Laughter may be best medicine -- for brain surgery

Illustration showing how an electrode was inserted into the cingulum bundle.

Credit: From Bijanki et al, J. Clin. Invest. (2019); Courtesy of American Society for Clinical Investigation

 

Neuroscientists at Emory University School of Medicine have discovered a focal pathway in the brain that when electrically stimulated causes immediate laughter, followed by a sense of calm and happiness, even during awake brain surgery. The effects of stimulation were observed in an epilepsy patient undergoing diagnostic monitoring for seizure diagnosis. These effects were then harnessed to help her complete a separate awake brain surgery two days later.

The behavioral effects of direct electrical stimulation of the cingulum bundle, a white matter tract in the brain, were confirmed in two other epilepsy patients undergoing diagnostic monitoring. The findings are scheduled for publication in the Journal of Clinical Investigation. Videos of the effects of cingulum bundle stimulation are available, with the patient's identity obscured.
Emory neurosurgeons see the technique as a "potentially transformative" way to calm some patients during awake brain surgery, even for people who are not especially anxious. For optimal protection of critical brain functions during surgery, patients may need to be awake and not sedated, so that doctors can talk with them, assess their language skills, and detect impairments that may arise from resection.
"Even well-prepared patients may panic during awake surgery, which can be dangerous," says lead author Kelly Bijanki, PhD, assistant professor of neurosurgery. "This particular patient was especially prone to it because of moderate baseline anxiety. And upon waking from global anesthesia, she did indeed begin to panic. When we turned on her cingulum stimulation, she immediately reported feeling happy and relaxed, told jokes about her family, and was able to tolerate the awake procedure successfully."
Outside of use during awake surgery, understanding how cingulum bundle stimulation works could also inform efforts to better treat depression, anxiety disorders, or chronic pain via deep brain stimulation.
Previous investigators have reported that direct electrical stimulation of other parts of the brain can trigger laughter, but the demonstration that anti-anxiety effects observed with cingulum bundle stimulation can provide meaningful clinical benefits make this study distinct, says senior author Jon T, Willie, MD, PhD, who performed the surgeries reported in the paper. He is assistant professor of neurosurgery and neurology at Emory University School of Medicine.
Additional Emory authors include Joseph Manns, PhD, Cory Inman, PhD, graduate student Sahar Harati , Nigel Pedersen, MD, Daniel Drane, PhD, and Rebecca Fasano, MD. Authors who are now at Mount Sinai in New York City are Ki Sueng Choi, PhD, Allison Waters, PhD and Helen Mayberg, MD, all previously at Emory.
Lying under the cortex and curving around the midbrain, the cingulum bundle has a shape resembling a girdle or belt -- hence its Latin name. The area that was a key to laughter and relaxation lies at the top and front of the bundle. The bundle is a logical target because of its many connections among brain regions coordinating complex emotional responses, Willie says.
The location of cingulum bundle stimulation is distinct from other brain locations that process reward, such as ventral striatum, which has been targeted for the treatment of depression and addiction. Because the cingulum bundle is a crossroads for white matter connecting several lobes, Willie and his team may be affecting widespread networks throughout the brain.
Willie says the locations of initial electrode placement were chosen in order to record brain activity and locate the onset of the first patient's seizures. The electrode initially used to stimulate the cingulum bundle was inserted into the brain in a way that was different than standard, he says. The unique trajectory was necessary because of the first patient's previous surgeries; the approach was from the rear (see illustration), leading to a broader extent of cingulum bundle being sampled and therefore accessible for electrical stimulation.
The JCI paper says that cingulum bundle stimulation "immediately elicited mirthful behavior, including smiling and laughing, and reports of positive emotional experience."
"The patient described the experience as pleasant and relaxing and completely unlike any component of her typical seizure or aura," the authors write. "She reported an involuntary urge to laugh that began at the onset of stimulation and evolved into a pleasant, relaxed feeling over the course of a few seconds of stimulation."
As a test of her mood and thought processes, the researchers tested how the first patient viewed faces and whether she interpreted them as happy, sad or neutral. Cingulum bundle stimulation shifted her view of faces so that they were interpreted as happier. This effect, called "affective bias" is known to correspond with the reduction of depressive symptoms, and suggests a potential use of cingulum stimulation in treating depression.
The two other patients that underwent cingulum stimulation and behavioral testing did not undergo awake surgery for epilepsy treatment. Upon stimulation, they both also smiled and reported mood elevation and pain relief, and at higher levels of current, experienced laughter. During stimulation, one of the later patients took tests of attention, memory and language and performed normally, except for delayed verbal recall on a list-learning task.
The researchers envision cingulum bundle stimulation as potentially applicable to surgery for brain tumors, as well as epilepsy.
"We could be surer of safe boundaries for removal of pathological tissue and preservation of tissue encoding critical human functions such as language, emotional, or sensory functions, which can't be evaluated with the patient sedated," Bijanki says. "In addition, although substantial further study is necessary in this area, the cingulum bundle could become a new target for chronic deep brain stimulation therapies for anxiety, mood, and pain disorders."
The research was supported by the American Foundation for Suicide Prevention (YIG-727 0-015-13), the National Center for Advancing Translational Sciences (UL1TR002378, KL2TR002381), the National Institute of Neurological Disease and Stroke (R21NS104953, K08NS105929, R01NS088748, K02NS070960) and the National Institute of Mental Health (K01MH116364).
 

