NS/ Tracking trust in human-robot work interactions
Neuroscience biweekly vol. 70, 26th October — 9th November
TL;DR
- Using functional near-infrared spectroscopy, a lab has captured functional brain activity as humans collaborated with robots on a manufacturing task.
- Researchers have confirmed a pathway in the brain that governs how animals, including humans, respond to stress. The findings could yield a better understanding of the physical- and mental health impacts of chronic stress in humans.
- Scientists reveal another factor implicated in the aging process — a class of lipids called SGDGs (3-sulfogalactosyl diacylglycerols) that decline in the brain with age and may have anti-inflammatory effects. The research helps unravel the molecular basis of brain aging, reveals new mechanisms underlying age-related neurological diseases, and offers future opportunities for therapeutic intervention.
- Our sense of smell has a powerful effect on our behavior and emotions. Aromas can evoke vivid memories of the past or warn us of a smoldering fire. Yet to neuroscientists, the smell remains the most mysterious of our five senses. Once the nose detects something, how does the brain determine what it means? Scientists aren’t sure. To help them figure it out, Cold Spring Harbor Laboratory (CSHL) investigators have created an extensive new map of the brain’s olfactory circuits.
- Scientists have used a mathematical model to reveal how toxic proteins cluster together inside the brain during the early stages of Alzheimer’s. The researchers say the discovery could have important implications for future treatments.
- Researchers have found that COVID-19 activates the same inflammatory response in the brain as Parkinson’s disease. The discovery identified a potential future risk for neurodegenerative conditions in people who’ve had COVID-19, but also a possible treatment.
- Study pinpoints the cluster of neurons that tell mice to eat, drink, and move around less when they’re fighting bacterial infections.
- Crossword puzzles are widely used but have not been studied systematically in mild cognitive impairment, which is associated with a high risk for dementia, including Alzheimer’s disease. The new study has documented short- and longer-term benefits for web-crossword puzzle training compared to another intervention.
- People with post-traumatic stress disorder (PTSD) experienced better sleep, a reduction in the severity of PTSD symptoms and more effective treatments after exposure to blue light therapy, according to a new study conducted by researchers in the University of Arizona College of Medicine — Tucson’s Department of Psychiatry and recently published in Frontiers in Behavioral Neuroscience.
- Oppressive, frightening, nerve-wracking: nightmares are particularly disturbing dreams. They are considered pathological when they occur frequently (>1 episode per week) and cause daytime fatigue, mood alteration and anxiety. Although Imagery Rehearsal Therapy (IRT) has shown some effectiveness, some patients do not respond to this treatment. A team has now developed a promising new technique combining this classic therapy with the Targeted Memory Reactivation (TMR) method. Thanks to this new therapy, the patients’nightmares decreased significantly and their positive dreams increased.
- And more!
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Latest news and research
Physiological and perceptual consequences of trust in collaborative robots: An empirical investigation of human and robot factors
by Sarah K. Hopko, Ranjana K. Mehta, Prabhakar R. Pagilla in Applied Ergonomics
As industries begin to see humans working closely with robots, there’s a need to ensure that the relationship is effective, smooth and beneficial to humans. Robot trustworthiness and humans’ willingness to trust robot behavior are vital to this working relationship. However, capturing human trust levels can be difficult due to subjectivity, a challenge researchers in the Wm Michael Barnes ’64 Department of Industrial and Systems Engineering at Texas A&M University aim to solve.
Dr. Ranjana Mehta, associate professor and director of the NeuroErgonomics Lab, said her lab’s human-autonomy trust research stemmed from a series of projects on human-robot Interactions in safety-critical work domains funded by the National Science Foundation (NSF).
“While our focus so far was to understand how operator states of fatigue and stress impact how humans interact with robots, trust became an important construct to study,” Mehta said. “We found that as humans get tired, they let their guards down and become more trusting of automation than they should. However, why that is the case becomes an important question to address.”
Mehta’s latest NSF-funded work, recently published in Human Factors: The Journal of the Human Factors and Ergonomics Society, focuses on understanding the brain-behavior relationships of why and how an operator’s trusting behaviors are influenced by both human and robot factors.
