Category Archives: Neurosonology

Introduction to the Emerging Field of Post Cranioplasty Neurosonography

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The field of neurosonography has evolved in the past few decades facilitating detailed anatomical evaluation of the central nervous system (CNS) of the unborn fetus (fetal neurosonography)1–2 and newborn child (neonatal neurosonography).3 During these early stages of life, neurosonography is possible due to the presence of physiologic acoustic windows such as the fontanelle and unfused sutures of the skull, allowing the ultrasound waves to penetrate the brain tissue. Both 2D and 3D ultrasound have been used to obtain the required images of neurosonography.4 This technique enables a high-resolution, safe, readily available, and relatively inexpensive modality to obtain a detailed evaluation of the intra-cranial anatomy and vascular system that may be comparable in quality to that of other imaging modalities such as MRI.5 As the fontanelle and cranial sutures close during early childhood and the skull bone thickens, ultrasound can no longer be used to generate images of the brain. Therefore, adult neurosonography has significant limitations with use limited to transcranial Doppler imaging.

Recently, full or partial replacements of skull composed of an ultrasound-penetrable synthetic substitute, ie sonolucent cranial implants, have been available for post craniotomy skull replacement. Early experience by neurosurgeons that elect to use this technique offer their patients the potential of postoperative bedside sonographic assessment of the CNS of these individuals.6

In this report, we share our collaborative experience and enthusiasm about the emerging field of post cranioplasty neurosonography. Craniotomy is one of the most common surgical procedures performed in the US with indications ranging from surgical evacuation of intracranial bleed, hydrocephalus, brain tumors, and vascular lesions. Sonolucent cranial implants may replace a portion of the native skull or be used as a fully customized implant to restore form and function for cranial reconstruction procedures. In addition to the different sizes and shapes, these next-generation implants allow for postoperative imaging with ultrasound.

The sonolucent implant provides an acoustic window via a synthetic adult “fontanelle”. Depending on the location and size of the device, the assessment of the brain may be facilitated in different planes and points of view. Most commonly, the implants are located above the pathology (figure 1) and off the skull midline with the sagittal sinus preserved. Thus, the acoustic window enables the ability to easily image the brain in the coronal (Figure 2) and axial (Figure 3) planes. In cases where the implant approaches or covers the midline, evaluation in the sagittal plane (paramedian and even midsagittal/median) is possible (Figure 4) in addition to that of the coronal plane. Moreover, the closer the implant is to the midline, the easier the access is to image both hemispheres.

Image demonstrating the sonolucent burr hole cover and its use for ultrasound of the adult brain.
Figure 1: Left, An adult skull with a sonolucent implant. Right, Ultrasound of the adult brain in the coronal plane through a sonolucent implant.
Figure 2: Coronal view of the brain through a temporal sonolucent implant.
Figure 3: Axial view of the brain through a temporal sonolucent implant.
Figure 4A: Sagittal view through the lateral ventricle (paramedian).
Figure 4B: Median/midsagittal view through a sonolucent implant over the sagittal suture.

Post cranioplasty neurosonography can be done with point-of-care ultrasound by the neurosurgical or neurology teams in the acute postoperative period, in-office surveillance visit, or as a detailed evaluation in a neuro-radiology unit set up. We have used this technique in these setups to assess several postoperative parameters such as evaluation for possible midline shift, lateral ventricles for size, shape, potential bleed, and location of a shunt or ventricular catheter, patency of vascular anastomosis, as well as the evaluation of the brain parenchyma for postoperative pathologies such as presence of tumor or intracranial hemorrhage. Sequential surveillance is facilitated by the fact that the acoustic window is fixed so images are easily obtained in the exact same anatomical plane on subsequent scans.

As the clinical utilization of sonolucent grafts and experience with post cranioplasty neurosonography expand, there is much to be determined on how to best incorporate this emerging technology into patient care. For example, identifying the ideal diagnostic probe as there is no designated probe currently in the market. We have used both a curvilinear probe with a high-resolution abdominal setting and a cardiac phased array probe, ie, small footprint probes, with success. Indeed, the probe characteristics may vary between different lesions requiring different levels of penetration. As the implant is hard, and in many cases convex and of small size, a wide-sector, small footprint, high-resolution probe may offer the best access.

