of each neurotechnology. Rendering a decision toward one neurotherapeutic certainly depends on the availability of resources and preferences of pain physicians and pain patients, hence a decision may be generated from case to case and should consider these mentioned and unmet issues. Despite this lack of evidence, standardized MRgFUS protocols need to be established in the near future. Further open questions remain, whether a patient is more likely to respond to sensory and/or affective ultrasound ablation.

Notably, no validated signatures and/or biomarkers are available to predict therapy responsiveness for MRgFUS as well as for the other brain modulation techniques. Study protocols including objective outcome measures such as neuroimaging, electrophysiology, and digital/molecular phenotyping are urgently needed in the field of pain therapy to counterbalance inter- and intra-individual variabilities relevant for patient selection and treatment outcome.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

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