Using functional near-infrared spectroscopy, Mehta’s lab captured functional brain activity as operators collaborated with robots on a manufacturing task. They found faulty robot actions decreased the operator’s trust in the robots. That distrust was associated with increased activation of regions in the frontal, motor and visual cortices, indicating increasing workload and heightened situational awareness. Interestingly, the same distrusting behavior was associated with the decoupling of these brain regions working together, which otherwise were well connected when the robot behaved reliably. Mehta said this decoupling was greater at higher robot autonomy levels, indicating that neural signatures of trust are influenced by the dynamics of human-autonomy teaming.
“What we found most interesting was that the neural signatures differed when we compared brain activation data across reliability conditions (manipulated using normal and faulty robot behavior) versus operator’s trust levels (collected via surveys) in the robot,” Mehta said. “This emphasized the importance of understanding and measuring brain-behavior relationships of trust in human-robot collaborations since perceptions of trust alone is not indicative of how operators’ trusting behaviors shape up.”
Dr. Sarah Hopko ’19, lead author on both papers and recent industrial engineering doctoral student, said neural responses and perceptions of trust are both symptoms of trusting and distrusting behaviors and relay distinct information on how trust builds, breaches and repairs with different robot behaviors. She emphasized the strengths of multimodal trust metrics — neural activity, eye tracking, behavioral analysis, etc. — can reveal new perspectives that subjective responses alone cannot offer.
The next step is to expand the research into a different work context, such as emergency response, and understand how trust in multi-human robot teams impact teamwork and taskwork in safety-critical environments. Mehta said the long-term goal is not to replace humans with autonomous robots but to support them by developing trust-aware autonomy agents.
“This work is critical, and we are motivated to ensure that humans-in-the-loop robotics design, evaluation and integration into the workplace are supportive and empowering of human capabilities,” Mehta said.
A class of anti-inflammatory lipids decrease with aging in the central nervous system
by Dan Tan, Srihari Konduri, Meric Erikci Ertunc, Pan Zhang, Justin Wang, Tina Chang, Antonio F. M. Pinto, Andrea Rocha, Cynthia J. Donaldson, Joan M. Vaughan, Raissa G. Ludwig, Elizabeth Willey, Manasi Iyer, Peter C. Gray, Pamela Maher, Nicola J. Allen, J. Bradley Zuchero, Andrew Dillin, Marcelo A. Mori, Steven G. Kohama, Dionicio Siegel, Alan Saghatelian in Nature Chemical Biology
Aging involves complicated plot twists and a large cast of characters: inflammation, stress, metabolism changes, and many others. Now, a team of Salk Institute and UC San Diego scientists reveal another factor implicated in the aging process — a class of lipids called SGDGs (3-sulfogalactosyl diacylglycerols) that decline in the brain with age and may have anti-inflammatory effects.
The research helps unravel the molecular basis of brain aging, reveals new mechanisms underlying age-related neurological diseases, and offers future opportunities for therapeutic intervention.
“These SGDGs clearly play an important role in aging, and this finding opens up the possibility that there are other critical aging pathways we’ve been missing,” says co-corresponding author Alan Saghatelian, professor in Salk’s Clayton Foundation Laboratories for Peptide Biology and holder of the Dr. Frederik Paulsen Chair. “This is a pretty clear case of something that should be dug into more in the future.”
SGDGs are a class of lipids, also called fats. Lipids contribute to the structure, development, and function of healthy brains, while badly regulated lipids are linked to aging and diseased brains. However, lipids, unlike genes and proteins, are not well understood and have often been overlooked in aging research. Saghatelian specializes in discovering new lipids and determining their structures.
His lab, in collaboration with Professor Dionicio Siegel at UC San Diego, made three discoveries involving SGDGs: In the brain, lipid levels are very different in older mice than in younger mice; all SGDG family members and related lipids change significantly with age; and SGDGs may be regulated by processes that are known to regulate aging.
To reach these findings, the team took an unusual, exploratory approach that combined the large-scale study of lipids (lipidomics) with structural chemistry and advanced data analytics. They first obtained lipid profiles of mouse brains at five ages, ranging from one to 18 months, using liquid chromatography-mass spectrometry. Technological advances in this instrumentation vastly expanded the number of data points available to the scientists, and advanced data analysis allowed them to determine age-related patterns in the enormous lipid profiles. The team then constructed SGDG molecules and tested them for biological activity.
“SGDGs were first identified in the 1970s, but there were few follow-up studies. These lipids were essentially forgotten and missing from the lipid databases. Nobody knew SGDGs would be changing or regulated in aging, let alone that they have bioactivity and, possibly, be therapeutically targetable,” says first author Dan Tan, a postdoctoral fellow in Saghatelian’s lab at Salk.