Future utilization and study will determine how post cranioplasty neurosonography influences the utilization of other imaging modalities (CT and MRI). Additional benefits potentially include decreased exposure to radiation, better point-of-care access to imaging, and a direct impact on healthcare costs.

Lastly, it is still to be determined which clinicians (neurosurgeons, neurologists, radiologists, neuro-intensivists, ACPs), and in which setup (point of care vs radiology suite) will master the techniques and take the lead in this emerging field. Regardless, it appears that the ultrasound community has a new and exciting opportunity at hand. 

References:

  1. Malinger G, Paladini D, Haratz KK, Monteagudo A, Pilu G, Timor-Tritsch IE. ISUOG Practice Guidelines (updated): sonographic examination of the fetal central nervous system. Part 1: performance of screening examination and indications for targeted neurosonography. Ultrasound Obstet Gynecol 2020; 56:476–484.
  2. Paladini D, Malinger G, Birnbaum R, et al. ISUOG Practice Guidelines (updated): sonographic examination of the fetal central nervous system. Part 2: performance of targeted neurosonography. Ultrasound Obstet Gynecol 2021; 57:661–671. https://doi.org/10.1002/uog.23616.
  3. Rossi A, Argyropoulou M, Zlatareva D, et al; ESNR Pediatric Neuroradiology Subspecialty Committee; ESPR Neuroradiology Taskforce. European recommendations on practices in pediatric neuroradiology: consensus document from the European Society of Neuroradiology (ESNR), European Society of Paediatric Radiology (ESPR) and European Union of Medical Specialists Division of Neuroradiology (UEMS). Pediatr Radiol 2023; 53:159–168. doi: 10.1007/s00247-022-05479-4.
  4. Bornstein E, Monteagudo A, Santos R, et al. Basic as well as detailed neurosonograms can be performed by offline analysis of three-dimensional fetal brain volumes. Ultrasound Obstet Gynecol 2010 Jul; 36(1):20–25. doi: 10.1002/uog.7527.
  5. Malinger G, Paladini D, Pilu G, Timor-Tritsch IE. Fetal cerebral magnetic resonance imaging, neurosonography and the brave new world of fetal medicine. Ultrasound Obstet Gynecol 2017; 50:679–680.
  6. Williams AL, Abu-Bonsrah N, Lee RP, et al. Letter: The role of sonolucent implants in global neurosurgery. Neurosurgery 2024; 94:e1–e5. doi: 10.1227/neu.0000000000002723.

Eran Bornstein, MD, FACOG, FAIUM

Dr Bornstein is an Associate Professor of Obstetrics & Gynecology at the Zucker School of Medicine at Hofstra, and the Director of the Center for Maternal Fetal Medicine and Ultrasound in OBGYN, at Lenox Hill Hospital, Northwell, in New York.

Netanel Ben-Shalom MD, FNPS

Dr Ben-Shalom is an Assistant Professor of Neurosurgery at the Zucker School of Medicine at Hofstra, and a neurosurgeon at Lenox Hill Hospital/Northwell, in New York.

David Langer, MD, FNPS

Dr Langer is an Associate Professor of Neurosurgery at the Zucker School of Medicine at Hofstra, and the Chair of the department of neurosurgery at Lenox Hill Hospital/Northwell, in New York.

Fetal Neurosonography

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A call for increased awareness and training within the United States

Routine evaluation of the fetal brain is performed during the second-trimester anatomical survey. This screening is conducted by transabdominal scan in 3 axial planes, namely, the transventricular, transthalamic, and transcerebellar planes.1 Targeted neurosonography, however, is a dedicated, detailed, and diagnostic examination of the fetal brain that is preferably performed with high-resolution transvaginal ultrasound via a transfontanelle approach, providing multiplanar assessment of the brain anatomy. Like fetal echocardiography in the context of suspected cardiac malformation, neurosonography provides greater diagnostic capacity for fetal brain malformations compared to the routine transabdominal screen in the axial planes.

