Discovery of Brain Biomarkers for Pain and Beyond:
Q&A With Dr. Rebecca Baker and Dr. John Ngai

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The human brain has been intensely studied by scientists for decades. This research has taught us that some health conditions share underlying biology – for example, pain, addiction, and mental illnesses such as depression and anxiety. Of these brain-based conditions, chronic pain looms large. A recent NIH study showed that new cases of chronic pain outnumber those of diabetes, depression, or hypertension.

Undertreated pain affects millions of Americans (one in five people), and the use of opioids to block pain contributes to the nation’s current overdose crisis. Since the 1990s, when healthcare providers began to prescribe increased numbers of opioid medications, prescribing of these drugs has gone way down – but we still don’t have safe and effective options for treating chronic pain. In part, this is because chronic pain is controlled by the brain in ways that are not well understood. This Q&A with the directors of two trans-NIH research initiatives (HEAL and BRAIN) visits how ongoing research to understand brain circuits is guiding us to precision medicine approaches for complex brain-based conditions like chronic pain.

Q: Recently, NIH-funded scientists led by Dr. Prasad Shirvalkar at the University of California, San Francisco, made significant progress in research targeting a specific brain circuit linked to chronic pain. What did they find and why is this important?

A (Rebecca Baker): In this study, the researchers recorded pain signals in real time from inside the brains of people with chronic pain disorders caused by stroke or amputation. They focused on regions of the brain associated with both pain perception and the emotional response to chronic pain. By analyzing the activity recorded while these individuals went about their everyday lives and experienced episodes of severe pain, they could identify distinct activity signatures or “biomarkers” unique to chronic pain.

A (John Ngai): From a technology standpoint, these results are a tour de force. Using sensitive electrical monitoring equipment and machine learning tools, the scientists were able to sort through massive amounts of recording data in people going about daily life. This research provides an important proof of principle for using this kind of data to unravel a complex disease like chronic pain.

These results are a testament to the value of the comprehensive BRAIN research investment we launched nearly 10 years ago. Our vision is to develop and leverage emerging technologies to build new therapies for human brain disorders, and we are starting to see exciting results like this.

Q: Why is it challenging to develop treatments for chronic pain and other brain diseases?

A (Rebecca Baker): The findings are also important because we don’t otherwise have a truly objective way to measure pain. A lot of pain research relies on people describing their pain on a scale of 1 to 10, which as you can imagine creates a lot of uncertainty because people are so different. This research blends sophisticated technology and the human experience, providing a window into the individual experience of pain. There is mounting evidence that treating chronic pain effectively will involve a person-specific treatment plan involving not only technology-based solutions, but also counseling or mindfulness, physical therapy or structured exercise, and other strategies.

A (John Ngai): Many say the brain is the most complex machine known to humankind. Moreover, each individual human’s brain is unique. The exciting news is that technology is giving us very powerful ways to “watch” what’s going on inside an individual brain – which was not long ago only possible in small animal brains. Using those tools is helping us to put together a clearer picture of what’s amiss in disease and to develop specific targets for treatments. New discoveries about neural circuits, like this research, help demystify the functional units of communication within the brain. With this research and other examples like it, we are one step closer to developing effective, circuit-based treatments – bringing hope to millions with debilitating brain disorders.

Q: Are there other conditions in which this type of research is leading to new knowledge and new treatments for brain diseases?

A (Rebecca Baker): Addiction is another health condition linked to brain wiring. Repeated drug use changes the brain, which is one reason addiction is so hard to overcome. Overstimulation of the brain’s reward center compared to its behavior control center create a difficult combination: the desire and physiological need to use more drugs with a reduced ability to resist. Ongoing HEAL research is testing deep brain stimulation that delivers a mild electrical current to bring these two circuits into balance.

A (John Ngai): We’ve seen some impressive progress from BRAIN Initiative-funded research in refining deep brain stimulation therapies, which have been around for decades for alleviating the symptoms of Parkinson’s disease. Deep brain stimulation is now being applied to other neurological and psychiatric conditions, including essential tremor, treatment-resistant depression, obsessive-compulsive disorder, binge-eating disorder, and post-traumatic stress disorder. In fact, the same research team reporting these new results about chronic pain signatures has shown the effectiveness of personalized deep brain stimulation for treatment-resistant depression. Very similar to the chronic pain experiments, they measured and analyzed brain activity in an individual with severe depression and then used this information to guide a treatment plan.

Q: What’s next?

A (John Ngai): Having reliable biomarkers is key for understanding when and how to treat an individual experiencing a particular health condition and knowing – objectively speaking – when a given treatment is working. In addition to extending and validating this small case study with a larger group of patients, one next step will be to use these chronic pain biomarkers to guide novel treatments. That includes, for example, deep brain stimulation therapy to stimulate or push the brain to a lower pain state. It will be exciting to see whether we can add chronic pain to the growing list of conditions that might be responsive to deep brain stimulation treatment. The next step toward reaching that goal (that these researchers are currently working on) is to develop a “closed loop” therapy. That’s when stimulation adapts or responds to a patient’s symptoms and day-to-day conditions automatically, sort of like an insulin pump that reacts to low blood sugar.

A (Rebecca Baker): Because pain and substance use disorders are complex conditions with many contributing factors, the HEAL research portfolio covers a lot of angles. We’re funding basic science to target the biology of pain, drug development to screen and test new non-addictive pain medications, and clinical studies that test non-medication-based pain treatments.

Amazing new technologies such as those developed through BRAIN and HEAL research are providing a path to untangle the complexity of little understood human brain circuits. This new patient-centric research is leading to new knowledge and novel treatment options for debilitating conditions like chronic pain, addiction, mental illnesses, and many others.

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