Journal Reference:

1. Kelly R. Bijanki, Joseph R. Manns, Cory S. Inman, Ki Sueng Choi, Sahar Harati, Nigel P. Pedersen, Daniel L. Drane, Allison C. Waters, Rebecca E. Fasano, Helen S. Mayberg, Jon T. Willie. Cingulum stimulation enhances positive affect and anxiolysis to facilitate awake craniotomy. Journal of Clinical Investigation, 2018; DOI: 10.1172/JCI120110 

Courtesy: ScienceDaily 
 

Story Source: Materials provided by Penn State. Note: Content may be edited for style and length.

A computational method helps scientists examine microbes at a larger, more comprehensive scale than previously possible.

Credit: Susanna M. Hamilton, Broad Communications

During the Zika virus outbreak of 2015-16, public health officials scrambled to contain the epidemic and curb the pathogen's devastating effects on pregnant women. At the same time, scientists around the globe tried to understand the genetics of this mysterious virus.

The problem was, there just aren't many Zika virus particles in the blood of a sick patient. Looking for it in clinical samples can be like fishing for a minnow in an ocean.

A new computational method developed by Broad Institute scientists helps overcome this hurdle. Built in the lab of Broad Institute researcher Pardis Sabeti, the "CATCH" method can be used to design molecular "baits" for any virus known to infect humans and all their known strains, including those that are present in low abundance in clinical samples, such as Zika. The approach can help small sequencing centers around the globe conduct disease surveillance more efficiently and cost-effectively, which can provide crucial information for controlling outbreaks.

The new study was led by MIT graduate student Hayden Metsky and postdoctoral researcher Katie Siddle, and it appears online in Nature Biotechnology.

"As genomic sequencing becomes a critical part of disease surveillance, tools like CATCH will help us and others detect outbreaks earlier and generate more data on pathogens that can be shared with the wider scientific and medical research communities," said Christian Matranga, a co-senior author of the new study who has joined a local biotech startup.

Scientists have been able to detect some low-abundance viruses by analyzing all the genetic material in a clinical sample, a technique known as "metagenomic" sequencing, but the approach often misses viral material that gets lost in the abundance of other microbes and the patient's own DNA.

Another approach is to "enrich" clinical samples for a particular virus. To do this, researchers use a kind of genetic "bait" to immobilize the target virus's genetic material, so that other genetic material can be washed away. Scientists in the Sabeti lab had successfully used baits, which are molecular probes made of short strands of RNA or DNA that pair with bits of viral DNA in the sample, to analyze the Ebola and Lassa virus genomes. However, the probes were always directed at a single microbe, meaning they had to know exactly what they were looking for, and they were not designed in a rigorous, efficient way.

What they needed was a computational method for designing probes that could provide a comprehensive view of the diverse microbial content in clinical samples, while enriching for low-abundance microbes like Zika.

"We wanted to rethink how we were actually designing the probes to do capture," said Metsky. "We realized that we could capture viruses, including their known diversity, with fewer probes than we'd used before. To make this an effective tool for surveillance, we then decided to try targeting about 20 viruses at a time, and we eventually scaled up to the 356 viral species known to infect humans."

Short for "Compact Aggregation of Targets for Comprehensive Hybridization," CATCH allows users to design custom sets of probes to capture genetic material of any combination of microbial species, including viruses or even all forms of all viruses known to infect humans.

