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2 Articles in this Series
Introduction
New Imaging Tools Drive Chronic Pain Research and Understanding
NIH Director, Surgeon General Discuss Intersection of Pain Management and Opioid Crisis

New Imaging Tools Drive Chronic Pain Research and Understanding

With Walter Koroshetz, MD, Director, National Institute of Neurological Disorders and Stroke

Innovative technologies, developed as part of the public-private Brain Research through Advancing Innovative Neurotechnologies, or BRAIN Initiative, are allowing researchers to see the brain in ways never before possible and helping to reveal the structure and function of the circuitry involved in pain, according to Walter Koroshetz, MD, director or the National Institute of Neurological Disorders and Stroke (NINDS) and co-chair of the initiative.

“I’m quite interested in things that are coming out of the BRAIN Initiative as tools that might make us much more successful in the long run and potentially shorten the timeframe” for developing new treatments for pain, he said. Dr. Koroshetz hosted a session on harnessing the technology of the BRAIN Initiative for pain research at the 2018 NIH Pain Consortium Symposium held May 31 and June 2, in Bethesda, Maryland. The consortium was established to foster collaboration in pain research across NIH institutes and centers.

Dr. Koroshetz explained the BRAIN Initiative approach to chronic pain treatment and, in particular, opioid-related fatalities. This White House initiative was launched in 2013, and in the first five years its focus has been on developing the technology to drive the second half of the initiative — emphasizing discovery-driven science. Examples include improving overdose reversal and prevention interventions; developing new medications, devices and other technologies to treat opioid addiction and chronic pain; and identifying safe, effective and non-addictive interventions for chronic pain.

Specifically, the BRAIN Initiative is focusing on targeting central nervous system nociceptive and pain circuits through the development of technologies that may enable the creation of detailed pain circuit maps and the means to monitor and modulate pain circuit activity. Ultimately, this mapping could lead to significant advances in the understanding of pain and nociception, therapeutic targets, and effective and circuit/cell-specific treatments.

Initiative Fosters New Technologies

New tools drive new science, not new concepts. As an example, Dr. Koroshetz showed an axial CT image from 1974 (when he finished medical school) and compared it with a more recent high-field magnetic resonance image that almost allows the observation of histological-level brain data.

It has never been possible before to see circuits in the brain, and “one of the first priorities of the BRAIN initiative is to focus on understanding circuit structure and function,” he explained. To do this, the initiative is supporting the development of new imaging tools to allow researchers to see circuits in vivo.

One day, it may be possible to diagnose patients based on their circuit function and better target therapy, Dr. Koroshetz said. It may also become possible to access specific cell types to create targeted treatments with the precision to “hit,” or precisely target, specific cells.

In fact, that future is getting closer. Researchers have been able to view specific brain circuits in zebrafish and fruit flies at the cellular level. Work is underway to do the same with mice, said Dr. Koroshetz.

While researchers have been able to look at specific circuits, new imaging allows them to look at molecular-level resolution all the way up to brain-wide images.

Another technology has taken advantage of genetic tools that cause individual cells to “light up” when they fire, allowing researchers to see not only the activity of individual cells but also cell connections. One of the great challenges going forward will be how to handle the tremendous amount of data garnered from technologies like these, but large-scale data sets could allow researchers to gain a better of idea of what these patterns of firing mean in terms of pain processing.

Seeing brain circuits in action could ultimately lead to understanding how to monitor and manipulate circuits for improved function, said Dr. Koroshetz. It could also lead to a better understanding of neurological, mental and substance use disorders.

Radiomagnetogenetics

Following Dr. Koroshetz’s overview of BRAIN initiative research goals for pain and addiction, Sarah Stanley, MBBCh, PhD, illustrated some of this work with a brief talk on radiomagnetogenetics. Dr. Stanley is an assistant professor of medicine, endocrinology, diabetes and bone disease, and an assistant professor of neuroscience at Mount Sinai in New York.

Radiomagnetogenetics combine the revolutionary tools known as optogenetics and magnetogenetics to visualize causal relationships between neuronal activity and behavioral outcomes. While optogenetics allow this visualization, it can be limited by the need to “shine” light on specific cells. Magnetogenetics overcame this problem by manipulating neurons that are tagged with special proteins using magnetic stimuli. While still in animal testing, the radiomagnetogenetics’ researchers have shown that electrical or genetic modulation of neural pathways does alter pain sensation. It remains to be seen whether specific promotors can lead to cell type-specific targeting, said Stanley.

Once refined and validated in humans, visualization tools such as those offered by radiomagnetogenetics may move the BRAIN Initiative further toward its second priority goal of teasing apart brain structures and functions related to pain and addiction, ultimately changing the lives of chronic pain patients.

 
Next summary: NIH Director, Surgeon General Discuss Intersection of Pain Management and Opioid Crisis
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