Neurosonography involves extensive evaluation in multiple successive coronal planes (Figure 1), the midsagittal/median plane (Figure 2), as well as successive parasagittal planes (side to side) to provide high-resolution imaging of detailed brain anatomy. These include structures such as the cavum septi pellucidy and cavum vergae, corpus callosum, vermis, 3rd and 4th ventricles, vein of Gallen, ganglionic eminence, the caudate nuclei and brain stem, the fetal brain cortex, gyration, sulcation, and parenchyma as well as detailed evaluation of the entire ventricular system and periventricular tissue.2

Figure 1: 3D tomographic display of successive coronal planes from the front to the back of the fetal brain. The top left box displays the midsagittal plane with several successive lines, each representing a coronal slice displayed in the following boxes.
Figure 2A–C: Midsagittal/median plane of a 21-week fetus obtained via transfontanelle approach. Detailed evaluation of the midline structures (A) with arrows to identify some important landmarks (B). Color high definition used to depict the course of the anterior cerebral artery and the pericallosal artery (C). Bs indicates brain stem; cc, corpus callosum; csp, cavum septi pellucidi; cm, cysterna magna; cv, cavum vergae; qc, quadrigeminal cistern; qp, quadrigeminal plate; tc, tela choroidea; V, vermis; 3v, third ventricle; 4v, fourth ventricle.

The use of 3D ultrasound is also frequently utilized to facilitate expert neurosonographic evaluation, obtain the diagnostic planes, and use display modalities, which may further enable the diagnostic process.3 This technique has been used to adequately diagnose multiple fetal brain pathologies including birth defects, fetal infections, brain tumors, vascular insults, AV malformations, and destructive lesions.

Given that the anatomy of the fetal brain evolves and changes throughout gestation, correlation of the anatomy to the gestational age is a key element required by experts in neurosonography. Thus, different pathologies in the development of the fetal brain can be appropriately detected at different gestational ages. For example, whereas a major malformation such as alobar holoprosencephaly can be reliably detected in the first trimester, most abnormalities of the corpus callosum and cerebellar vermis are reliably diagnosed during the second-trimester scan, while malformations of cortical development, migrational disorders, and some tumors and destructive lesions may not be appropriately detected until the third trimester.

Despite its great diagnostic strength, fetal neurosonography is not commonly practiced in the US. Most providers who provide fetal anatomy scans are not adequately trained to perform transvaginal transfontanelle brain scans, interpret fetal brain images in the nontraditional axial planes (such as the coronal and sagittal planes), or correlate these images with the evolution of the brain anatomy throughout the different gestational ages. Therefore, in some centers, the mere suspicion of a fetal brain malformation may result in immediate referral for a fetal MRI. Although MRI is a complementary method to image the fetal brain that in expert hands may provide valuable information to neurosonography, it is a second-line imaging modality, which is far more expensive and less accessible. Importantly, like neurosonography, fetal MRI is also highly operator-dependent, requiring a high level of expertise in both obtaining the appropriate sequences as well as interpreting the images and correlating them with the gestational age. Moreover, the value of fetal MRI increases in the third trimester when evaluation of the cortex and parenchyma is feasible, whereas neurosonography provides superior images during the first- and second-trimester evaluations.4

Of note, current American guidelines for neurosonography are limited to evaluation of neonates and infants5 rather than fetuses. The most comprehensive guidelines for fetal neurosonography are published by the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG).6  These guidelines also define the indications for detailed neurosonography: such as suspicion of brain malformation on routine screening ultrasound or nuchal translucency scan, family history or prior pregnancy affected by brain malformation, fetal congenital heart disease, monochorionic twins, suspected congenital intrauterine infection, exposure to teratogens affecting neurogenesis, and microarray findings of unknown significance.

Not only does neurosonography facilitate accurate diagnosis of a large variety of brain malformations, it also enables us to reassure many anxious patients in which malformation was suspected on a basic scan whereas detailed neurosonography confirmed normal brain development with no pathology.

Therefore, increased awareness of the value of fetal neurosonography and appropriate utilization may result in the referral of patients with appropriate indications to centers with expertise in neurosonography, as well as highlighting the need for specific education and training. Additionally, there is no specific Current Procedural Terminology (CPT®) code for fetal neurosonography in the US. Creation of such a code will facilitate the acceptance of this practice for indicated cases and help solidify training programs and providers’ interest in becoming proficient.