To run CATCH truly comprehensively, users can easily input genomes from all forms of all human viruses that have been uploaded to the National Center for Biotechnology Information's GenBank sequence database. The program determines the best set of probes based on what the user wants to recover, whether that's all viruses or only a subset. The list of probe sequences can be sent to one of a few companies that synthesize probes for research. Scientists and clinical researchers looking to detect and study the microbes can then use the probes like fishing hooks to catch desired microbial DNA for sequencing, thereby enriching the samples for the microbe of interest.

Tests of probe sets designed with CATCH showed that after enrichment, viral content made up 18 times more of the sequencing data than before enrichment, allowing the team to assemble genomes that could not be generated from un-enriched samples. They validated the method by examining 30 samples with known content spanning eight viruses. The researchers also showed that samples of Lassa virus from the 2018 Lassa outbreak in Nigeria that proved difficult to sequence without enrichment could be "rescued" by using a set of CATCH-designed probes against all human viruses. In addition, the team was able to improve viral detection in samples with unknown content from patients and mosquitos.

Using CATCH, Metsky and colleagues generated a subset of viral probes directed at Zika and chikungunya, another mosquito-borne virus found in the same geographic regions. Along with Zika genomes generated with other methods, the data they generated using CATCH-designed probes helped them discover that the Zika virus had been introduced in several regions months before scientists were able to detect it, a finding that can inform efforts to control future outbreaks.

To demonstrate other potential applications of CATCH, Siddle used samples from a range of different viruses. Siddle and others have been working with scientists in West Africa, where viral outbreaks and hard-to-diagnose fevers are common, to establish laboratories and workflows for analyzing pathogen genomes on-site. "We'd like our partners in Nigeria to be able to efficiently perform metagenomic sequencing from diverse samples, and CATCH helps them boost the sensitivity for these pathogens," said Siddle.

The method is also a powerful way to investigate undiagnosed fevers with a suspected viral cause. "We're excited about the potential to use metagenomic sequencing to shed light on those cases and, in particular, the possibility of doing so locally in affected countries," said Siddle.

One advantage of the CATCH method is its adaptability. As new mutations are identified and new sequences are added to GenBank, users can quickly redesign a set of probes with up-to-date information. In addition, while most probe designs are proprietary, Metsky and Siddle have made publicly available all of the ones they designed with CATCH. Users have access to the actual probe sequences in CATCH, allowing researchers to explore and customize the probe designs before they are synthesized.

Sabeti and fellow researchers are excited about the potential for CATCH to improve large-scale high-resolution studies of microbial communities. They are also hopeful that the method could one day have utility in diagnostic applications, in which results are returned to patients to make clinical decisions. For now, they're encouraged by its potential to improve genomic surveillance of viral outbreaks like Zika and Lassa, and other applications requiring a comprehensive view of low-level microbial content.

The CATCH software is publicly accessible on GitHub. Its development and validation, supervised by Sabeti and Matranga, is described online in Nature Biotechnology.

Journal Reference:

1. Hayden C. Metsky, Katherine J. Siddle, Adrianne Gladden-Young, James Qu, David K. Yang, Patrick Brehio, Andrew Goldfarb, Anne Piantadosi, Shirlee Wohl, Amber Carter, Aaron E. Lin, Kayla G. Barnes, Damien C. Tully, Bjӧrn Corleis, Scott Hennigan, Giselle Barbosa-Lima, Yasmine R. Vieira, Lauren M. Paul, Amanda L. Tan, Kimberly F. Garcia, Leda A. Parham, Ikponmwosa Odia, Philomena Eromon, Onikepe A. Folarin, Augustine Goba, Etienne Simon-Lorière, Lisa Hensley, Angel Balmaseda, Eva Harris, Douglas S. Kwon, Todd M. Allen, Jonathan A. Runstadler, Sandra Smole, Fernando A. Bozza, Thiago M. L. Souza, Sharon Isern, Scott F. Michael, Ivette Lorenzana, Lee Gehrke, Irene Bosch, Gregory Ebel, Donald S. Grant, Christian T. Happi, Daniel J. Park, Andreas Gnirke, Pardis C. Sabeti, Christian B. Matranga. Capturing sequence diversity in metagenomes with comprehensive and scalable probe design. Nature Biotechnology, 2019; 37 (2): 160 DOI: 10.1038/s41587-018-0006-x 

Courtesy: ScienceDaily