Neuromodulation comprises a range of therapeutic approaches to relieving symptoms, such as pain or tremors, or to restore movement or function.
Therapeutic stimulation of neurons with electrical energy or chemicals – and potentially with acoustic waves – can amplify or dampen neuronal impulses in the brain or body.
Acoustic signals in the form of ultrasound offer a promising class of neuromodulation which would be an especially valuable approach because it is non-invasive – no surgical procedure to implant electrodes for stimulation is required.
Ultrasound offers a temporary modulation that can be tuned for a desired effect. Now researchers have demonstrated that it has the potential to be targeted at neurons with specific functions.
A team led by Bin He, Ph.D., professor of biomedical engineering at Carnegie Mellon University, and funded in part by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), has demonstrated the potential of a neuromodulation approach that uses low-intensity ultrasound energy, called transcranial focused ultrasound – or tFUS.
In a paper published in the May 4, 2021, issue of Nature Communications, the authors describe tFUS in experiments with rodents that demonstrate the non-invasive neuromodulation alternative.
“Transcranial focused ultrasound is a promising approach that could be used to treat forms of chronic pain, among other applications,” said Moria Bittmann, Ph.D., director of the NIBIB program in Biorobotic Systems. “In conditions where symptoms include debilitating pain, externally generated impulses of ultrasound at controlled frequencies and intensity could inhibit pain signals.”
For their studies, He and his team designed an assembly that included an ultrasound transducer and a device that records data from neuron signals, called a multi-electrode array. During experiments with anesthetized rodents, the researchers penetrated the skull and brain with various brief pulses of acoustic waves, targeting specific neurons in the brain cortex.
They simultaneously recorded the change in electrophysiological signals from different neuron types with the multi-electrode array.
When a signal is sent from one neuron to another, whether engaging the senses or controlling movement, the firing of that signal across the synapse, or junction, between neurons is called a spike. Two types of neurons observed by the researchers are excitatory and inhibitory neurons.
When the researchers used tFUS to emit repeated bursts of ultrasound stimulation directly at excitatory neurons, they observed an elevated impulse rate, or spike.
They observed that inhibitory neurons subjected to the same tFUS energy did not display a significant spike rate disturbance.
The study demonstrated that the ultrasound signal can be transmitted through the skull to selectively activate specific neuron sub-populations, in effect targeting neurons with different functions.
“Our research addresses an unmet need to develop non-toxic, non-addictive, non-pharmacologic therapies for human use,” said He. “We hope to further develop the tFUS approach with variation in ultrasound frequencies and to pursue insights into neuronal activity so that this technology has the optimal chance for benefiting brain health.”
The application of this research has broad implications; it’s not just limited to one disease. For many people suffering from pain, depression and addiction, He believes non-invasive tFUS neuromodulation could be used to facilitate treatment.
“If we can localize and target areas of the brain using acoustic, ultrasound energy, I believe we can potentially treat a myriad of neurological and psychiatric diseases and conditions,” He said.
The editors at Nature Communications also selected the paper for a special feature, called “From brain to behaviour,” which comprises some of the most exciting work on the brain published this year by the journal.
Focused Ultrasound Neuromodulation
Transcranial focused ultrasound (tFUS) is a new tool for noninvasive neuromodulation . Compared to classic noninvasive brain stimulation techniques, like magnetic or electric stimulations, tFUS can stimulate deep structures showing a higher spatial resolution. Thanks to this feature, tFUS can target, virtually, any site of the peripheral or central nervous system ; therefore, it is a perfect candidate as a tool for pain neuromodulation.
In addition, tFUS allows a wide spectrum of stimulation parameters, which leads to different biological effects: from reversible neural activity facilitation or suppression (low-intensity, low-frequency ultrasound (LILFUS)) to irreversible tissue ablation (high-intensity focused ultrasounds (HIFU)) .
HIFU for Pain Management
Although neuromodulatory approaches have replaced many neurosurgical interventions in the management of chronic pain, ablative surgery remains an important part of the therapeutic approach for selected patients . It is important to note that to date only FUS-mediated thalamotomy for chronic neuropathic pain and FUS-mediated ablation of selected tumors (bone metastases, osteoid osteoma, uterine fibroids, breast fibroadenoma, and pancreatic cancer) have been approved for human applications. All the remaining is represented by potential applications at a research stage. In Table 1, the most relevant studies on HIFU pain management are listed, with targets on central or peripheral nervous system.