References:

  1. Malinger G, Paladini D, Haratz KK, Monteagudo A, Pilu G, Timor-Tritsch IE. ISUOG Practice Guidelines (updated): sonographic examination of the fetal central nervous system. Part 1: performance of screening examination and indications for targeted neurosonography. Ultrasound Obstet Gynecol 2020; 56:476–484.
  2. Timor-Tritsch IE, Monteagudo A. Transvaginal fetal neurosonography: standardization of the planes and sections by anatomic landmarks. Ultrasound Obstet Gynecol 1996; 8:42–47.
  3. Bornstein E, Monteagudo A, Santos R, Strock I, Tsymbal T, Lenchner E, Timor-Tritsch IE. Basic as well as detailed neurosonograms can be performed by offline analysis of three-dimensional fetal brain volumes. Ultrasound Obstet Gynecol 2010 Jul; 36(1):20–25. doi: 10.1002/uog.7527. PMID: 20069671.
  4. Malinger G, Paladini D, Pilu G, Timor-Tritsch IE. Fetal cerebral magnetic resonance imaging, neurosonography and the brave new world of fetal medicine. Ultrasound Obstet Gynecol 2017; 50:679–680.
  5. AIUM practice parameter for the performance of neurosonography in neonates and infants. J Ultrasound Med 2020; 39: E57–E61. https://doi.org/10.1002/jum.15264.
  6. Paladini D, Malinger G, Birnbaum R, Monteagudo A, Pilu G, Salomon LJ, Timor IE. ISUOG practice guidelines (updated): sonographic examination of the fetal central nervous system. Part 2: performance of targeted neurosonography. Ultrasound Obstet Gynecol 2021; 57: 661–671. https://doi.org/10.1002/uog.23616.

About the Author

Eran Bornstein, MD, FACOG, is an associate professor of Obstetrics & Gynecology in the Zucker School of Medicine/HOFSTRA, and the Director of the Center for Maternal Fetal Medicine and Ultrasound in OBGYN, at Lenox Hill Hospital, Northwell, in New York.

Interested in learning more about fetal neurosonography? Check out the following articles from the American Institute of Ultrasound in Medicine’s (AIUM’s) Journal of Ultrasound in Medicine (JUM). Members of AIUM can access them for free after logging in to the AIUM. Join the AIUM today!

Good Vibration – Ultrasound as a New Mode of Neuromodulation

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Biomedical applications of ultrasound have taken great strides into a new arena of noninvasive brain stimulation (NIBS). The journey can be traced back to the work by E. Newton Harvey (an early 20th-century zoologist, also one of the early pioneers in bioluminescence research), who discovered that ultrasound modifies the function of electrically excitable biological tissues. Subsequent investigations by William and Francis Fry as well as Leonid Gavrilov during the 1950s have demonstrated that ultrasound can temporarily alter the function of the brain and the peripheral nerves.

Ultrasound technology has since evolved, enabling the delivery of highly focused acoustic energy not only to the cortical surface, but also to deep regions of the brain through the intact skull, with a focal size measuring only a few millimeters. The advent of this transcranial focused ultrasound (tFUS) technique is owed to the development of multi-array ultrasound transducer/control systems as well as advances in image-guidance methods through which the location and intensity of the invisible acoustic focus can be accurately controlled after being transmitted through the skull.

Armed with technological advances, together with the wisdom of the past, a series of studies through the last decade have revealed that FUS, given in a batch of pulses at a low intensity (below the threshold for heat generation or mechanical damage), can reversibly modulate (increase or decrease) the excitability of brain tissue.1–3 This revelation has opened new possibilities for tuning up/down regional brain function due to the exquisite spatial selectivity and depth control of tFUS.

Existing NIBS techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct/alternating current stimulation (tDCS/tACS), offer non-pharmacological alternatives for modifying brain function; however, they cannot reach deep brain areas with sufficient spatial selectivity. In addition, emerging evidence indicates that the modulatory effects of tFUS outlast the duration of sonication, which is critical for its therapeutic effects to occur.4,5 Together, noninvasive neuromodulation by ultrasound may present a unique opportunity to treat various brain-related conditions, ranging from neurological to psychiatric.

Although the precise mechanisms that underlie the neuromodulatory effects of ultrasound remain unclear, several candidate mechanisms have been proposed, including transient changes in transmembrane capacitance and subsequent effects on action potential generation, functional modulation of mechanosensitive ion channels, and the modification of glial cell excitability.6 It is quite exciting to witness a rising number of publications interrogating the mechanisms surrounding ultrasound-mediated neuromodulation.

