Our bodies maintain a state of equilibrium, or homeostasis, through our peripheral nervous system, through neural reflexes that modulate the function of organ systems such as the heart, stomach, intestines, or bladder. For instance, the vagus nerve linking the brain to the heart can stimulate the heart when an anxiety stimulus is experienced or can stimulate the stomach when hunger is recorded.
If researchers could map the neural circuits governing these systems, they might then be able to develop minimally invasive neural and bio-interface technologies with unprecedented levels of precision, targeting, and scale. The Defense Advanced Research Projects Agency (DARPA) has established a new Electrical Prescriptions (ElectRx) program to help spur research in this area, with the goal to develop new technologies that could improve physical and mental health by using targeted stimulation of the peripheral nervous system to exploit the body’s natural ability to quickly and effectively heal itself.
The agency recently selected seven teams, including a Columbia Engineering team led by Elisa Konofagou, professor of biomedical engineering, which will begin work on Phase 1. Backed by the four-year $3.33 million grant, Konofagou’s team will work on developing a new way to use focused ultrasound for stimulation of peripheral nerves that will ultimately be able to control organ function.
“What we’re working on is a very exciting application for ultrasound,” says Konofagou, who has a joint appointment in radiology (physics). “We could, for the first time, provide a noninvasive approach to nerve and organ stimulation while at the same time advance our understanding of the coupling between the mechanical and electrical activity at the cellular, multi-cellular, and organ levels. We think targeted ultrasound could be a good option for managing conditions such as chronic pain and neuropathy.”
Imagine if there were a way to detect early-stage cardiovascular disease or cancer without exposing a patient to potentially harmful radiation. Consider the benefits of a therapeutic application that could destroy tumors without surgery or stimulate motor control in the brain of a patient suffering from Parkinson’s disease. Funded by the National Institutes of Health, Elisa Konofagou, professor of biomedical engineering, and her research team are bringing these medical marvels closer to reality using the acoustic energy of ultrasound technology.
Though ultrasound—the use of high-frequency sound waves to produce images—is not itself a new technology, Konofagou and her team have developed novel ways to use it in the detection and treatment of specific medical problems.
“We have pioneered a way to use ultrasound to assess the elasticity of tissues such as the heart, the vessels, and tumors in the breast and pancreas,” says Konofagou. “We use the intrinsic movement of the organ, or the movement induced by the acoustic wave, to detect the elasticity.”
The method of harmonic motion imaging can effectively identify cancerous tissue—which typically has greater stiffness than normal soft tissues—and can measure mechanical functions of the heart muscle, disruptions in which can indicate disease.
Top: Focused ultrasound (FUS) in combination with microbubbles is used to noninvasively and transiently open the blood-brain barrier (BBB) in the caudate putamen region. The BBB opened region is revealed with contrast-enhanced MRI as the highlighted region; middle: Adeno-Associated Virus (AAV) carrying green fluorescent protein (GFP) gene was successfully delivered across the blood-brain barrier (BBB) with transcranial FUS, where AAV transduction was observed in neurons (green); bottom: Three-dimensional Harmonic Motion Imaging of the human breast before (left) and after (right) thermal ablation. (Images courtesy of Elisa Konofagou)
“A radiation-free method is important because it is safely used for children (who are more sensitive to radiation doses), eliminates burn risks, and allows for follow-ups at necessary frequencies without worrying about a build-up of radiation,” says Konofagou.
A new technique developed by Elisa Konofagou, professor of biomedical engineering and radiology at Columbia Engineering, has demonstrated for the first time that the size of molecules penetrating the blood-brain barrier (BBB) can be controlled using acoustic pressure—the pressure of an ultrasound beam—to let specific molecules through. The study was published in the July issue of the Journal of Cerebral Blood Flow & Metabolism.
Fluorescence images of the murine hippocampus after diffusion of dextran of distinct sizes through the opened blood-brain barrier with ultrasound (on the left) unlike the contralateral hippocampus (on the right) that shows no uptake due to intact BBB. These images show that higher amounts and larger areas of dextran delivery were achieved for smaller-size dextrans but all sizes permeate the hippocampus at this pressure. (Credit: Elisa Konofagou)
“This is an important breakthrough in getting drugs delivered to specific parts of the brain precisely, non-invasively, and safely, and may help in the treatment of central nervous system diseases like Parkinson’s and Alzheimer’s,” says Konofagou, whose National Institutes of Health Research Project Grant (R01) funding was just renewed for another four years for an additional $2.22 million. The award is for research to determine the role of the microbubble in controlling both the efficacy and safety of drug safety through the BBB with a specific application for treating Parkinson’s disease.
