Short Ultrasound Pulses Used to Reach Neurons Through Blood-Brain Barrier

A new ultrasound technique offers safe and noninvasive drug delivery to the brain regions affected by diseases such as Alzheimer’s, Parkinson’s, and epilepsy.

Engineers from Columbia University’s Fu Foundation School of Engineering and Applied Science (New York, NY, USA) have 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 demonstrated that very short pulses of ultrasound waves can open the BBB--with the added benefits of safety and uniform molecular delivery--and that the molecule injected systemically could reach and target the targeted neurons noninvasively.

The study, led by Dr. Elisa Konofagou, associate professor of biomedical engineering and radiology, was published in the journal Proceedings of the [US] National Academy of Sciences the week of September 19, 2011. “This is a great step forward,” said Dr. 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.”

Highly specific delivery of drugs to human organs is crucial for the effective treatment of many disorders. But the brain presents a difficult hurdle: it has a unique vascular system--the BBB--that acts as a closed door to prevent the entry of foreign molecules. While it protects the brain from potentially toxic substances, it also prevents the delivery of therapeutic drugs to the brain. Because many molecules cannot cross the BBB, available treatments for patients with neurologic disorders have been severely limited. Dr. Konofagou and her team are focused on getting the door opened enough to safely reach those cells that need to be treated.

Dr. Konofagou and her team have designed a focused ultrasound method that can target only the area of the hippocampus that is affected in early Alzheimer’s. In this study, they administered microbubbles to enhance the intended mechanical effect, and a high-field magnetic resonance imaging (MRI) to detect and map the area of BBB opening as well as quantify the permeability of the opened BBB. They also used fluorescence confocal microscopy to visualize the molecular diffusion and neuronal enhancement in three-dimensions (3D) to identify both highlighted neurons and their network.

More testing is planned with therapeutic drug treatments. The investigators have shown that therapeutic molecules initiate downstream effects after diffusion through the blood-brain barrier, starting with the cell membrane and all the way through the nucleus. They also are revealing the mechanism of the opening that involves stable oscillation or collapse of the bubble, with the former being the preferred mechanism because it is completely controlled by the pressure and microbubble size.

The BBB has been shown to recover within the range of three hours to three days depending on the aforementioned parameters used. Dr. Konofagou’s group has also recently reported that transcranial human targeting of the hippocampus, caudate, and putamen in the human brain is possible in both simulations and in vitro experiments, thereby paving the way towards clinical applications.

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Columbia University’s Fu Foundation School of Engineering and Applied Science