Along with a promising safety record in small/large animals, non-human primates, and studies involving healthy individuals7, various clinical trials are being conducted or completed. Some examples include the treatment of major depressive disorder, epilepsy, Alzheimer’s disease, disorders of consciousness, and substance use disorder. The applications of ultrasound-mediated neuromodulation also extend to treating peripheral nerve diseases or noninvasive evaluation of regional brain function. The scope of clinical application is expected to expand since there are virtually no other known (noninvasive) means to selectively modulate local brain function across the brain volume.

So far, only a very limited number of incidents of minor discomfort (at the scalp) or temporary neurological symptoms (including ones that may not be directly related to the sonication) have been reported, which attest to the encouraging safety profile of this new technique. Notwithstanding, the absence of concrete information on the operational envelope and device characteristics impedes its rapid translation into clinical practice. Fortunately, a group of scientists, doctors, and engineers around the world have formed a consortium called the International Transcranial Ultrasonic Stimulation Safety and Standards (iTRUSST) and started to establish expert opinions and consensus on regulatory guidelines and standardization of the technique.8

With immense potential in introducing new treatment options, it will be interesting and exhilarating to see how ultrasound neuromodulation will become one of the mainstream neurotherapeutic modalities of the future.

References

1. Bystritsky A, Korb AS, Douglas PK, et al. A review of low-intensity focused ultrasound pulsation. Brain Stimul 2011; 4:125–136. doi:10.1016/j.brs.2011.03.007.

2. Darmani G, Bergmann TO, Butts Pauly K, et al. Non-invasive transcranial ultrasound stimulation for neuromodulation. Clin Neurophysiol 2022; 135:51–73. doi:10.1016/j.clinph.2021.12.010.

3. Arulpragasam AR, van ‘t Wout-Frank M, Barredo J, Faucher CR, Greenberg BD, Philip NS. Low intensity focused ultrasound for non-invasive and reversible deep brain neuromodulation-A paradigm shift in psychiatric research. Front Psychiatry 2022; 13:825802. doi:10.3389/fpsyt.2022.825802.

4. Verhagen L, Gallea C, Folloni D, et al. Offline impact of transcranial focused ultrasound on cortical activation in primates. Elife 2019; 8: e40541. doi:10.7554/eLife.40541.

5. Kim HC, Lee W, Weisholtz DS, Yoo SS. Transcranial focused ultrasound stimulation of cortical and thalamic somatosensory areas in human. PLoS ONE 2023; 18:e0288654. doi:10.1371/journal.pone.0288654.

6. Fomenko A, Neudorfer C, Dallapiazza RF, Kalia SK, Lozano AM. Low-intensity ultrasound neuromodulation: An overview of mechanisms and emerging human applications. Brain Stimul 2018; 11:1209–1217. doi:10.1016/j.brs.2018.08.013.

7. Lee W, Weisholtz DS, Strangman GE, Yoo SS. Safety review and perspectives of transcranial focused ultrasound brain stimulation. Brain Neurorehabil 2021; 14:e4. doi:10.12786/bn.2021.14.e4.

8. Attali D, Tiennot T, Schafer M, et al. Three-layer model with absorption for conservative estimation of the maximum acoustic transmission coefficient through the human skull for transcranial ultrasound stimulation. Brain Stimul 2023; 16:48–55. doi:10.1016/j.brs.2022.12.005.

About the Author

Seung Schik Yoo, PhD, MBA, is an Associate Professor of Radiology at Harvard Medical School, a Director of the Neuromodulation and Tissue Engineering Laboratory (NTEL) at Brigham and Women’s Hospital, and a faculty of Harvard’s Mind Brain Behavior Interfaculty Initiative.

Interested in reading more about neurosonology? Check out these posts from the Scan:

Focused Ultrasound for Brain Tumors: Hope for the Future of GBM

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In John Grisham’s book The Tumor, he tells a story of the typical clinical pathway and trajectory of a patient diagnosed with glioblastoma (GBM), a devastating brain tumor. Then, he sets the stage for a re-imagination of this patient’s clinical course if focused ultrasound were added to his treatment armamentarium. What this could look like is less suffering, longer life expectancy, and cost savings.

Glioblastoma has a 90% mortality rate within 5 years of diagnosis. This disease has lacked any significant improvement in survival in over 30 years, despite scientific advances in many areas, such as molecular subtyping, tailored chemotherapy regimens, and immunotherapy. The current standard-of-care treatment for GBM includes surgical resection, chemotherapy, and radiation.

