Transcranial focused ultrasound (tFUS) at low intensities has been reported to directly evoke responses and reversibly inhibit function in the central nervous system. While some doubt has been cast on the ability of ultrasound to directly evoke neuronal responses, spatially-restricted transcranial ultrasound has demonstrated consistent, inhibitory effects
Transcranial magnetic resonance guided focused ultrasound is increasingly used to non-invasively treat a wide variety of neurological disorders including essential tremors, Parkinson disease and neuropathic pain. Although this treatment is an MRI-guided procedure, the current pre-treatment screening and planning involve a CT of the head to obtain three-dimensional skull images. These images are necessary for estimating the proportion of absorbed energy and the acoustic phase shift associated with the skull and determining the transmit energy of ultrasonic wave to create thermal lesions at a desired focal spot. Ultrashort Echo Time MRI sequences are able to capture signals from tissues such as bone which has a very short transverse relaxation time 2).
In contrast to traditional ablative interventions, transcranial MRgFUS surgery is entirely imaging-guided and uses continuous temperature measurements at the target and surrounding tissue taken in real-time. Unlike Gamma Knife radiosurgery, MRgFUS surgery can make a lesion immediately and does not use ionizing radiation. Moreover, since no metallic device is implanted, MR imaging-based diagnosis is not restricted throughout life.
An additional strength of transcranial MRgFUS surgery is its ability to focus acoustic energy through the intact skull onto deep-seated targets, while minimizing adjacent tissue damage. Even though the established indications of MRgFUS include bone metastases, uterine fibroids, and breast lesions, several promising preclinical and phase I clinical trials of neuropathic pain, essential tremor, Parkinson's disease (PD), and obsessive-compulsive disorder have demonstrated that the delivery of focused ultrasound energy promises to be a broadly applicable technique. For instance, this technique can be used to generate focal intracranial thermal ablative lesions of brain tumors, or to silence dysfunctional neural circuits and disrupt the blood-brain barrier for targeted drug delivery and the modulation of neural activity 3).
The objective of the research in the last decade was to be able to apply FUS also to the treatment of intracranial neoplastic diseases, using both the thermal effects (thermal ablation) and, above all, the ability to permeabilize Blood Brain Barrier (BBB) and modify the tumor microenvironment. This may allow the use of drugs that are currently poorly active on the CNS or active at high doses and selectively, minimizing the side effects and substantially modifying the prognosis of patients affected by these diseases. In the future, targeted drug delivery, immunotherapy and gene therapy will probably become main players in the treatment of brain neoplasms, finding a precious aid in MRgFUS. In this way, it will be possible to directly intervene on tumor cells while preserving healthy tissue at the same time 4).
Magnetic resonance imaging-guided focused ultrasound surgery (MRgFUS) is especially appealing for applications in the brain where target volumes have to be accessed with high precision without inflicting collateral damage to surrounding healthy tissue. In 2013 a MRgFUS system was CE certified for the treatment of functional neurological disorders, such as chronic neuropathic pain and movement disorders. Currently, some 400 patients have been treated worldwide using this system, which is also undergoing clinical testing for the treatment of primary brain tumors and brain metastases 5).
The MRgFUS procedure is clinically established in particular for the treatment of symptomatic uterine fibroids, followed by palliative ablation of painful bone metastases. Furthermore, promising results have been shown for the treatment of adenomyosis, malignant tumors of the prostate, breast and liver and for various intracranial applications, such as thermal ablation of brain tumors, functional neurosurgery and transient disruption of the blood-brain barrier 6).
For transcranial brain therapy, the skull bone is a major limitation, however, new adaptive techniques of phase correction for focusing ultrasound through the skull have recently been implemented by research systems, paving the way for HIFU therapy to become an interesting alternative to brain surgery and radiotherapy 7).
The thermal injury to nervous tissue within a specific threshold of 50°C to 60°C with the tissue near the sonication center yielding the greatest effect; adjacent tissue showed minimal changes. Additional studies utilizing this technology are required to further establish accurate threshold parameters for optic nerve thermo-ablation 8).
Future clinical applications of magnetic resonance imaging-guided high-intensity focused ultrasound (MRgHIFU) are moving toward the management of different intracranial pathologies.
Transcranial focused ultrasound (FUS) can noninvasively transmit acoustic energy with a high degree of accuracy and safety to targets and regions within the brain.
Transcranial focused ultrasound (tcFUS) is an attractive noninvasive modality for neurosurgical interventions. The presence of the skull, however, compromises the efficiency of tcFUS therapy, as its heterogeneous nature and acoustic characteristics induce significant distortion of the acoustic energy deposition, focal shifts, and thermal gain decrease. Phased-array transducers allow for partial compensation of skull-induced aberrations by application of precalculated phase and amplitude corrections.
Technological advances, including phased-array transducers and real-time temperature monitoring with magnetic resonance thermometry, have created new opportunities for FUS research and clinical translation.
Simulation-based approaches to calculate aberration corrections may aid in the extension of the tcFUS treatment envelope as well as predict and avoid secondary effects (standing waves, skull heating). Due to their superior performance, simulationbased techniques may prove invaluable in the amelioration of skull-induced aberration effects in tcFUS therapy. The next steps are to investigate shear-wave-induced effects in order to reliably exclude secondary hot-spots, and to develop comprehensive uncertainty assessment and validation procedures 9).
In a report, investigators sought to establish the ability of transcranial focused ultrasound (tFUS) to modulate brain activity in the human primary somatosensory cortex 10).