HIFU for pain management.
|Site||Guide||FUS application||Target||Ongoing clinical trials||Published results||Stage|
|CNS||MR||Chronic neuropathic pain||Thalamus (CL nucleus)||NCT03111277||[51,52]||Human ¶|
|MR||Chronic pain from spinal cord injury|
|MR||Phantom limb pain|
|MR||Chronic trigeminal neuropathic pain||Medial thalamus||NCT03309813|
|NA||Chronic neuropathic pain||Spinal commissurotomy||—||||Preclinical (not further developed)|
|PNS||Management of tumor-related pain|
|MR or US||(1) Bone metastases and primary bone malignancies related pain||Lesion||NCT02616016|
|[54–67]||Human ¶, §|
|MR or US||(1) Osteoid osteoma and other benign bone tumors related pain||Lesion||NCT02618369|
|MR or US||(1) Uterine fibroids related pain||Lesion||NCT02736435||[76–93]||Human ¶, §|
|MR or US||(1) Breast fibroadenoma related pain||Lesion||NCT02488655|
|MR or US||(1) Pancreatic cancer-related pain palliative treatment||Lesion||NCT01786850 (expanded acc.)|
|NA||(1) Recurrent rectal cancer-related pain palliative treatment||Lesion||NCT02528175||—||Human|
|NA||(1) Recurrent gynecological cancer-related pain palliative treatment||Lesion||NCT02714621||||Human (case report)|
|NA||(1) Advanced rectal and gynecological cancers-related pain palliative treatment||Lesion||NCT01097239||—||—|
|Other nontumoral gynecologic conditions|
|US||(1) Endometriosis related pain||Lesion||—||[103, 115–117]||Human|
|US||(1) Adenomyosis related pain||Lesion||—||||Human|
|Management of bone/joint nontumoral pain|
|MR||(1) Low back pain from lumbar facet joint osteoarthritis (without radiculopathy)||Facet joint/lumbar medial branch nerve||NCT03321344||[119, 120]||(a) Human ¶|
|MR||(1) Low back pain from lumbar sacroiliac joint dysfunction||Sacroiliac joint||—||||Preclinical|
|NA||(1) Spinal disc herniation related pain||Intervertebral disc||—||[122, 123]||Preclinical (not further developed)|
|MR||(1) Knee osteoarthritis related chronic pain||Knee joint||—||||Human|
|MR||Phantom/residual limb pain||Stump neuromas||NCT03255395||—||Human|
|MR or US||Chronic neuropathic pain (nerve ablation, irreversible conduction block)||Peripheral nerves||—||[120, 125–128]||Preclinical|
HIFU at the CNS Level
Among the different potential pain networks’ targets (Figure 1), in the central nervous system to date, the approved indication in Europe for MR-guided HIFU is the thalamus for chronic neuropathic pain treatment.
(1) HIFU Thalamotomy. Neuropathic pain (NP) is pain arising as a direct consequence of a lesion or disease affecting the somatosensory system . It has an estimated prevalence of 7–10% in the general population, it can have multiple central and peripheral etiologies, and its pathophysiology has not been fully clarified . Management of NP is complex, and many patients do not respond to pharmacologic treatment . For selected patients with refractory NP, alternative interventional strategies are considered, which include nerve blocks, surgical procedures that deliver drugs to desired areas, neuromodulation, and, less frequently, ablative procedures. However, controversies about these interventions exist [37, 38].
The posterior part of the CL nucleus, defined according to the Morel Stereotactic Atlas , has been proposed as a key target for pain management. However, placing proper lesions in CL nucleus is difficult, due to the complex three-dimensional structure of the nucleus .
Following a consolidated experience in stereotactic radiofrequency intracranial ablative procedures, the group from the Department of Functional Neurosurgery of the University Hospital of Zurich, Switzerland, used the HIFU technology to obtain the first noninvasive medial thalamotomies in patients suffering from chronic neuropathic pain. Preliminary results were published in 2009  and extended results in 2012 . Overall, 12 patients were treated (aged 45–75 years old), suffering from different types of neuropathic pain (facial, thoracic, lower extremity, upper extremity, and hemi body) of central or peripheral origin. Thermolesions were obtained in 11 over 12 treated subjects. CL thalamotomy was centered at the posterior part of the CL nucleus of the thalamus. Lesions were bilateral in 6 patients, and unilateral (contralateral to pain location) in 5 patients. Four patients had been previously treated with radiofrequency. Two patients had too small lesions. Therefore, analysis of global pain relief was reported for 9 patients only (8 patients at 1-year follow-up). Mean group pain relief was 71% at 2 days after treatment (9 patients), 49% at 3 months (9 patients), and 57% at 1 year (8 patients). VAS improvement was similar at 3 months (42%) and 1 year (41%). One patient had a focal bleed in the target site, associated with motor thalamus ischemia. All patients presented transient somatosensory, vestibular, or vegetative effects during sonication. In 8 patients, EEG recordings were carried out at baseline, 3 months, and 12 months, revealing a progressive reduction towards normal values of the spectral power amplitudes.