The analysis showed that SGDGs possess anti-inflammatory properties, which could have implications for neurodegenerative disorders and other neurological conditions that involve increased inflammation in the brain.
The team also discovered that SGDGs exist in human and primate brains, suggesting that SGDGs may play an important role in animals other than mice. Further research will be required to show if SGDGs contribute to human neuroinflammation.
In the future, the team will examine how SGDGs are regulated with aging and what proteins are responsible for making them and breaking them down, which may open the door to discovering novel genetic activity associated with aging.
“With the understanding of the structure of SGDGs and our ability to create them in the laboratory, the study of these important lipids is now wide open and ripe for discovery,” says Siegel, co-corresponding author of the study.
Sticker-and-spacer model for amyloid beta condensation and fibrillation
by Jack P. Connor, Steven D. Quinn, Charley Schaefer in Frontiers in Molecular Neuroscience
Scientists have used a mathematical model to reveal how toxic proteins cluster together inside the brain during the early stages of Alzheimer’s.
The researchers, from the University of York’s School of Physics, Engineering and Technology, say the discovery could have important implications for future treatments.
The study revealed that a major class of proteins implicated in Alzheimer’s disease — so called amyloids — condense into objects that resemble liquid droplets, before forming clusters that impact normal brain activity.
Alzheimer’s disease is the most common form of dementia. Over 50 million people worldwide have the disease, and that number is expected to triple by 2050.
On the nanoscale, toxic amyloid proteins inside the brain cluster together around 10–15 years before the first symptoms arise, but the precise way in which they do so has remained unclear. By understanding precisely how the protein clusters form, scientists may be in a far better position to develop targeted drug treatments to block them.
Dr Steve Quinn, an Alzheimer’s Research UK Fellow and Lecturer in Biophysics at the University of York, said:
“Understanding the precise molecular-level ways through which amyloid clusters form may help us to design better anti-cluster drugs that combat Alzheimer’s disease at the earliest possible stage.
“We realised that the same methodologies that have been used previously to understand the growth of silk produced in spiders could also be applied to our understanding of amyloid clustering. Our work now provides theoretical support for the so-called Amyloid Hypothesis, and helps to explain the conditions under which clusters form.”
For the study, the scientists looked at two variations of the amyloid protein, both of which are found extensively in disease. The researchers found that the proteins may initially form droplets — so called liquid liquid phase separation condensates — before forming clusters enriched with the longer, more toxic, version of the protein.
Amyloid proteins are believed to be an important part of the immune system, but when they abnormally change shape, they can cluster together into potent biological structures. These structures can interfere with normal brain activities, for example by punching holes within cells, or by influencing the behaviour of vitally important biomolecules.
Dr Charley Schaefer, Research Associate at the University of York and lead author of the study, said:
“The properties of large pre-formed clusters have been studied in extensive detail, but until now, the molecular level details of their early-stage assembly have been difficult to assess.”
Dr Quinn and Dr Schaefer of the Physics of Life team apply experimental and theoretical tools to try and learn more about important interactions implicated in human life and disease.
Dr Schaefer added, “We hope that our approaches could also be applied to understand the building blocks of many other forms of dementia, including Parkinson’s and Huntington’s. The idea that proteins form liquid-like droplets prior to assembling into clusters may not be unique to Alzheimer’s disease, and perhaps more common than once thought.”
Activity in a prefrontal-periaqueductal gray circuit overcomes behavioral and endocrine features of the passive coping stress response
by Shane B. Johnson, Ryan T. Lingg, Timothy D. Skog, Dalton C. Hinz, Sara A. Romig-Martin, Victor Viau, Nandakumar S. Narayanan, Jason J. Radley in Proceedings of the National Academy of Sciences
At one time or another, we’ve all felt paralyzed by a threat or danger.
University of Iowa researchers have traced where that reaction to a threat arises. In a new study, the researchers confirmed a neural circuit linking two separate regions in the brain governs how animals, including humans, react to a stressful situation. Through experiments, the researchers showed how rats responded to a threat either passively or actively — and linked each reaction to a specific pathway in the brain.
In another test, the researchers successfully manipulated the neural circuit, so that rats overcame what would have been a paralyzing response to danger and instead responded aggressively to the threat.
