Kullervo Hynynen

Thrombotic occlusions of large blood vessels are increasingly treated with catheter based mechanical approaches, one of the most prominent being to employ aspiration to extract clots through a hollow catheter lumen. A central technical challenge for aspiration catheters is to achieve sufficient suction force to overcome the resistance of clot material entering into the distal tip. In this study, we examine the feasibility of inducing cavitation within hollow cylindrical transducers with a view to ultimately using them to degrade the mechanical integrity of thrombus within the tip of an aspiration catheter...

New England Journal of Medicine, Volume 390, Issue 1, Page 82-85, January 2024.

Convolutional neural networks (CNNs), initially developed for image processing applications, have recently received significant attention within the field of medical ultrasound imaging. In this study, passive cavitation imaging/mapping (PCI/PAM), which is used to map cavitation sources based on the correlation of signals across an array of receivers, is evaluated. Traditional reconstruction techniques in PCI, such as delay-and-sum, yield high spatial resolution at the cost of a substantial computational time...

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BACKGROUND: High resolution imaging of the microvasculature plays an important role in both diagnostic and therapeutic applications in the brain. However, ultrasound pulse-echo sonography imaging the brain vasculatures has been limited to narrow acoustic windows and low frequencies due to the distortion of the skull bone, which sacrifices axial resolution since it is pulse length dependent. PURPOSE: To overcome the detect limit, a large aperture 256-module sparse hemispherical transmit/receive array was used to visualize the acoustic emissions of ultrasound-vaporized lipid-coated decafluorobutane nanodroplets flowing through tube phantoms and within rabbit cerebral vasculature in vivo via passive acoustic mapping and super resolution techniques...

UNLABELLED: Recently, MRI-guided focused ultrasound (FUS) has shown great promise in treating various conditions non-invasively. OBJECTIVE: The focus of this article is to introduce an MRI-guided FUS device, which can provide full electronic steering range without mechanical movement and with low near-field heating. A pilot study was conducted in order to investigate the feasibility, and safety of the device in a large animal model and a pilot clinical trial. METHODS: A flat, fully steerable FUS phased array with 4096 elements was designed and manufactured to be compatible with an MR scanner...

Drug-loaded perfluorocarbon nanodroplets (NDs) can be activated non-invasively by focused ultrasound (FUS) and allow for precise drug-delivery. Anesthetic-loaded NDs and transcranial FUS have previously achieved targeted neuromodulation. To assess the clinical potential of anesthetic-loaded NDs, in depth physical characterization and investigation of storage strategies and triggered-activation is necessary. Pentobarbital-loaded decafluorobutane nanodroplets (PBNDs) with a Definity-derived lipid shell (237 nm; 4...

We present MiniVess, the first annotated dataset of rodent cerebrovasculature, acquired using two-photon fluorescence microscopy. MiniVess consists of 70 3D image volumes with segmented ground truths. Segmentations were created using traditional image processing operations, a U-Net, and manual proofreading. Code for image preprocessing steps and the U-Net are provided. Supervised machine learning methods have been widely used for automated image processing of biomedical images. While much emphasis has been placed on the development of new network architectures and loss functions, there has been an increased emphasis on the need for publicly available annotated, or segmented, datasets...

Transcranial ultrasound combined with intravenous microbubbles can be used to increase blood-brain barrier permeability or, at lower pressures, to mediate sonoselective gene delivery to endothelial cells. Previously, sonoselective gene delivery with plasmid-coated microbubbles as gene carriers resulted in transient transgene expression in the brain endothelium. We investigated the potential of recombinant adeno-associated virus 9 (rAAV9), a serotype known for its efficient transduction and long-term transgene expression, for sonoselective gene delivery to endothelial cells of the brain...

The real-time monitoring of spectral characteristics of microbubble (MB) acoustic emissions permits the prediction of increases in blood-brain barrier (BBB) permeability and of tissue damage in MB-mediated focused ultrasound (FUS) brain therapy. Single-element passive cavitation detectors provide limited spatial information regarding MB activity, greatly affecting the performance of acoustic control. However, an array of receivers can be used to spatially map cavitation events and thus improve treatment control...

OBJECTIVE: Alzheimer's disease (AD) is often associated with neuropsychiatric symptoms, including agitation and aggressive behavior. These symptoms increase with disease severity, ranging from 10% in mild cognitive impairment to 50% in patients with moderate-to-severe AD, pose a great risk for self-injury and injury to caregivers, result in high rates of institutionalization and great suffering for patients and families. Current pharmacological therapies have limited efficacy and a high potential for severe side effects...