Focused ultrasound is an emerging therapeutic technology that has the potential to change the treatment landscape and clinical trajectory for a multitude of diseases and conditions, including GBM. The fascinating thing about focused ultrasound is that scientists and clinicians have discovered that the properties of the ultrasound energy can be manipulated in such a way as to induce a variety of different biological effects and mechanisms of action. The technology was initially designed to thermally ablate tissue, but since that time, more than 20 mechanisms of action have been identified.

In GBM, there are three focused ultrasound mechanisms of action that are being employed as an adjunct or complement to traditional therapies: opening of the blood-brain barrier (BBB), sonodynamic therapy (SDT), and radiation sensitization or enhancement (Figure 1).1,2

Figure 1: Focused Ultrasound (FUS) Mechanisms of Action related to brain tumor therapy (A) Blood Brain Barrier Opening (BBBO): In the presence of focused ultrasound, intravenously injected microbubbles oscillate inside the brain’s blood vessels and stretch the tight junctions, allowing therapeutics to diffuse into the targeted region. Not depicted here are the additional mechanisms of sonoporation and increased transcytosis, which also occur with FUS-mediated BBBO. (B) Sonodynamic Therapy: Intravenous injection of a sonosensitizer such as 5-ALA accumulates preferentially inside brain tumor cells. Conversion of the sonosensitizer into an active substrate (ie PpIX) induces tumor cell death. (C) Radiation Sensitization: The proposed mechanism of action involves ceramide-induced endothelial apoptosis, which subsequently enhances radiation by causing vascular disruption. Distortion of the endothelial cell membrane by oscillating microbubbles in the presence of the FUS beam releases ceramide, which then causes platelet aggregation and thrombosis.

The most clinically advanced of these three focused ultrasound mechanisms is BBB opening, which is currently being investigated in numerous clinical trials that combine this technique with delivery of chemotherapeutic agents.3–5 Thus far, safety and efficacy have been confirmed, and I am excited to see additional clinical trial results. SDT clinical trials are also underway and have shown promise. Lastly, using focused ultrasound to enhance radiation is being investigated.

There are also a variety of focused ultrasound devices being investigated for use, from MRI-guided to neuronavigation-guided to implantable devices. Each system offers unique benefits and challenges, which continue to be elucidated through ongoing clinical work.

One more promising frontier for focused ultrasound and GBM is liquid biopsy. Just as focused ultrasound plus microbubbles can disrupt the BBB to allow the passage of therapeutics into the tumor, this method also allows for the leakage of tumor biomarkers into the blood from the tumor, enabling enhanced diagnosis and monitoring methodologies for GBM.6

While this blog post provides a brief overview of focused ultrasound for GBM, it hopefully conveys that the technology is ripe for helping patients live longer, more comfortable lives. The Focused Ultrasound Foundation is on a mission to engage and convene the scientific and medical communities to make this happen as quickly, safely, and effectively as possible so that the fictional character that Grisham described can become a reality.

Author’s note: The Foundation is also enthusiastic about using this technology in a similar fashion for children with diffuse intrinsic pontine glioma (DIPG)/diffuse midline glioma (DMG), and this area has experienced significant growth over the past year. To learn more, visit the Foundation’s webpage dedicated to DIPG/DMG.

References

  1. Roberts JW, Powlovich L, Sheybani N, LeBlang S. Focused ultrasound for the treatment of glioblastoma. J Neurooncol 2022; 157(2):237–247. doi: 10.1007/s11060-022-03974-0. Epub 2022 Mar 10. PMID: 35267132; PMCID: PMC9021052.
  2. Parekh K, LeBlang S, Nazarian J, et al. Past, present and future of focused ultrasound as an adjunct or complement to DIPG/DMG therapy: A consensus of the 2021 FUSF DIPG meeting. Neoplasia 2023; 37:100876. doi: 10.1016/j.neo.2023.100876. Epub 2023 Jan 28. PMID: 36709715; PMCID: PMC9900434.
  3. Bunevicius A, McDannold NJ, Golby AJ. Focused ultrasound strategies for brain tumor therapy. Oper Neurosurg 2020; 19:9–18. doi: 10.1093/ons/opz374
  4. Mainprize T, Lipsman N, Huang Y, et al. Blood-brain barrier opening in primary brain tumors with non-invasive MR-guided focused ultrasound: a clinical safety and feasibility study. Sci Rep 2019; 9:321. doi: 10.1038/s41598-018-36340-0.
  5. Meng Y, Hynynen K, Lipsman N. Applications of focused ultrasound in the brain: From thermoablation to drug delivery. Nat Rev Neurol 2021; 17:7–22. doi: 10.1038/s41582-020-00418-z. 
  6. Meng Y, Pople CB, Suppiah S, et al. MR-guided focused ultrasound liquid biopsy enriches circulating biomarkers in patients with brain tumors. Neuro Oncol 2021; 23:1789–1797. doi: 10.1093/neuonc/noab057.