The neural circuit identified with stress response connects the caudal medial prefrontal cortex to the midbrain dorsolateral periaqueductal gray. Clinching the connection, and how it regulates stress, is important, due to the known physical- and mental health impacts of chronic stress.
“A lot of chronic stress diseases like depression and anxiety disorders are associated with what we call a passive coping behavior,” explains Jason Radley, associate professor in the Department of Psychological and Brain Sciences and the study’s corresponding author. “We know that a lot of these conditions are caused by life stress. The simplest reason we’re interested in this pathway is thinking about it as a circuit that can promote resilience against stress.”
Previous research has identified the caudal medial prefrontal cortex-midbrain dorsolateral periaqueductal gray as a key pathway governing how animals respond to stress. Radley’s team confirmed the pathway’s importance by inactivating it, then observing how the rats responded to a threat. The rats could respond in two basic ways: One is passively, meaning in essence they did not move in response to the threat. The other is actively, through a range of behaviors, such as burying the threat (a shock probe, in the experiments), rearing up on hind legs, or seeking an escape route.
The researchers learned that when they inactivated the rats’ stress neural circuit, the animals responded passively, meaning they did not directly respond to the threat.
“That shows this pathway is necessary for active coping behavior,” Radley says.
Next, the researchers forced the rats to respond passively, by removing the bedding in their cage, which prevents them from trying to bury the threat mechanism. When the team activated the neural pathway, the rats switched their behavior, and responded actively to the threat. The active response occurred even though the animals were left without their bedding, which should have triggered a passive reply. Moreover, blood samples taken before and after the rats’ neural circuits that had been activated showed their stress hormone levels did not spike when confronted with the threat.
“What that means is by activating the pathway, we saw broad stress-buffering effects,” Radley says. “It not only revived the rats’ active coping behaviors, it also restored them and greatly decreased stress hormone release.”
In the third set of experiments, the researchers subjected rats to chronic variable stress, meaning they were exposed to regular stress over two weeks. After the two-week conditioning, the rats were placed in cages and exposed to the threat. They responded passively, unwilling to move, and their stress hormones shot up, as the researchers had hypothesized.
The chronic stress test is important, Radley says, because humans face chronic stress. For reasons that are unknown, some people continue to carry those stress burdens, which can lead to physical and mental disorders. Others, though, show little to no past memory of the chronic stress. The researchers’ term this behavior “stress resilience.”
“It’s possible we can co-opt some of these brain circuits if we could understand the processes in the brain that can regulate resilience,” Radley says, though he adds this is not an imminent option.
The researchers plan to investigate the neutral connections that are upstream and downstream of the caudal medial prefrontal cortex-midbrain dorsolateral periaqueductal gray pathway.
“We don’t understand how these effects are altering the brain more widely,” Radley says.
High-throughput sequencing of single neuron projections reveals spatial organization in the olfactory cortex
by Chen Y, Chen X, Baserdem B, et al. in Cell
Our sense of smell has a powerful effect on our behavior and emotions. Aromas can evoke vivid memories of the past or warn us of a smoldering fire. Yet to neuroscientists, smell remains the most mysterious of our five senses. Once the nose detects something, how does the brain determine what it means? Scientists aren’t sure. To help them figure it out, Cold Spring Harbor Laboratory (CSHL) investigators have created an extensive new map of the brain’s olfactory circuits.
“It’s an open question at this point, how exactly we process smell,” says Albeanu. “What are the features in the odor space that the brain is extracting and using to create percepts of olfactory objects? And exactly what are the mechanisms in the brain?”
Because previous studies of the olfactory cortex failed to find any logical organization among neurons there, many neuroscientists suspected information about odors was relayed randomly through the brain. But those studies examined connectivity patterns of just a few dozen neurons.
Using new DNA-based brain-mapping technologies developed in Zador’s lab, called MAPseq and BARseq, the CSHL team can trace the paths of more individual olfactory-processing neurons than ever before — thousands within the brain of a single mouse. Thanks to their work, scientists may be able to make sense of the olfactory circuitry and its underlying logic.
The new map charts the way sensory information is routed between olfactory-processing parts of the brain. These include the olfactory bulb, which receives sensory information from the nose, the primary smell-processing hub called the piriform cortex, and several other brain regions that receive inputs from the olfactory bulb.
