Seeing the Light with Optical Imaging Technologies

It’s late August 2020, the tail end of a long, fraught summer, and David Boas is watching flames dance around the edges of the logs stacked in a fire pit on his patio. Boas, a pioneer in the field of near-infrared spectroscopy and other optical imaging techniques, is musing over a question about what originally brought him to the Martinos Center in the late 1990s. Finally, he looks up from the flames and, in his quiet, deliberate way, starts to tell the story.

This history of the Optics group at the Martinos Center dates back to 1998, when Boas was a young researcher and faculty member in the Tufts University Department of Biomedical Engineering. During his graduate work in the early 1990s, he had pioneered the technology near-infrared spectroscopy (NIRS), which can noninvasively measure oxygen levels in tissue, and he was now developing the technology further for biomedical applications—including building one of the first-ever functional NIRS devices for monitoring brain activity.

At the same time, some five miles down the road in Charlestown, Martinos Center director Bruce Rosen was looking to validate the still-emerging functional MRI by comparing its results with those from other, related technologies. He learned of Boas’ work and, after meeting with him and discussing the possibilities in working with near-infrared spectroscopy, invited him to join the Center’s ranks.

Boas accepted. In the years that followed, the Martinos Center’s burgeoning Optics group made one important stride after another with near-infrared spectroscopy. First was further technology development and validation. NIRS works by sending near-infrared light into the brain—tissue is opaque to light in the near-infrared range—and detecting it as it emerges elsewhere on the head. Taking advantage of the light absorption and scattering properties of hemoglobin, the protein in the blood that transports oxygen, it can then determine oxygenation levels in particular regions of the brain.

The Center’s David Boas and Anders Dale on a ferry to the Greek island of Mykonos during a 2002 meeting in Athens

By 2001, the Optics group had built a fourth-generation NIRS system with 18 lasers and 16 detectors providing whole-head coverage, enabling localization of the NIRS signal throughout the brain. The design worked so well that the researchers still use it today, albeit with more lasers and detectors and additional digital signal processing. “It’s still basically the same fundamental design,” Boas says, “just faster, with more digital stuff.”

Having established the design, the group turned its attention to cross-validation of the technology with fMRI, and then to combining the two modalities to learn more the hemodynamic response to brain activity—the ”neurovascular coupling” in which vascular changes reflect the underlying metabolic response to neural activity. In developing improved understandings of this relationship, the researchers were better able to extract information about brain activity using the portable, noninvasive technology.

The fire continues to crackle. Maria Angela Franceschini, now one of the co-directors of the Optics group, returns to the patio after looking for one of her cats, who has wandered off seeking whatever sorts of adventure cats like to seek. She sits down and picks up the story about the group’s early progress with near-infrared spectroscopy.

Maria Angela Franceschini

In 2003, she says, she was applying the technology to a set of functional studies. But analysis of functional NIRS data was still a tedious if not arduous task, involving writing and implementing strings of computer code for every operation. “David and [then-Optics faculty] Joe Culver and Andy Dunn were giving me all of these MATLAB scripts that I had to modify in a million places to analyze my data,” she continues. “I said, ‘No, I want something I can click on and it works. So for my birthday that year, David developed and gave me HOMER.” HOMER, a Simpsons homage and a loosely defined acronym for “Hemodynamic Evoked Response,” was a data analysis package with a straightforward graphical user interface (GUI) in place of often-unwieldy scripts. It is, today, the most widely used NIRS package in the world.

New Directions

Over the next several years, Franceschini, also studying brain development in infants, reported a number of studies looking at changes in cerebral blood volume and oxygenation in healthy and diseased infants. In about 2005, she started thinking about incorporating into her work a technique known as diffuse correlation spectroscopy (DCS), which, by adding measures of blood flow, could provide deeper insights into the developing brain. There was a hitch, though: while Boas had already purchased the parts for a DCS system, there was nobody in the lab who could build it.

This is when Stefan Carp joined the Optics group.

Stefan Carp

Carp, now also a co-director of the group, alongside Franceschini and Sava Sakadžić, first came to the Center to work on an optical breast imaging project then underway. The project was briefly held up when he arrived so he asked Boas if there were any other projects he could tackle. “He wanted to do something,” Boas recalls, “so I said, ‘Here are the parts to build a DCS system, build it.’ I thought I would hear from him a few weeks later. He came back the next day and said, ‘Now what?’ ”

In the years since, Carp has also built a research program focused on the development and clinical translation of near-infrared spectroscopy and diffuse correlation spectroscopy to advance both brain health monitoring and breast cancer management. For example, in a 2013 paper, he and colleagues reported a new biomarker—that is, an indicator of disease or the effects of its progression—for breast cancer diagnosis and therapy monitoring based on the breast tissue’s response as measured by a novel optical imaging instrument. Following this work, in a 2017 study, they showed they could use the biomarker to characterize the early response of breast tumors to neoadjuvant chemotherapy and predict the eventual treatment outcome. Thus, the optical imaging technology could prove useful in guiding neoadjuvant chemotherapy.

Other major research streams have emerged as well. The early foray into optical breast imaging also spawned an optical molecular imaging effort, now led by Anand Kumar, director of the Optical Molecular Imaging Laboratory at the Martinos Center. In the years since the launch of this effort, Kumar’s lab has made significant strides with optical molecular imaging using time-domain fluorescence tomography, specifically by exploiting fluorescence lifetime as a contrast mechanism. The group is currently applying the technology to address challenging questions related to cancer, cardiac disease and neuropathology.

Sava Sakadžić and Optics faculty alum Abbas Yaseen in 2008

Parallel to all of the above, researchers in the Optics group have used microscopy techniques to uncover aspects of neurovascular coupling that aren’t accessible in human studies using NIRS. For example, in 2010, Sava Sakadžić, who is today another co-director of the Optics group, completed an advanced multi-photon microscope that could provide, for the first time, high-resolution maps of both microvascular and tissue oxygenation in animal models. This was possible by pairing the microscope with a special phosphorescent probe that glows briefly when excited with light. The more oxygen surrounding the probe, the briefer the phosphorescence, so the lifetime of the glow becomes a measure of oxygenation in particular regions of the brain.

In the decade since, the tool has enabled numerous discoveries about the ways in which oxygen is transported to the tissue and diffuses through the tissue. Recently, in a 2020 study reported in Journal of Cerebral Blood Flow and Metabolism, Sakadžić and colleagues applied the two-photon microscopy technique to measure microcirculation in the white matter of the brain, an area that is currently poorly understood, largely due to a lack of appropriate imaging methods. The findings of the study provided new insights into the regulation of blood flow in white matter, which could shed light on the mechanisms of white matter deterioration in certain brain conditions.

The Optics @ Martinos group in December 2019