Most small—and all large—molecule drugs do not currently penetrate the blood-brain barrier that sits between the vascular bed and the brain tissue. “As a result,” Konofagou explains, “all central nervous system diseases remain undertreated at best. For example, we know that Parkinson’s disease would benefit by delivery of therapeutic molecules to the neurons so as to impede their slow death. But because of the virtually impermeable barrier, these drugs can only reach the brain through direct injection and that requires anesthesia and drilling the skull while also increasing the risk of infection and limiting the number of sites of injection. And transcranial injections rarely work—only about one in ten is successful.”
Thanks to a new study from Columbia Engineering School, doctors may now be able to diagnose in their offices non-periodic arrhythmias-noninvasively and at low cost-within a single heartbeat. Non-periodic arrhythmias include atrial and ventricular fibrillation, which are associated with severely abnormal heart rhythm that can in some cases be life-threatening.
Using Electromechanical Wave Imaging (EWI), a technique recently developed at Columbia Engineering, the researchers sent unfocused ultrasound waves through the closed chest and into the heart. They were able to capture fast-frame-rate images that enabled them-for the first time-to map transient events such as the electromechanical activation that occurs over a few tens of milliseconds while also imaging the entire heart within a single beat.
The Columbia Engineering study was recently published in IOPscience (“Electromechanical wave imaging for arrhythmias,” Phys Med Biol. 2011 Nov 21;56(22):L1-L11, http://www.ncbi.nlm.nih.gov/pubmed/22024555. “We are very excited about extending the capabilities of our new technique,” says Elisa Konofagou, an associate professor of biomedical engineering and radiology at Columbia University’s Fu Foundation School of Engineering and Applied Science.
A team of researchers, led by Elisa Konofagou, associate professor of biomedical engineering and radiology, has developed a new technique to reach neurons through the blood-brain barrier (BBB) and deliver drugs safely and noninvasively. Up until now, scientists have thought that long ultrasound pulses, which can inflict collateral damage, were required. But in this new study, the Columbia Engineering team show that extremely short pulses of ultrasound waves can open the blood-brain barrier—with the added advantages of safety and uniform molecular delivery— and that the molecule injected systemically could reach and highlight the targeted neurons noninvasively.
The study will be published in the online Early Edition of the Proceedings of the National Academy of Sciences the week of September 19, 2011.
“This is a great step forward,” says Konofagou. “Devastating diseases such as Alzheimer’s and Parkinson’s that affect millions of people are currently severely undertreated. We hope our new research will open new avenues in helping eradicate them.”
Two Columbia Engineering professors are among the 85 nationwide selected to take part in the National Academy of Engineering’s (NAE) 17th annual U.S. Frontiers of Engineering symposium next month in California.
The NAE selected Elisa Konofagou, assistant professor of biomedical engineering and radiology, and Luca Carloni, associate professor of computer science, from among the nation’s brightest young engineers between 30 and 45 years old who are performing exceptional engineering research and technical work in industry, academia, and government.
“The young engineering innovators of today are solving the grand challenges that face us in the coming century,” said NAE President Charles M. Vest. “We are proud that our Frontiers of Engineering program brings this diverse group of people together and gives them an opportunity to share and showcase their work.”
Abnormalities in cardiac conduction — the rate at which the heart conducts electrical impulses to contract and relax — are a major cause of death and disability around the world.
Researchers at Columbia Engineering School lead by Professor Elisa Konofagou have been developing a new method, Electromechanical Wave Imaging (EWI), that is the first non-invasive direct technique to map the electrical activation of the heart. Based on ultrasound imaging, EWI will enable doctors to treat arrhythmias more efficiently and more precisely. The study was published online in the May 9 issue of Proceedings of the National Academy of Sciences.
Up until now, other research groups have mostly focused on measuring the electrical activation directly but invasively, through electrode contact, or non-invasively but indirectly, through complex mathematical modeling based on remote measurements.