Within the piriform cortex, the team found that neurons toward the front of the brain had different connectivity patterns than those in the back.
“As you move along this axis, you see the neurons’ projection pattern gradually changing in terms of how it broadcasts information into other brain regions,” Koulakov says. “That is synchronized with the way the olfactory bulb projects to those brain regions, as well as to the same locations within the piriform cortex,” he explains. Each of these parallel “circuit motifs” may process different aspects of odor information.
This recalls what neuroscientists have found in other parts of the brain where neurons’ connections and locations correspond to specific features of sensory inputs like sights and sounds. In the auditory system, neurons’ position along an axis relates to the sound frequencies we hear. Similarly, in the visual system, neurons’ position conveys information about a seen object’s location, among other characteristics, and different neural circuits are tuned to objects’ locations and identities (“where” vs. “what” pathways).
Researchers say the olfactory map could offer inroads to “the last frontier of sensory neuroscience.” They suggest it points toward the existence of different neural circuits dedicated to assessing the identity of a smell, how pleasant it is, or where it’s coming from, and how to act on it. “It puts us and the field in a way, in a very different state of mind,” Albeanu says. “It’s a step toward understanding the nature of olfactory processing.”
SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein
by Eduardo A. Albornoz, Alberto A. Amarilla, Naphak Modhiran, Sandra Parker, Xaria X. Li, Danushka K. Wijesundara, Julio Aguado, Adriana Pliego Zamora, Christopher L. D. McMillan, Benjamin Liang, Nias Y. G. Peng, Julian D. J. Sng, Fatema Tuj Saima in Molecular Psychiatry
Research led by The University of Queensland has found COVID-19 activates the same inflammatory response in the brain as Parkinson’s disease.
The discovery identified a potential future risk for neurodegenerative conditions in people who’ve had COVID-19, but also a possible treatment. The UQ team was led by Professor Trent Woodruff and Dr Eduardo Albornoz Balmaceda from UQ’s School of Biomedical Sciences, and virologists from the School of Chemistry and Molecular Biosciences.
“We studied the effect of the virus on the brain’s immune cells, ‘microglia’ which are the key cells involved in the progression of brain diseases like Parkinson’s and Alzheimer’s,” Professor Woodruff said. “Our team grew human microglia in the laboratory and infected the cells with SARS-CoV-2, the virus that causes COVID-19. We found the cells effectively became ‘angry’, activating the same pathway that Parkinson’s and Alzheimer’s proteins can activate in disease, the inflammasomes.”
Dr Albornoz Balmaceda said triggering the inflammasome pathway sparked a ‘fire’ in the brain, which begins a chronic and sustained process of killing off neurons.
“It’s kind of a silent killer, because you don’t see any outward symptoms for manyyears,” Dr Albornoz Balmaceda said. “It may explain why some people who’ve had COVID-19 are more vulnerable to developing neurological symptoms similar to Parkinson’s disease.”
The researchers found the spike protein of the virus was enough to start the process and was further exacerbated when there were already proteins in the brain linked to Parkinson’s.
“So if someone is already pre-disposed to Parkinson’s, having COVID-19 could be like pouring more fuel on that ‘fire’ in the brain,” Professor Woodruff said. “The same would apply for a predisposition for Alzheimer’s and other dementias that have been linked to inflammasomes.”
But the study also found a potential treatment.
The researchers administered a class of UQ-developed inhibitory drugs which are currently in clinical trials with Parkinson’s patients.
“We found it successfully blocked the inflammatory pathway activated by COVID-19, essentially putting out the fire,” Dr Albornoz Balmaceda said. “The drug reduced inflammation in both COVID-19-infected mice and the microglia cells from humans, suggesting a possible treatment approach to prevent neurodegeneration in the future.”
Professor Woodruff said while the similarity between how COVID-19 and dementia diseases affect the brain was concerning, it also meant a possible treatment was already in existence.
“Further research is needed, but this is potentially a new approach to treating a virus that could otherwise have untold long-term health ramifications.”
Enhancing imagery rehearsal therapy for nightmares with targeted memory reactivation
by Sophie Schwartz, Alice Clerget, Lampros Perogamvros in Current Biology
Oppressive, frightening, nerve-wracking: nightmares are particularly disturbing dreams. They are considered pathological when they occur frequently (>1 episode per week) and cause daytime fatigue, mood alteration and anxiety. Although Imagery Rehearsal Therapy (IRT) has shown some effectiveness, some patients do not respond to this treatment. A team from the UNIGE and the HUG has developed a promising new technique combining this classic therapy with the Targeted Memory Reactivation (TMR) method. Thanks to this new therapy, the patients’nightmares decreased significantly and their positive dreams increased. These results can be found in the journal Current Biology.
