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Chronic Pain

Discovering a Source of Laughter in the Brain

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cingulum bundle
Illustration showing how an electrode was inserted into the cingulum bundle. Courtesy of American Society for Clinical Investigation

If laughter really is the best medicine, wouldn’t it be great if we could learn more about what goes on in the brain when we laugh? Neuroscientists recently made some major progress on this front by pinpointing a part of the brain that, when stimulated, never fails to induce smiles and laughter.

In their study conducted in three patients undergoing electrical stimulation brain mapping as part of epilepsy treatment, the NIH-funded team found that stimulation of a specific tract of neural fibers, called the cingulum bundle, triggered laughter, smiles, and a sense of calm. Not only do the findings shed new light on the biology of laughter, researchers hope they may also lead to new strategies for treating a range of conditions, including anxiety, depression, and chronic pain.

In people with epilepsy whose seizures are poorly controlled with medication, surgery to remove seizure-inducing brain tissue sometimes helps. People awaiting such surgeries must first undergo a procedure known as intracranial electroencephalography (iEEG). This involves temporarily placing 10 to 20 arrays of tiny electrodes in the brain for up to several weeks, in order to pinpoint the source of a patient’s seizures in the brain. With the patient’s permission, those electrodes can also enable physician-researchers to stimulate various regions of the patient’s brain to map their functions and make potentially new and unexpected discoveries.

In the new study, published in The Journal of Clinical Investigation, Jon T. Willie, Kelly Bijanki, and their colleagues at Emory University School of Medicine, Atlanta, looked at a 23-year-old undergoing iEEG for 8 weeks in preparation for surgery to treat her uncontrolled epilepsy [1]. One of the electrodes implanted in her brain was located within the cingulum bundle and, when that area was stimulated for research purposes, the woman experienced an uncontrollable urge to laugh. Not only was the woman given to smiles and giggles, she also reported feeling relaxed and calm.

As a further and more objective test of her mood, the researchers asked the woman to interpret the expression of faces on a computer screen as happy, sad, or neutral. Electrical stimulation to the cingulum bundle led her to see those faces as happier, a sign of a generally more positive mood. A full evaluation of her mental state also showed she was fully aware and alert.

To confirm the findings, the researchers looked to two other patients, a 40-year-old man and a 28-year-old woman, both undergoing iEEG in the course of epilepsy treatment. In those two volunteers, stimulation of the cingulum bundle also triggered laughter and reduced anxiety with otherwise normal cognition.

Willie notes that the cingulum bundle links many brain areas together. He likens it to a super highway with lots of on and off ramps. He suspects the spot they’ve uncovered lies at a key intersection, providing access to various brain networks regulating mood, emotion, and social interaction.

Previous research has shown that stimulation of other parts of the brain can also prompt patients to laugh. However, what makes stimulation of the cingulum bundle a particularly promising approach is that it not only triggers laughter, but also reduces anxiety.

The new findings suggest that stimulation of the cingulum bundle may be useful for calming patients’ anxieties during neurosurgeries in which they must remain awake. In fact, Willie’s team did so during their 23-year-old woman’s subsequent epilepsy surgery. Each time she became distressed, the stimulation provided immediate relief. Also, if traditional deep brain stimulation or less invasive means of brain stimulation can be developed and found to be safe for long-term use, they may offer new ways to treat depression, anxiety disorders, and/or chronic pain.

Meanwhile, Willie’s team is hard at work using similar approaches to map brain areas involved in other aspects of mood, including fear, sadness, and anxiety. Together with the multidisciplinary work being mounted by the NIH-led BRAIN Initiative, these kinds of studies promise to reveal functionalities of the human brain that have previously been out of reach, with profound consequences for neuroscience and human medicine.

Reference:

[1] Cingulum stimulation enhances positive affect and anxiolysis to facilitate awake craniotomy. Bijanki KR, Manns JR, Inman CS, Choi KS, Harati S, Pedersen NP, Drane DL, Waters AC, Fasano RE, Mayberg HS, Willie JT. J Clin Invest. 2018 Dec 27.

Links:

Video: Patient’s Response (Bijanki et al. The Journal of Clinical Investigation)

Epilepsy Information Page (National Institute of Neurological Disease and Stroke/NIH)

Jon T. Willie (Emory University, Atlanta, GA)

NIH Support: National Institute of Neurological Disease and Stroke; National Center for Advancing Translational Sciences


Researchers Elucidate Role of Stress Gene in Chronic Pain

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Credit: Getty Images/simonkr

For most people, pain eventually fades away as an injury heals. But for others, the pain persists beyond the initial healing and becomes chronic, hanging on for weeks, months, or even years. Now, we may have uncovered an answer to help explain why: subtle differences in a gene that controls how the body responds to stress.

In a recent study of more than 1,600 people injured in traffic accidents, researchers discovered that individuals with a certain variant in a stress-controlling gene, called FKBP5, were more likely to develop chronic pain than those with other variants [1]. These findings may point to new non-addictive strategies for preventing or controlling chronic pain, and underscore the importance of NIH-funded research for tackling our nation’s opioid overuse crisis.


Managing Chronic Pain: Opioids Are Often Not the Answer

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Opioids and researchThe term “silent epidemic” sometimes gets overused in medicine. But, for prescription opioid drugs, the term fits disturbingly well. In 2012, more than 259 million prescriptions were written in the United States for Vicodin, OxyContin, and other opioid painkillers. That equals one bottle of pain pills for every U.S. adult. And here’s an even more distressing statistic: in 2011, overdoses of prescription painkillers, most unintentional, claimed the lives about 17,000 Americans—46 people a day [1].

The issue isn’t whether opioid painkillers have a role in managing chronic pain, such as that caused by cancer or severe injuries. They do. What’s been lacking is an unbiased review of the scientific literature to examine evidence on the safety of long-term prescription opioid use and the impact of such use on patients’ pain, function, and quality of life. The NIH Office of Disease Prevention (ODP) recently convened an independent panel to conduct such a review, and what it found is eye-opening. People with chronic pain have often been lumped into a single category and treated with generalized approaches, even though very little scientific evidence exists to support this practice.


How Does Acute Pain Become Chronic?

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Woman holding her headChronic pain is a major medical problem, affecting as many as 100 million Americans, robbing them of a full sense of well-being, disrupting their ability to work and earn a living, and causing untold suffering for the patient and family. This condition costs the country an estimated $560-635 billion annually—a staggering economic burden [1]. Worst of all, chronic pain is often resistant to treatment. NIH launched the Grand Challenge on Chronic Pain [2] to investigate how acute pain (which is part of daily experience) evolves into a chronic condition and what biological factors contribute to this transition.

But you may wonder: what, exactly, is the difference between acute and chronic pain?