Diffuse Intrinsic Pontine Glioma (DIPG), now known as Diffuse Midline Glioma (DMG) is a devastating pediatric brain tumor with limited treatment options and a very poor prognosis. Despite more than 250 clinical trials aimed to treat children diagnosed with DMG, no curative therapies currently exist for this patient population. A major obstacle has been the intact blood brain barrier (BBB) which prevents most therapeutics from crossing into the tumor bed. Focused Ultrasound (FUS) is an emerging, noninvasive medical technology which has been shown in both preclinical and clinical research to disrupt the blood brain barrier safely and temporarily...

The blood-brain barrier (BBB) protects the brain but is also an important obstacle for the effective delivery of therapeutics in Alzheimer's disease and other neurodegenerative disorders. Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly disrupt the BBB. However, treatment of diffuse regions across the brain along with the effect on Alzheimer's disease relevant pathology need to be better characterized. This study is an open-labelled single-arm trial (NCT04118764) to investigate the feasibility of modulating BBB permeability in the default mode network and the impact on cognition, amyloid and tau pathology as well as BBB integrity...

Magnetic resonance-guided focused ultrasound (MRgFUS), in conjunction with circulating microbubbles, is an emerging technology that can transiently enhance the permeability of the blood-brain barrier (BBB) locally and non-invasively to facilitate targeted drug delivery to the brain. In this clinical trial, the feasibility and safety of BBB modulation in the putamen were evaluated for biweekly therapeutic agent delivery in patients with Parkinson's disease. The performance of the clinical MRgFUS system's cavitation feedback controller for active power modulation throughout the exposures was examined...

Magnetic resonance imaging-guided focused ultrasound combined with microbubbles injected in the bloodstream (MRIgFUS) temporarily increases the permeability of the blood-brain barrier (BBB), which facilitates the entry of intravenously administered adeno-associated viruses (AAVs) from the blood to targeted brain areas. To date, the properties of the AAVs used for MRIgFUS delivery resulted in cell transduction limited to MRIgFUS-targeted sites. Considering future clinical applications, strategies are needed to deliver genes to multiple locations and large brain volumes while creating minimal BBB modulation...

Focused ultrasound combined with intravenously injected microbubbles (FUS) is known to non-invasively, locally, and transiently increase the permeability of the blood-brain barrier (BBB). A promising approach for non-invasive gene delivery to the brain is to administer recombinant adeno-associated viruses (AAVs) intravenously and allow them to cross the BBB at precise FUS-targeted brain regions. FUS-AAV delivery has been achieved in animal models; however, the key elements influencing, guiding, and monitoring the success of FUS-AAV delivery to the brain remain largely unknown...

BACKGROUND: GBA1 mutation is the most common genetic risk factor for Parkinson's disease (PD). Replacement of the lysosomal enzyme glucocerebrosidase (GCase) slows neurodegeneration in PD models and may be a promising disease-modifying therapy in patients with PD. However, recombinant GCase has limited penetration through the blood-brain barrier (BBB). Microbubble-mediated magnetic resonance-guided focused ultrasound (MRgFUS) can reversibly disrupt the BBB for drug delivery. METHODS: This open-label phase I study investigated the safety and feasibility of MRgFUS putaminal delivery of intravenous GCase at escalating doses (15 to 30 to 60 IU/kg) every 2 weeks in four patients with PD with GBA1 mutations...

BACKGROUND: MR-guided focused ultrasound (MRgFUS) thalamotomy has been shown to be a safe and effective treatment for essential tremor (ET). OBJECTIVE: To investigate the effects of MRgFUS in patients with ET with an emphasis on ipsilateral-hand and axial tremor subscores. METHODS: Tremor scores and adverse effects of 100 patients treated between 2012 and 2018 were assessed at 1 week, 3, 12, and 24 months. A subgroup analysis of ipsilateral-hand tremor responders (defined as patients with ≥30% improvement at any time point) and non-responders was performed...

OBJECTIVE: The objective of this study was to evaluate, at 4 and 5 years posttreatment, the long-term safety and efficacy of unilateral MRI-guided focused ultrasound (MRgFUS) thalamotomy for medication-refractory essential tremor in a cohort of patients from a prospective, controlled, multicenter clinical trial. METHODS: Outcomes per the Clinical Rating Scale for Tremor (CRST), including postural tremor scores (CRST Part A), combined hand tremor/motor scores (CRST Parts A and B), and functional disability scores (CRST Part C), were measured by a qualified neurologist...

In sonodynamic therapy, cellular toxicity from sonosensitizer drugs, such as 5-aminolevulinic acid hydrochloride (5-ALA), may be triggered with focused ultrasound through the production of reactive oxygen species (ROS). Here we show that by increasing local oxygen during treatment, using oxygen-loaded perfluorocarbon nanodroplets (250 +/- 8 nm), we can increase the damage induced by 5-ALA, and monitor the severity by recording acoustic emissions in the brain. To achieve this, we sonicated the right striatum of 16 healthy rats after an intravenous dose of 5-ALA (200 mg/kg), followed by saline, nanodroplets, or oxygen-loaded nanodroplets...