Nightmares are dreams with strong negative emotions that occur during rapid eye movement (REM) sleep. Clinicians distinguish them from simple ‘’bad dreams’’. In contrast to nightmares, the latter seem to have a useful function in promoting the regulation of emotions. Scientists also make a distinction between traumatic nightmares — i.e. linked to a state of post-traumatic stress — and nightmares without traumatic origin.
According to the ‘’International Classification of Sleep Disorders’’, established by the American Academy of Sleep Medicine, nightmares become pathological when they are recurrent and have an impact during the day causing, for example, fatigue, anxiety, dysphoria or intrusive nightmare imagery. This is known as ‘’nightmare disorder’’ and is an increasingly common reason for medical consultation.
Imagery Rehearsal Therapy (IRT) is frequently used to treat this disorder. This cognitive technique requires that the patients imagine alternative and positive outcomes to their nightmare scenarios every day for five to ten minutes. ‘’After two weeks of practice, it has been shown that the frequency of nightmares decreases,’’ says Lampros Perogamvros, a privat-docent in the Department of Basic Neurosciences at the UNIGE Faculty of Medicine and a senior clinical fellow at the HUG’s Center for Sleep Medicine.
However, some patients are not receptive to this method. To overcome this limitation and boost the treatment process, Dr Lampros Perogamvros and his colleagues have coupled IRT with the Targeted Memory Reactivation (TMR) method. By sending specific stimuli to the brain of the sleeping person — often odours or sounds previously associated with recent experiences — it is possible to reinforce the memory of this experience. In this case, the aim was to reactivate memories related to the IRT exercises.
The team from the UNIGE and the HUG gathered 36 patients suffering from the non-traumatic type of nightmares. Two groups were formed: one to practice the coupled therapy, the other the classical therapy with IRT only.
‘’We asked the patients to imagine positive alternative scenarios to their nightmares. However, one of the two groups of patients did this exercise while a sound — a major piano chord — was played every ten seconds. The aim was for this sound to be associated with the imagined positive scenario. In this way, when the sound was then played again but now during sleep, it was more likely to reactivate a positive memory in dreams,’’ explains Sophie Schwartz, a full professor in the Department of Basic Neurosciences at the UNIGE Faculty of Medicine and the Swiss Center for Affective Sciences.
Each participant was then given a sleep headband containing electrodes that measure brain activity. At home, thanks to this device detecting the different stages of sleep, the piano chord was replayed every ten seconds each time the patient reached REM sleep. The exercise was repeated every night for two weeks.
At the end of the experiment, the frequency of nightmares decreased in both groups, but significantly more in the group where the positive scenario was associated with the sound. ‘’Moreover, this association resulted in an increase in positive dreams,’’ says Alice Clerget, a master’s student in the Department of Basic Neuroscience at the Faculty of Medicine, who actively participated in the study. Finally, the benefits of the coupled treatment were still perceptible three months after the experiment, with patients in the TMR group still having fewer nightmares than those in the group without TMR.
‘’While the results of the therapy coupling will need to be replicated before this method can be widely applied, there is every indication that it is a particularly effective new treatment for the nightmare disorder. The next step for us will be to test this method on nightmares linked to post-traumatic stress,’’ concludes Lampros Perogamvros. These results also open up new perspectives for the treatment of other disorders such as insomnia and other symptoms of post-traumatic stress, such as flashbacks and anxiety.
Brainstem ADCYAP1+ neurons control multiple aspects of sickness behaviour
by Anoj Ilanges, Rani Shiao, Jordan Shaked, Ji-Dung Luo, Xiaofei Yu, Jeffrey M. Friedman in Nature
We tend to eat, drink, and move less when we’re feeling under the weather. And we’re not alone — most animals reduce those same three behaviors when they’re fighting an infection.
Now, a new study pinpoints the cluster of neurons that control these responses, referred to as sickness behaviors. By provoking immune responses in mice, researchers demonstrated that a specific population of cells in the brainstem potently induce three telltale sickness behaviors. In addition, inhibiting these neurons blunts each of these behavioral elements of the sickness response. The findings, published in Nature, directly link inflammation to neural pathways regulating behavior, offering insight into how the immune system interacts with the brain.