Lauren Powlovich, MD, MBA(c), serves as Associate Chief Medical Officer at the Focused Ultrasound Foundation (FUSF). She brings together key stakeholders and synthesizes and executes cohesive plans to lead initiatives in the advancement of focused ultrasound for several applications including glioblastoma, neurodegenerative disorders, pediatrics, pain management, and sonodynamic therapy. She is a co-leader of the Research and Education Team, which strategizes on the allocation of FUSF’s resources to best position the field for success. Prior to joining the Foundation, Lauren trained as an anesthesiologist, and she has always been passionate about putting patients first. She continues to have that mindset and works hard to ensure that focused ultrasound reaches patients as efficiently and safely as possible.

Focused Ultrasound and the Blood-Brain Barrier

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When does a barrier protect and when does it hinder? This question is central to the challenge of delivering therapeutics to the brain. For many neuropathologies, the answer is clear: there is a critical need for strategies that can allow clinicians to effectively deliver drugs to the brain. We believe focused ultrasound (FUS) has the potential to be a powerful tool in this quest.

Charissa Poon
Dallan McMahon

Part of this challenge lies in the unique nature of the blood vessels in the brain. The cells that line these vessels are tightly linked together, creating a complex obstacle—called the blood-brain barrier (BBB)—that prevents the vast majority of drugs from entering the brain from the bloodstream. Throughout the years, several strategies of bypassing the BBB have been used, with limited success and many adverse effects. These range from directly inserting a needle into the brain for injections, to the administration of hyperosmotic solutions, which create gaps between cells in the BBB throughout a large volume.

In 1956, Bakay et al successfully ablated brain tumors using high-intensity FUS. In doing so, he observed that the permeability of the BBB was enhanced in the periphery of the ablated tissue. While this was exciting news for BBB enthusiasts, the necessity of damaging tissue in the process of opening the BBB was clearly unacceptable. Several decades later, this approach was successfully modified by administering microbubbles, an ultrasound contrast agent, before sonicating (Hynynen et al 2001). This made it possible to use much lower power levels to produce the desired increase in BBB permeability, thereby avoiding brain damage. By adjusting where the ultrasound energy is focused, specific brain regions can be targeted. For a few hours after treatment, drugs can be administered intravenously, bypass the BBB, and enter the neural tissue in the targeted areas.

Over the past 16 years, many preclinical studies have used FUS to increase the permeability of the BBB, delivering a wide range of therapeutic agents to the brain, from chemotherapeutics and viruses, to antibodies and stem cells. Efficacy has been demonstrated in models of Alzheimer’s disease, Parkinson’s, brain tumors, and others. Moreover, the safety of using FUS to increase BBB permeability has been tested in every commonly used laboratory animal.

The flexibility of FUS as a tool for treating neuropathologies may go beyond the delivery of drugs to the brain. Recently, FUS was shown to reduce the amount of β-amyloid plaques and improve memory deficits in the brains of transgenic mice (Burgess et al 2014, Leinenga and Gotz 2015, Jordao et al 2013).

The success of these preclinical trials has led to the initiation of 3 human trials. Two of these trials are testing the safety of increasing the permeability of the BBB in brain tumors for chemotherapy delivery, and the third is evaluating the safety and initial effectiveness of FUS in patients with early stage Alzheimer’s disease. The rapid movement towards clinical testing has been accompanied by impressive technological advancements in the equipment used to focus ultrasound through the human skull. Arrays of thousands of ultrasound transducers can be controlled to produce sound waves that travel through bone and brain, and arrive at precisely the same time in the targeted location. The sound produced by vibrating microbubbles can be detected and used to ensure the treatment is progressing as planned.

