Prior to performing brain surgery, surgeons carefully plan the operation by analyzing images of a patient’s brain. Visualizations of the brain are constructed by computed tomography (CT) and magnetic resonance imaging (MRI), providing a high-quality stereotactic model that can be used to identify and target structures. However, what the surgeons see when they actually start operating can sometimes be very different from what they interpreted from these images, forcing them to change their operational procedure on-the-fly.
The incredible complexity of the human brain, composed of 100 billion neurons and thousands of blood vessels, leads to inevitable difficulties in reconciling imaging with real tissue. “We would like to create globally accepted solutions for neuro-related applications,” says Wieslaw L. Nowinski, a professor and director of the Biomedical Imaging Lab, part of A*STAR’s Singapore Bioimaging Consortium.
At the forefront of brain atlas development
The solution, Nowinski says, is “to construct computer brain atlases and develop atlas-assisted applications” for clinicians, researchers and students. Nowinski’s attempt is not completely new; atlases of the brain have been available since the early 1950s in print. Technological progress since then has made it possible to construct three-dimensional visualization with additional functionality such as segmentation and structure labels. “But,” says Nowinski, “we are the first to introduce brain atlases into clinical practice.”
Nowinski’s atlases, named Cerefy, are the most widely used in stereotactic and functional neurosurgery. The popularity of Cerefy is due to the product’s comprehensiveness, high user interactivity, detail and extensive labeling, not to mention its high resolution and volumetric accuracy. The colorful graphical brain model can also be easily mapped to scanned images and updated online by users. Nowinski’s personal commitment to the project is plain to see—the brain mapped by the recent Cerefy atlases is his own, a process that required him to put his head in an ultra-high-field MRI and staying still for as long as four hours to acquire consistent and distinct images.
Nowinski’s pioneering endeavors have led to the production of 22 atlases in collaboration with prestigious hospitals and universities, accompanied by the submission of 58 patent applications (20 of which have been granted) and the creation of two venture companies. The atlases are currently used on more than 1,500 neurosurgical workstations worldwide and have been distributed to about 5,000 medical schools and hospitals. The technologies underpinning these applications have won numerous awards, including the Magna cum Laude and Excellence in Design awards received at the Radiological Society of North America Scientific Annual Meeting in 2009.
Evolution of brain atlases
The first of the Cerefy atlas series was the anatomic atlas, which was released in 1997 in a two-dimensional format. The atlases have since been continuously upgraded and now also contain digitized versions of classic print anatomic atlases in both two- and three-dimensional formats to complement new clinical data.
Although the stereotactic atlases are used widely, the question of how to deal with high variability is a major concern of clinicians. “There are certain controversies regarding the mismatch between imaging and electrophysiology as well as the incompleteness of target structures in the scans,” says Nowinski. To address the variability issue, he has developed a ‘probabilistic functional atlas’ for Parkinson’s disease based on electrophysiological and neuroimaging data acquired from hundreds of patients during deep brain stimulation with an electrode—one of the treatments for the disease. The key technology is a special algorithm that converts multiple sets of data into maps showing the possible distribution of cerebral structures and predicting the optimal placement of the electrode during surgery. In combination with the anatomic atlases, the probabilistic atlas has become a powerful tool for surgeons to not only pinpoint treatment targets more accurately but also identify new targets.
The most recent commercial release in the Cerefy series, the Cerefy Atlas of Cerebral Vasculature unveiled in 2009, correlates the three-dimensional cerebrovasculature with surface and sectional neuro-anatomy. Using this fully interactive atlas, the operator can select groups of vessels and other structures, rotate, zoom and label the model, and construct vascular networks and self-tests with the click of a mouse. The latest development, the Brain Atlas of Structure, Vasculature and Connections, is a three-dimensional model constructed from multiple high-field MRI scans and contains more than 1,200 components, including cortical and subcortical structures, arteries, veins and even white matter tracts. The smallest vessels in the brain, measuring only 90 micrometers in diameter, can be missed by conventional MRI, but not with Cerefy. The atlas even allows the user to cut the brain to reveal underlying structures, just like in a real brain.
Atlas-aided software for stroke treatment
In 2004, Nowinski launched another long-awaited project that evolved out of the development of the Cerefy atlases: computer-aided diagnosis/detection (CAD) for the treatment of stroke. Stroke is the second leading cause of death in the world and a condition that is typically managed by catheter delivery or intravenous/intra-arterial injection of a drug to break up a blood clot (thrombolysis). Although CAD has been applied for other purposes, such as mammography and brain cancer diagnosis, Nowinski was the first to apply the technique to the treatment of stroke.
The project, called the Singapore Stroke Suite, covers acute ischemic stroke, hemorrhagic stroke and stroke in the emergency room, and is assisted by Nowinski’s anatomic atlases and another atlas featuring blood supply territories. It is designed to help clinicians analyze data acquired by CT and MRI in a situation where “time is brain.” For acute ischemic stroke, caused by blockages in brain arteries, the CAD system offers simultaneous visualization and quantification of two- and three-dimensional images along with the underlying anatomy and the indications of the mismatch between the damaged tissues and those at risk of infarction. It can also help families of a patient to make the difficult decision of whether to perform thrombolysis, which incurs the risk of some brain function loss. “It’s better to know what would be lost, compared to knowing only what the risks are,” says Nowinski. The system is now trial-licensed to more than a dozen companies and medical institutes.
In an emergency room setting, the CAD system detects the location of infarcts and hemorrhages automatically and offers statistic analysis of the differences between the left and right hemispheres, helping non-specialists in the emergency room make better decisions in the short time they have. “Our system is very much like an experienced doctor,” Nowinski says. Another CAD system designed to support the evacuation of hemorrhages by thrombolytic treatment is now in Phase III trials.
Despite the impressive results already obtained, Nowinski is still not fully satisfied with the quality and application of the Cerefy atlases and intends to keep improving them. His team has built a probabilistic atlas for stroke to predict what would happen to a patient based on hundreds of previous similar cases. He has also developed software capable of fast-mapping anatomic atlases into a scan in less than five seconds. Among the team’s forays into new applications is the development of brain atlases for neurological disorders as well as for the assessment of meditation in collaboration with a yoga center in India. “We are doing novel things, so it’s not always easy to introduce our concepts into clinical practices quickly,” Nowinski says. “But the demand for our technologies is proven given the number of leading clinicians we are working with.”
Cerefy is the result of a collaboration between Thieme, a leading medical publisher, and the Biomedical Imaging Lab, an A*STAR research center. Cerefy produces atlases and model-based solutions for the diagnosis and treatment of human brain and central nervous system disorders, for human brain research and medical education. Cerefy atlases are currently used by leading companies including Medtronic (USA), BrainLab (Germany) and Elekta (Sweden). More information on the Cerefy atlases can be found on the Cerefy website.
About the Singapore Bioimaging Consortium
The Singapore Bioimaging Consortium (SIBC) was established in 2005 with the aim of harnessing existing imaging expertise and capabilities in Singapore — across local research institutes, universities and hospitals — in order to develop a focused national platform to support the growth of multi-disciplinary research activities and accelerate the development of biomedical research discoveries.