“We are still in the early days of trying to understand the brain’s role in infection,” says Jeffrey M. Friedman, Marilyn M. Simpson Professor at The Rockefeller University. “But with these results, we now have a unique opportunity to ask: What does your brain look like when you’re sick?”
Sickness behaviors have been shown to play an important role in an animal’s recovery from an infection. Prior studies have bolstered that theory by demonstrating that animals forced to eat when they’re sick showed a significantly increased mortality. “These behavioral changes during infection are really important for survival,” says lead author Anoj Ilanges, a former graduate student in Friedman’s lab, now a group leader at the HHMI Janelia Research Campus
But it has never been clear how the brain coordinates that near-universal urge to refuse meals and curl up under the covers with the onset of infection. So Friedman and Ilanges set out to map the brain regions behind sickness behaviors in mice.
The team began by exposing mice to LPS, a piece of the bacterial cell wall that activates the immune system and potently induces sickness behavior. Shortly after the injection of LPS, there was a spike in activity in a brainstem region known as the dorsal vagal complex, among a population of neurons expressing the neuropeptide ADCYAP1. To confirm that they had found the right brain cells, the researchers then activated those neurons in healthy mice and they found that the animals ate, drank, and moved around less. In contrast, when the ADCYAP1 neurons were deactivated, the effect of LPS on these behaviors was significantly reduced.
“We didn’t know if the same or different neurons regulated each of these behaviors,” Friedman says, “We found it surprising that a single neuronal population appears to regulate each of these components of the sickness response.”
The authors were not, however, altogether surprised that this brainstem region was involved in mediating sickness behaviors. The dorsal vagal complex is one of a precious few physiological crossroads of the central nervous system, where an absence of the blood brain barrier enables circulating factors in the blood to pass information directly to the brain.
“This region has emerged as a kind of alert center for the brain, conveying information about aversive or noxious substances that, more often than not, reduce food intake,” Friedman says.
In the coming months, Friedman’s team at Rockefeller intends to incorporate these findings into their overall goal of understanding the physiological signals and neural circuitry that regulate feeding behavior. They are specifically interested in understanding why even mice engineered to eat voraciously will nonetheless stop eating when exposed to bacterial infections.
Meanwhile, Ilanges plans to investigate what role other brain regions play in response to infections, expanding our knowledge of the brain’s role during this critical process.
“We looked at one region of the brain, but there are many others that become activated with the immune response,” he says. “This opens the door to asking what the brain is doing, holistically, during infection.”
Computerized Games versus Crosswords Training in Mild Cognitive Impairment
by D. P. Devanand, Terry E. Goldberg, Min Qian, Sara N. Rushia, Joel R. Sneed, Howard F. Andrews, Izael Nino, Julia Phillips, Sierra T. Pence, Alexandra R. Linares, Caroline A. Hellegers, Andrew M. Michael, Nancy A. Kerner, Jeffrey R. Petrella, P. Murali Doraiswamy in NEJM Evidence
A new study by researchers from Columbia University and Duke University published in the journal NEJM Evidence shows that doing crossword puzzles has an advantage over computer video games for memory functioning inolder adults with mild cognitive impairment.
In a randomized, controlled trial, led by D.P. Devanand, MD, professor of psychiatry and neurology at Columbia, with Murali Doraiswamy, MD, professor of psychiatry and medicine at Duke, researchers determined that participants (average age 71) trained in doing web-based crossword puzzles demonstrated greater cognitive improvement than those who were trained on cognitive video games.
“This is the first study to document both short-term and longer-term benefits for home-based crossword puzzles training compared to another intervention,” said Dr. Devanand, who oversees brain aging and mental health research at Columbia. “The results are important in light of difficulty in showing improvement with interventions in mild cognitive impairment.”
Crossword puzzles are widely used but have not been studied systematically in mild cognitive impairment, which is associated with a high risk for dementia, including Alzheimer’s disease.
To conduct their study, researchers at Columbia and Duke randomly assigned 107 participants with mild cognitive impairment (MCI) at the two different sites to either crossword puzzles training or cognitive games training with intensive training for 12 weeks followed by booster sessions up to 78 weeks. Both interventions were delivered via a computerized platform with weekly compliance monitoring.