Data about the safety and efficacy of noninvasive HIFU mediated CL thalamotomies should be interpreted with caution, due to the small and heterogeneous population treated. Long-term clinical efficacy and long-term radiological evolution of the lesions should be assessed. Two clinical trials on MRgHIFU-mediated medial thalamotomies are ongoing: one (phase 1, single arm) including patients with chronic neuropathic pain due to radiculopathy, spinal cord injury, and phantom limb pain (NCT03111277). The other one (randomized, crossover, sham-controlled) is recruiting patients with chronic trigeminal neuropathic pain (NCT03309813). A global, multicenter, open-label, observational registry for data related to thalamotomy and pallidotomy procedures in multiple neurological diseases has been created (NCT03100474).
(2) HIFU at Spinal Cord Level. Another region of the CNS to which HIFU has been applied is the spinal cord (single preclinical study). Interventional approaches at the spinal cord level are considered in selected cases of refractory chronic neuropathic pain.
Destructive interventions aimed at interrupting selected spinal pain pathways are technically risky and are considered in a few selected cases. They include cordotomy (lesion of the lateral spinothalamic tract), trigeminal tractotomy at the C1 level, and extralemniscal myelotomy. Such interventions can be performed with minimally invasive stereotactic procedures .
In the early stages of FUS development, Shealy and Hanneman stimulated invasively spinal cord in animals, obtaining reversible effects on spinal reflexes . Later, a specific study for pain was carried out. Following some evidence of pain relief after invasive neurosurgical procedures, discrete HIFU mediated spinal commissurotomies were performed in cats. At that time, a preliminary laminectomy was technically required. A partial reduction in gamma, delta, and pain-related C fibers-evoked potentials was observed .
HIFU at the PNS Level
When targeting the peripheral nervous system (PNS), HIFU can be MR or US guided, depending on the target, the device, and the procedure.
Since the earliest stage of FUS development, experimental data are consistent with the hypothesis that FUS can induce a reversible or irreversible peripheral nerve ablation depending on doses. Lele  showed that some effects of FUS were temperature dependent and that the threshold between ablation and reversible effects could be narrow .
Other early studies on small animal models showed that FUS can selectively target C fibers while leaving A fibers relatively unaffected [140, 141].
Then, Foley et al. [142–144], in animal studies, observed that, depending on parameters, FUS treatment could induce a range of effects on nerves, going from temporary to complete conduction block acting on myelin with multiple mechanisms, with histological evidence of axonal demyelination and necrosis of Schwann cells  or on axons lesioning these structures, with histological evidence of axon degeneration . They discussed how this property of FUS may be beneficial for patients with different severities of spasticity and pain [142–144].
Also, other studies on small animal models showed a range of possible FUS effects, on normal  and neuropathic (diabetic) peripheral nerves [146, 147], depending on stimulation parameters. Incidental findings of FUS reversible effects on peripheral nerves come from other applications, for example, reversible vocal cord paresis following HIFU treatment on thyroid nodules  or transient neuropathies after bone metastases treatment (REF). However, the mechanisms underlying the effects of FUS on tissues are still only partially understood . Further preclinical research is important to clearly understand them before application in humans.
The major application of ablative HIFU at the PNS level is for pain relief in bone metastases. For this indication, MRgHIFU technology received both, the CE mark and the FDA approval. Phase III and phase IV clinical trials are ongoing. The other approved indication is the treatment of low back pain due to facet joint osteoarthritis. Further applications are in the research stage:
(1) Cancer-Related Pain. Cancer pain has a high prevalence among cancer patients and cancer survivors [159, 160]. Multiple causes contribute to its origin and persistence (including chemotherapy and surgery-related pain) and different types of pain (nociceptive, visceral, neuropathic, and incident cancer pain) can coexist . Management of cancer pain is complex and associated with adverse effects, and often it is only partially successful . The persistence of pain has a significant negative impact on the quality of life, morbidity, and mortality of cancer patients and can interfere with the therapeutic management (e.g., requiring reduced doses of chemotherapy) .
