Kullervo Hynynen

Systems and methods are provided for performing transcranial diagnostic procedures using a transcranial ultrasound transducer array. The array elements are positioned and oriented such that far field regions respectively associated therewith spatially overlap within the brain of a patient. The array elements may be oriented approximately normal to the skull, permitting efficient coupling of ultrasound energy into the brain. The array elements are controlled to generate ultrasound pulses, where the timing of the pulses is controlled, based on registration between the array elements and volumetric image data, such that ultrasound energy is focused at a target within spatially overlapping far fields of the array elements. The transcranial ultrasound transducer array elements may be positioned and oriented relative to the skull such that their respective ultrasound beams are focused within the skull and diverging with the …

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. Hollow cylindrical radially polarized PZT transducers with 3.3/2.5 mm outer/inner diameters were assessed. Finite element simulations and hydrophone experiments were used to investigate the pressure field distribution as a function of element length and resonant mode (thickness, length). Operating in thickness mode (∼5 …

The Blood–Brain Barrier and Alzheimer’s Disease This editorial describes the science behind a trial involving a breach of the blood−brain barrier to deliver drugs to the brain.

Focused ultrasound (FUS) is an incisionless surgical procedure that uses nonionizing energy to precisely ablate tissue for disconnecting circuits or to perform neuromodulation in treatment-resistant psychiatric disorders. Preliminary open-label studies in obsessive-compulsive disorder (OCD) and major depressive disorder (MDD) demonstrate favorable efficacy and safety profiles. This chapter provides an overview of the FUS technique and its applications in psychiatric disorders.

Gene delivery via adeno-associated viral vectors can provide lasting clinical benefits following a one-time treatment. Delivery throughout the brain is needed for the treatment of neurological disorders with widespread pathology, including Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis. Most gene vectors have poor diffusion in the brain tissue. Furthermore, it is only at high intravenous doses that gene vectors can overcome the blood-brain barrier. In contrast, relatively lower doses of gene vectors injected in the cerebrospinal fluid enable significant transduction of superficial brain regions. The remaining challenge and unmet need of gene therapy is to deliver gene vectors to deep brain structures using a minimally invasive strategy. Here, we demonstrate that non-invasive focused ultrasound blood-brain barrier modulation can increase the delivery of recombinant adeno-associated virus by 5-fold to deep brain structures following injection in the cisterna magna. Delivery of adeno-associated viral vectors to the central nervous system, via administration in the cerebrospinal fluid, is being evaluated in several clinical trials for treating beta-galactosidase-1 deficiency, Batten disease, Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. Our findings suggest that the efficacy of gene therapies delivered in the cerebrospinal fluid can be enhanced by targeting brain areas of interest with focused ultrasound.

Ultrasound devices and systems are disclosed in which cooling of an active acoustic element of an ultrasound transducer is achieved via an electrically conductive member that extends beyond a proximal side of the active acoustic element to contact a heat exchanger. The electrically conductive member delivers electrical driving signals to the active acoustic element while conducting heat to the heat exchanger. A region of the proximal surface of the active acoustic element that is free from contact with the electrically conductive member may also absent from contact with a liquid or a solid, thereby facilitating reflection of ultrasound energy. The heat exchanger may include an electrically insulating fluid that contacts the electrically conductive member to remove the heat conducted through the electrically conductive member. The active acoustic element may be a multilayer lateral mode element, and the electrically …

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 (NCT03739905) 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. Nine participants [mean age 70.2 ± 7.2 years, mean Mini-Mental State Examination (MMSE) 21.9] underwent three biweekly procedures with follow-up visits up to 6 months. The BBB permeability of the bilateral hippocampi …

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. Thus, there is a growing need to develop novel therapeutics tailored to safely and effectively reduce agitation and aggressive behavior in AD. Here, we investigate for the first time the use of focused ultrasound combined with anesthetic‐loaded nanodroplets (nanoFUS) targeting the amygdala (key structure in the neurocircuitry of agitation) as a novel minimally invasive tool to modulate local neural …