The most striking findings of the trial were:
- Crossword puzzles were superior to cognitive games on the primary cognitive outcome measure, ADAS-Cog, at both 12 weeks and 78 weeks. Crossword puzzles were superior on FAQ, a measure of daily functioning, at 78 weeks.
- Crossword puzzles were superior for participants at a later disease stage but both forms of training were equally effective in an earlier stage.
- Brain shrinkage (measured with MRI) was less for crossword puzzles at 78 weeks.
“The benefits were seen not only in cognition but also in daily activities with indications of brain shrinkage on MRI that suggests that the effects are clinically meaningful,” Dr. Devanand said.
The study also highlights the importance of engagement. Based on remote electronic monitoring of computer use, participants at a later stage of impairment may have better engaged with the more familiar crossword puzzles than with computerized cognitive games.
Two strengths of the trial are the 28% participation rate of individuals from racial and ethnic minority groups and the low drop-out rate (15%) for such a lengthy home-based trial. A study limitation was the absence of a control group that did not receive cognitive training.
While these results are highly encouraging, the authors stress the need for replication in a larger controlled trial with an inactive control group.
“The trifecta of improving cognition, function and neuroprotection is the Holy Grail for the field,” said Dr. Doraiswamy. “Further research to scale brain training as a home-based digital therapeutic for delaying Alzheimer’s should be a priority for the field.”
Morning blue light treatment improves sleep complaints, symptom severity, and retention of fear extinction memory in post-traumatic stress disorder
by John R. Vanuk, Edward F. Pace-Schott, Ayla Bullock, Simon Esbit, Natalie S. Dailey, William D. S. Killgore in Frontiers in Behavioral Neuroscience
People with post-traumatic stress disorder (PTSD) experienced better sleep, a reduction in the severity of PTSD symptoms and more effective treatments after exposure to blue light therapy, according to a new study conducted by researchers at the University of Arizona College of Medicine — Tucson’s Department of Psychiatry and recently published in Frontiers in Behavioral Neuroscience.
Sleep is crucial for maintaining physical and mental health, and inadequate sleep over time can impact all aspects of life with serious implications for long-term health, relationships, and cognitive abilities such as learning, and healing.
The influence of sleep disruption on PTSD symptom severity is well established. Those who seek treatment to allay their PTSD symptoms often face a vicious cycle where poor sleep interferes with the effectiveness of treatments, negating any lessening of symptoms, which in turn contributes to sleep disruptions. To reduce and eliminate the emotional impact of traumatic memories, the patient needs quality sleep to integrate healing mechanisms achieved through cognitive or exposure therapy treatments.
“This research is exciting and unique because it points to an easy-to-use method for helping those with PTSD to retain the benefits of therapy long after the treatment ends,” said psychiatry professor William “Scott” Killgore, PhD, director of the Social, Cognitive and Affective Neuroscience (SCAN) Lab and senior author on the paper, “Morning blue light treatment improves sleep complaints, symptom severity, and retention of fear extinction memory in post-traumatic stress disorder.”
Dr. Killgore and the SCAN Lab team conducted a comprehensive assessment of daily morning blue-wavelength light exposure on individuals with clinically significant levels of PTSD. The goal was to ascertain if blue light therapy would help improve sleep and PTSD symptoms and sustain learned fear extinction memories, an analog of therapeutic treatment for trauma.
Study participants committed to 30 minutes of morning light exposure daily for six weeks, with half of the participants using blue-wavelength light and half using amber light. Researchers examined the neurobiological, autonomic, and behavioral outcome changes during the study.
The 43 participants who received blue light therapy not only demonstrated significant improvements in the severity of their PTSD symptoms but also reported improvements in sleep and showed increased retention of fear extinction memories. In comparison, the 39 study participants who received amber light did not show the same retention of the extinction memories but rather showed a return of the original fear memories.
“While the limitations of the research include its modest sample size and difficulties monitoring compliance, the possibilities of utilizing a treatment that is relatively simple, drug-free, and inexpensive can offer hope for the large population of people living with the intense challenges of post-traumatic stress disorder,” Dr. Killgore said.
“The data are thrilling,” said Jordan Karp, MD, professor and chair of the College of Medicine — Tucson’s Department of Psychiatry. “This nonpharmacological intervention is a promising life-changing and life-saving possibility for people suffering from PTSD.”
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