While focused ultrasound is by no means a whole new innovation in neurotherapy – having first been deployed in the 1950s, if not earlier, for therapeutic and non-invasive purposes – the emergence of guidance Using magnetic resonance imaging (MRI) and other new technologies have dramatically increased their applications since the turn of the century, and the potential unrealized uses it has today in interventional neurology may be even greater. This theme and the possibility of a “revolution in neurotherapy” were explored during the 7th Congress of the European Academy of Neurology (EAN; June 19-22, 2021, virtual) during a session where transcranial and ultrasound surgery of the tremors, blood brain barrier opening, and focal neuromodulation with ultrasound all shown.
Andres M Lozano, President of the Neurosurgery Department at Toronto Western Hospital (Toronto, Canada), began the session by describing the use of focused ultrasound in neurosurgery, as it can be used to non-invasively penetrate the skull and create Therapeutic lesions, a technique that can be further optimized with MRI guidance. Lozano reported examples of deploying this approach to treat tremors via thalamotomy, with sound energy being delivered to an awake patient for about 13 seconds at a time.
“We usually start making small lesions at low temperatures, and gradually raise the temperature through subsequent sonications until the tremor subsides – and the effects, of course, are immediate,” he added. Lozano said that, following evidence for the effectiveness of this technique from a randomized clinical trial published in the New England Journal of Medicine (NEJM) In 2016, MRI-Guided Focused Ultrasound (MRgFUS) joined a group comprising three other major treatment options that Toronto Western Hospital offers to ambulatory patients with Parkinson’s disease and other movement disorders that have failed drugs, the first line of treatment. These surgeries are radiofrequency (RF) injury, deep brain stimulation (DBS), and gamma knife radiosurgery.
Lozano reported that around 90% of patients at the center currently opt for MRgFUS when given the choice between these four treatments. “Focused ultrasound has overtaken DBS, which ranks second among patients with tremor, and so it has really revolutionized our treatment of tremor because patients now come in and ask for focused ultrasound – and many patients don’t want to. ‘invasive therapy like RF or DBS,’ he added. Lozano asserted that there is currently a “general trend” towards minimally invasive, low-maintenance therapies like MRgFUS, and that patients and physicians who have previously avoided surgery will accept focused ultrasound as a viable option, according to her. experience.
In addition to expanding the use of focused ultrasound to bilateral staged thalamotomies for essential tremors, which has been performed in a handful of patients to date, as well as other movement disorders like dystonia, Lozano noted the possibility target other areas of the brain with focused ultrasound beyond the ventral intermediate nucleus (VIM), including the internal globus pallidus (GPi), subthalamic nucleus (STN) and pallidothalamic tract (PTT).
Concluding his presentation, Lozano hinted at many other larger areas of neurotherapy where focused ultrasound could be used, ranging from brain tumor removal to psychiatric indications such as depression, anxiety and pain, many of which are currently being studied in phase I or preclinical. testing. He also highlighted the treatment of epilepsy and hydrocephalus, and the idea of dissolving blood clots, as particularly “exciting” therapeutic possibilities, but tempered this by stating that there was still “work to be done. to do ”to explore these concepts further.
Opening of the blood-brain barrier
The second conference of the session saw Jean-François Aubry, research director at the French National Center for Scientific Research (Physics for Medicine Paris, Paris, France), discussing efforts to transiently and safely open the blood barrier. encephalic using ultrasound, which he claimed is a clinical need, as around 95% of therapeutic drugs are currently unable to cross this barrier and enter the brain.
As is also the case with the neurosurgical applications of Lozano discussed previously, the history of focal opening of the blood-brain barrier with ultrasound dates back to the mid-20th century, according to Aubry, although these early efforts provoked damage to the barrier, and their effect was irreversible. He said, however, that a “game changer” was discovered in the early 2000s, with the use of contrast agents being the principle upon which the safe opening of the blood-brain barrier is based today. hui.
And, while the majority of examples of this fact have involved animal subjects, some applications have been made in humans. Aubry hinted at a 2019 report of a clinical safety and feasibility study, published in Scientific reports, which demonstrated the use of the opening of the blood-brain barrier, followed by the administration of chemotherapy to treat brain tumors, in five patients. Additionally, he referred to a 2018 study in Nature Communication which achieved its primary goal of safely opening the barrier in five patients with early-to-moderate Alzheimer’s disease. According to Aubry, the initial results of these two studies are now broadened and deepened.
“So this is a very important job to pave the way for many treatments, but, in fact, it is also very interesting in the development of new devices which can be smaller and easier to use on patients,” he said. he added. A team from Columbia University in the United States has developed its own neuronavigation-guided, single-element focused ultrasound transducer, Aubry told the EAN audience and, as of December 2020, the used to treat her first patient via the blood brain barrier. opening as part of a clinical trial.
Aubry went on to highlight a handful of alternative methods for opening the blood-brain barrier using ultrasound, including work by his own team to develop a cheaper, yet still high-quality and accurate focused ultrasound technique. using a 3D printed acoustic lens that costs “a few dollars” and a single element transducer. Finally, he mentioned the potential of another technique, developed by the French start-up CarThera, which consists of implanting a device. transducer to the surface of the brain before using a transdermal needle powered by a generator to apply ultrasound. This approach was evaluated in a safety and feasibility study of 21 patients with recurrent glioblastoma, according to Aubry, whose results were published in Clinical cancer research Last year.
Before concluding, Aubry briefly touched on ultrasound neurostimulation, adding that while many of the principles this technique is based on are similar to those seen in opening the blood-brain barrier by ultrasound, a key distinction is that the first does not require a contrast agent. . He added that more than 250 papers on ultrasound stimulation have been published since 2000, with the number of new papers in this space increasing dramatically every year since 2015, leading Aubry to claim that “the field is growing exponentially.”
These closing remarks provided a fitting introduction to the final presentation of the session, which saw Roland Beisteiner, Associate Professor in the Department of Neurology at the University of Medicine Vienna (Vienna, Austria), take a closer look at focal neuromodulation. ultrasound for clinical therapy. . While claiming that over the past few years several different technologies have emerged in this space, he chose to focus on the latest of these breakthroughs: transcranial impulse stimulation (TPS).
Beisteiner described the various advantages of TPS over previous focused ultrasound techniques, including the fact that its pulse generation is based on an already widely established and clinically established technology, its “very short pulses” avoiding maximum secondary stimulation and associated risks to the brain. heating is also not present during the process. He went on to elaborate on the particular advantages of TPS over approaches such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), including “unprecedented precision” in targeting brain tissue with conductivities. pathological, which may open up new possibilities in the treatment of movement disorders, stroke and multiple sclerosis (MS), and the fact that TPS can be considered a similar clinical option to non-invasive DBS .
Beisteiner described the latter as a “really fantastic” new option, relaying that many psychiatric and neurological illnesses, ranging from drug addiction, depression and obsessive-compulsive disorder (OCD) to Alzheimer’s disease, epilepsy and pain, could benefit from a non-invasive form of DBS like this. On Alzheimer’s disease in particular, he referred to data from a 2019 study published in Advanced sciences, who showed “significant long-term improvement in memory” three months after TPS, before referring to a separate study from 2021 which built on this research by showing that TPS can reduce cortical atrophy in patients with Alzheimer’s disease.