If the barrier to drug delivery to the brain can be bridged by FUS, the development of effective treatment strategies for a wide range of neuropathologies will expand. Given the clear need for such treatments and the flexibility of FUS, the recent push toward clinical testing is encouraging. The coming years will be critical in demonstrating the safety of the technique and spreading awareness. Success in these regards will go a long way in establishing FUS as an impactful tool in the fight against inflictions of the central nervous system.

If you deliver drugs to the brain, how do you do so? Have you found a way to permeate the blood-brain barrier using ultrasound? Comment below or let us know on Twitter: @AIUM_Ultrasound.

Charissa Poon and Dallan McMahon are PhD students at the Institute of Biomaterials & Biomedical Engineering, University of Toronto, and the department of Medical Biophysics, University of Toronto, respectively.

Kullervo Hynynen, PhD, is professor at the department of Medical Biophysics and the Institute of Biomaterials & Biomedical Engineering, University of Toronto, and a senior scientist at Sunnybrook Research Institute in Toronto, Canada.

A Personal Vignette From the ’60s and ’70s

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In the mid to late 1960s, neurologic sonography at the Neurological Institute at Columbia Presbyterian Medical Center was being performed by Lewis B. Grossman, MD, and Georgina Wodraska within the Neuroradiology section. I had developed a friendship with Dr Grossman in part due to a similarity in our family medical histories of early demise due to coronary artery disease. We had discussed this one evening and the following morning Dr Grossman did not show up for work and had died of a heart attack.

Two other life-changing events happened later that day. First, Georgina Wodraska informed me that I was to be the new head of Neurologic Sonography, much to my astonishment and with significant doubt as my exposure to sonography was extremely limited and I had significant doubt regarding its capabilities beyond that of detecting midline displacements of the brain. Second, that afternoon I started on a physical activity regimen that progressed over time from walking to long distance running (and now in my 80s back to walking).

20170521_191539

Dr Tenner and his daughter, Sallye,
wrapped in mylar while waiting out a flash storm
in a Utah canyon alcove in May 2017.
Sallye, ARDMSRVT, is a sonographer at
Bay Pines Veterans Health Center in St. Petersburg, Florida.

In the mid to late ’60s, the neuroradiologists’ armamentarium consisted of an x-ray tube for radiographs and a needle. The needle was placed directly into an artery (carotid, vertebral, brachial) or into the subarachnoid space to perform arteriography or pneumoencephalography, respectively. To better understand the source of brain echo reflections, ultrasound using a 1.5-MHz transducer using the thin squamosa of the temporal bone as a window was done while vigorously flushing the carotid needle with a bolus of normal saline, which caused an amplification of the echo reflections within the intracerebral arterial vasculature. We also realized that lesions within the brain that were within the field of view of insonation may also be seen. Although the acoustic impedance of normal brain tissue and brain tumors have little difference ex vivo, there are significant differences in vivo due to 1) the basic angioarchitecture of the tumor, which is distended in vivo and collapsed ex vivo, and 2) surrounding brain edema and areas of liquefaction necrosis and cyst formation within the tumor. Hydrocephalus, arterio-venous malformations, giant aneurysms, intra and extra axial tumors, and some congenital malformations were also detectable.

A mode neurosonography is heavily operator-dependent and required an in-depth knowledge of neuroanatomy and neuropathology. Training a sonographer required a dedicated teacher and a highly motivated and dedicated student.

In 1971 I headed the section of Neuroradiology at SUNY Downstate Medical Center where a sonography school was formed and we were able to attract a student, Larry Waldroup, who had a keen interest in neurosonography. He subsequently took a position with Barry Goldberg, MD, and had a most productive and distinguished career.

Our experience with neurosonography resulted in the publication of a textbook “Diagnostic Ultrasound in Neurology” in 1975. This was also the time that computer tomography was becoming widely available. Needless to say, the timing of the publication and the introduction of computed tomography, a mainstay of diagnostic radiology, did not bode well for the sales of the textbook. Although, the Preface of the textbook states “in recent years there has been striking progress in the scope and pace of ultrasonic examinations and methodology,” which is still true today. Ultrasound of the brain has now also found a mainstay nitch in neonatal, intraoperative neurosonography, and transcranial Doppler.

Do you have any stories to tell of the evolution of ultrasound? Who are your mentors? Comment below or let us know on Twitter: @AIUM_Ultrasound.

Dr Michael Tenner is a Professor of Radiology and Neurosurgery and Professor and Director of Neuroradiology at New York Medical College in Valhalla, New York.