HIFU is being applied in many cancer-related painful conditions . Following the experience on uterine fibroids —frequent benign tumors that can cause pelvic pain —HIFU has been applied to the palliative treatment of bone metastases, a frequent and multifactorial cause of cancer pain .
Mechanisms by which FUS induces analgesia in bone metastases are not entirely understood. Periosteal denervation and tumor debulking (alone or in combination) have been suggested . A decrease in circulating immunosuppressive cytokines after MRgHIFU treatment [167, 168] has also been reported. However, its significance is still unknown. Procedure-related pain, skin burns, posttreatment fractures and neuropathy have been reported among the side effects of HIFU treatment of bone metastases . The safety and efficacy profiles, the potential to perform multiple repeated treatments (in contrast with radiation therapy) in an outpatient modality make this approach extremely promising. MR-guided HIFU is now recommended as a second-line treatment for palliation of pain related to nonspinal and nonskull bone metastases after the failure of radiation therapy and it can be used as a first-line treatment when radiation therapy is contraindicated or the patient refuses it .
HIFU is also being applied with encouraging results to the palliative treatment of nonresectable pancreatic cancer [169, 170], which is a cause of pain in about 80% of cases .
To date, HIFU received both the CE mark and the FDA approval for the treatment of uterine fibroids and bone metastases. Furthermore, it has the CE mark for the treatment of osteoid osteoma and pancreatic cancer.
(2) Nontumoral Bone/Joint Disease. MRgHIFU is approved in Europe for the treatment of facet joint osteoarthritis. HIFU has been successfully applied in humans also to the knee joint. Preclinical research is ongoing on the sacroiliac joint. Studies on HIFU-mediated intervertebral disc nucleolysis are ongoing (cf. below).
(3) Facet Joint Arthritis. Facet joint arthritis is a common cause of low back pain and disability. Facet joints (or zygapophyseal joints) are innervated by the medial branches of the dorsal primary branch of the spinal nerves. Nociceptive stimuli can arise from mechanical factors and synovial inflammation and are often associated with a reflex painful muscular spasm of paraspinal muscles .
HIFU sonication is thought to induce a thermal ablation of the nerve terminals on the facet joints, although noninvasively. This application of HIFU could reduce complication risks and could be applied for outpatient pain management. Weeks et al.  published the results of a phase I, single-arm, open-label, prospective clinical trial. They treated 18 patients (mean age 48.2 years) affected by chronic back pain from facet joint arthritis. 13 patients were included in the follow-up. A significant improvement in pain scores and functional disability measures was observed. Results at 6 months were considered comparable to RF denervation. No adverse side effect was reported . This trial provides preliminary data about the safety and efficacy of MRgFUS application in the treatment of low back pain due to facet joint osteoarthritis. For this indication, the ExAblate system (InSightec) received the CE mark. Preclinical research is also ongoing to address some technical issues .
A different approach targeting nerve endings on the facet joints has been recently explored at a preclinical level. Kaye et al.  demonstrated that, similar to radiofrequency neurotomy, a direct MRgHIFU ablation of the medial branch nerve can be achieved. Histology showed a clear nerve thermal necrosis without damage to adjacent structures . A single-arm, open-label RCT is ongoing (NCT03321344, using Neurolyser XR portable device, FUSMobile Inc.).
(4) Sacroiliac Joint Dysfunction. Sacroiliac joint pain has an estimated prevalence of about 25% among patients with low back pain . When conservative management has failed, interventional treatments for pain relief are considered. They include intra-articular injections, periarticular injections, sacral branch blocks, radiofrequency ablation of the supplying nerves, and minimally invasive fusion surgery [175, 176]. The sacroiliac joint is innervated by the dorsal branch of L5 and S1–S4 roots. However, individual variability exists . This anatomical variability could give rise to incomplete radiofrequency ablation. For its unique noninvasiveness and high imaging definition, MRgHIFU-mediated ablation has been considered a potential additional strategy to explore. To date, one preliminary experiment has been performed in a swine model, as a proof of concept .
(5) Spinal Disc Herniation. The use of HIFU for the treatment of intervertebral disc herniation as a potential alternative strategy to percutaneous electrothermal treatment has been explored. Preliminary data about the feasibility of HIFU mediated approaches have been published for in vitro , ex vivo, and invasive in vivo models .