Legon et al employed a single-element tFUS transducer to transmit a 0.5 MHz pulsed wave for 500 ms. The acoustic power of the tFUS waveform used was well below the maximum recommended limit for diagnostic imaging applications. The authors first characterized the acoustic pressure field emitted from the tFUS transducer in an acoustic test-tank. Next, a magnetic resonance imaging-based 3-D simulation model of a human head was created to estimate acoustic field distribution in the brain during tFUS. Ultimately the authors assessed the neuromodulating influence and spatial resolution of tFUS targeted to Brodmann area 3b by examining effects on somatosensory evoked potentials (SEPs) and sensory detection thresholds via within-subjects, sham-controlled, blinded design study of 12 volunteers. Primary endpoints included amplitude of short-latency and late-onset evoked potentials by median nerve stimulation, as well as two-point and frequency discrimination tasks. The focal volume of the ellipsoid acoustic beam produced was 0.21cm3 at 50% maximum intensity line and demonstrated spatial resolution of 4.9mm laterally and 18mm axially when focused through the human skull. Electrophysiologic studies demonstrated that tFUS targeted to Brodmann area 3b significantly reduced the amplitude of short-latency and late-onset evoked cortical activity elicited by median-nerve SEPs. The effects of tFUS on SEP activity were abolished when targeted to brain regions 1 cm posterior or 1 cm anterior to the postcentral gyrus. Functional investigations revealed that tFUS targeted to somatosensory cortex significantly enhanced discrimination of pins at closer distances as well as frequency of air puffs, without affecting response bias or task attention. Additionally, the authors noted that volunteers did not report thermal or mechanical sensations due to tFUS transmission through the scalp. Similarly, there were no reports of perceptual differences between the sham and tFUS conditions. These data demonstrate that a pulsed acoustic beam created by a single-element 0.5-MHz tFUS transducer for 500 ms can be used to transiently and noninvasively modulate neuronal activity in the cortex of humans. tFUS may transiently shift the balance of neuronal activity in favor of local inhibition, perhaps through either dampening thalamocortical excitation or increasing interneuron inhibitory firing. One hypothesis for the paradoxical improvement in somatosensory discrimination provided by the authors is through filtering by local inhibition. In other words, the inhibition produced by tFUS may reduce spatial spread of cortical excitation resulting in restricted neuronal population activation and a more precise cortical representation of tactile stimuli. Although this study provided evidence that the influence of tFUS can be restricted to discrete modules of cortex, it did not elucidate which cellular structures tFUS most affects. Further studies are needed to characterize whether neurophysiologic effects vary according to anatomic location and/or cytoarchitectonic division. One of the most enticing applications of tFUS is the possibility of noninvasive, functional brain mapping of both cortical and sub-cortical structures and circuits. Subablative sonication targeting the ventral intermediate region of the thalamus has already been used to provide functional target confirmation prior to lesioning with MR guided high-intensity FUS. However, the current study highlights the nondestructive capabilities of tFUS and inspires exploration of potential applications in both the research and clinical settings. 11).
Focused ultrasound (FUS) produces a region of high intensity at the focal zone of the beam but with minimal effects at adjacent areas, allowing the sonication of deep targets throughout the body. Despite early obstacles to transmitting ultrasound energy through the skull, recent advances in ultrasound technology, software, and real-time monitoring have resulted in a renewed interest in the clinical applications of transcranial FUS. Following extensive pre- clinical studies, ultrasound-induced thermal ablation has been approved by several countries for the treatment of essential tremor, Parkinson's disease, obsessive-compulsive disorder, depression, and neuropathic pain. Ongoing clinical trials involving patients with brain tumors, Alzheimer's disease, or epilepsy, and pre-clinical work involving stroke and hydrocephalus have the potential to significantly expand the possible indications for transcranial FUS in the future 12).
High Intensity focused ultrasound (HIFU) is a novel, totally non-invasive, image guided therapy that allow for achieving tissue destruction with the application of focused ultrasound at high intensity. This technique has been successfully applied for the treatment of a large variety of diseases, including oncological and non-oncological diseases. One of the most fascinating aspects of image-guided ablations, and particularly of HIFU, is the reported possibility of determining a sort of stimulation of the immune system, with an unexpected “systemic” response to treatments designed to be “local” 13).
Focused Ultrasound (FUS), in conjunction with microbubbles, is the only technique that can induce localized blood brain barrier opening noninvasively and regionally. FUS may thus have a huge impact in trans-BBB brain drug delivery. The primary objective is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS, which are responsible for inducing the BBB disruption. The mechanism of the BBB opening in vivo is monitored through the MRI and passive cavitation detection (PCD), and the safety of BBB disruption is assessed using H&E histology at distinct pressures, pulse lengths and microbubble diameters. It is hereby shown that the BBB can be disrupted safely and transiently under specific acoustic pressures (under 0.45 MPa) and microbubble (diameter under 8 μm) conditions 14).
The effects of focused ultrasound (FUS) on neuronal activity have been studied since the 1920s, and in animals have been shown to modulate activity of peripheral nerves, the retina, spinal reflexes, hippocampus, and motor cortex.
Unlike high intensity, continuous ultrasound (US), FUS can exert nondestructive mechanical pressure effects on cellular membranes and ion channels without producing cavitation and thermal injury. Animal studies have demonstrated the ability of FUS to reversibly suppress visual evoked potentials, modulate activity of the frontal eye fields, and disrupt seizure activity, all in the absence of cellular damage.