(6) Knee Osteoarthritis. Following the evidence of successful pain relief obtained by MRgHIFU-mediated treatment of bone metastases and facet joint arthritis, Izumi et al.  performed MRgHIFU-mediated knee treatment in 8 subjects affected by chronic pain from knee osteoarthritis. Sonication targeted the bone surface, below the rim osteophyte of the medial tibial plateau. The hypothesized mechanism of action is a denervation effect; 6 out of 8 patients had an immediate and significant VAS reduction, which was still present at 6-month follow-up in 4 subjects. No adverse side effects were reported .
Moreover, low-intensity FUS has been applied to knee osteoarthritis in a prospective randomized placebo-controlled clinical trial . 106 patients were treated with “FLIPUS” (focused low-intensity pulsed ultrasound) + diclofenac sodium sustained-release tablets (53 patients with real FLIPUS, 53 with sham, all with diclofenac). FLIPUS stimulation was applied to both sides of the knee, for 20 min, once daily, for 10 days. The primary outcome was knee pain on movement for 5 minutes, assessed by VAS. The real stimulation group had a significantly greater improvement in VAS scores compared to the sham stimulation group. The improvement lasted for about 4 weeks after treatment. No FLIPUS-related adverse events were reported. In animal models, FLIPUS showed to promote bone regeneration  and extracellular matrix production through a downregulation of chondrocyte apoptosis, of the joint effusion volume, and of the release of prostaglandin E2 and nitric oxide .
Due to the high prevalence and socioeconomic impact of knee osteoarthritis, both approaches seem promising and deserve further research.
Other Potential HIFU Applications at the PNS Level
(1) Phantom Limb Pain. Phantom limb is a heterogeneous disorder, with an estimated prevalence of 43%–51% in amputee and is frequently associated with phantom limb sensations [180, 181]. The causes of variable individual susceptibility are not known. Stump neuromas, which contain disorganized A fiber and C fiber terminals, are frequently associated with a phantom limb. The central nervous system is also involved: pathological phenomena at the spinal cord level (sprouting of fibers from lamina III and IV in lamina II, increased excitability, and expansion of the dorsal horn receptive field) and at a supraspinal level (thalamus, sensorimotor cortex) have been described. Surgical invasive procedures are limited to selected refractory cases and include neuroma ablations, dorsal root entry zone lesioning, anterolateral cordotomy (of the spinothalamic tract), thalamotomy, and sympathectomy. However, pain relief produced by these procedures is often short-lived . Transected nerve endings in residual limbs of amputee patients have been found more sensitive to HIFU sonication compared to control tissue and intact nerves . Preclinical studies had already shown similar data, starting from pioneering studies [140, 141]. This higher sensitivity of transected nerve endings to FUS stimulation could allow selective denervation. A clinical trial is ongoing (single group, open-label, NCT03255395) to assess feasibility, safety, and efficacy of MRgHIFU-mediated ablation of stump neuromas (also trial NCT03111277 recruits patients suffering from phantom limb pain, which will be treated by MRgHIFU-mediated CL thalamotomy). However, data about the safety and long-term efficacy are needed.
(2) Ablation of Peripheral Nerves. FUS is being studied as a potential noninvasive option for producing peripheral nerve ablations.
Peripheral nerve ablation is a technique used in some cases of chronic neuropathic pain and cancer pain . It is also used for patients suffering from low back pain, to predict the outcome of ablative procedures (see above). Ablative methods include chemical denervation, cryoneurolysis, and radiofrequency ablation. In swine models of intercostal nerves ablation, HIFU mediated lesions showed a well-demarcated thermal necrosis immediately after the procedure. At the same time, neither RF ablations nor alcohol ablations showed radiological signs of lesions, suggesting a different mechanism of action of FUS .
The feasibility of MRgHIFU-mediated ablations was demonstrated in other large animal studies for the sciatic nerve  and the lumbar medial branch nerve . Some difficulties exist in visualizing superficial peripheral nerves with MR. In a pilot study, 3D MR neurography showed high potential for guiding HIFU therapy ablation of peripheral nerves . An ultrasound-guided approach for HIFU peripheral nerve block has been demonstrated feasible in an in vivo large-animal study. However, at the current stage, only MR-guided procedures allow a noninvasive temperature monitoring strategy. A noninvasive thermometry technology for ultrasound-guided ablation is at a developmental stage .
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261174/
More information: Kai Yu et al, Intrinsic functional neuron-type selectivity of transcranial focused ultrasound neuromodulation, Nature Communications (2021). DOI: 10.1038/s41467-021-22743-7