NS/ Wearable microscopes advance spinal cord imaging in mice
Neuroscience biweekly vol. 81, 15th March — 29th March
TL;DR
- Scientists have created wearable microscopes to enable unprecedented insight into the signaling patterns that occur within the spinal cords of mice. This technological advancement will help researchers better understand the neural basis of sensations and movement in healthy and disease contexts, such as chronic pain, itch, amyotrophic lateral sclerosis, or multiple sclerosis.
- New research aims to increase autonomy for individuals with such motor impairments by introducing a head-worn device that will help them control a mobile manipulator. Teleoperated mobile manipulators can aid individuals in completing daily activities, but many existing technologies like hand-operated joysticks or web interfaces require a user to have substantial fine motor skills to effectively control them. Research offers a new device equipped with a hands-free microphone and head-worn sensor that allows users to control a mobile robot via head motion and speech recognition.
- A key feature of the severe allergic reaction known as anaphylaxis is an abrupt drop in blood pressure and body temperature, causing people to faint and, if untreated, potentially die. That response has long been attributed to a sudden dilation and leakage of blood vessels. But in a study using mice, researchers have found that this response, especially body temperature drop, requires an additional mechanism — the nervous system.
- A small nucleus in the brainstem called locus coeruleus (literally the ‘blue spot,’) is the primary source of a major neuromodulator, norepinephrine (NE), an important mediator of the ‘fight or flight’ response in animals. However, very little is known about the local connections of this small albeit critically important group of neurons. A recent pioneering study now reveals the cellular composition and circuit organization of the locus coeruleus in adult mice.
- Cognitive decline associated with aging is caused by the loss of cholinergic nerve supply to the hippocampus of our brain. Since the hippocampus is the center of learning and memory, a reduction in its synaptic functions leads to cognitive disorders like Alzheimer’s disease. To prevent cognitive diseases, it is critical to understand the role of the neurotransmitter acetylcholine in regulating synaptic functions. Scientists now demonstrate the molecular mechanisms underlying these functions.
- Scientists have gleaned new insights into how psychedelics alter conscious experience via their action on brain activity.
- Using vision to efficiently move through an area by foot uses a unique region of the brain’s cortex, according to a study funded by the National Eye Institute (NEI). The region called the occipital place area (OPA), fails to activate during other modes of moving, such as crawling. The finding may help explain developmental milestones as children learn to interact with and navigate their near environments. The study was published in the journal Cerebral Cortex.
- Since the development of functional magnetic resonance imaging in the 1990s, the reliance on neuroimaging has skyrocketed as researchers investigate how fMRI data from the brain at rest, and anatomical brain structure itself, can be used to predict individual traits, such as depression, cognitive decline, and brain disorders. But how reliable brain imaging is for detecting traits has been a subject of wide debate. Researchers now report that stronger links between brain measures and traits can be obtained when state-of-the-art pattern recognition (or ‘machine learning’) algorithms are utilized, which can garner high-powered results from moderate sample sizes.
- Hypnosis is an effective treatment for pain for many individuals but determining which patients will benefit most can be challenging. Hypnotizability testing requires special training and in-person evaluation is rarely available in the clinical setting. Now, investigators have developed a fast, point-of-care molecular diagnostic test that identifies a subset of individuals who are most likely to benefit from hypnosis interventions for pain treatment. Their study also found that a subset of highly hypnotizable individuals may be more likely to experience high levels of postoperative pain.
- The University of Helsinki and Taiwanese researchers have found a new way to remove waste from the brain after haemorrhage.
- And more!
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The latest news and research
Multiplex translaminar imaging in the spinal cord of behaving mice
by Pavel Shekhtmeyster, Erin M. Carey, Daniela Duarte, Alexander Ngo, Grace Gao, Nicholas A. Nelson, Charles L. Clark, Axel Nimmerjahn in Nature Communications
The spinal cord acts as a messenger, carrying signals between the brain and body to regulate everything from breathing to movement. While the spinal cord is known to play an essential role in relaying pain signals, technology has limited scientists’ understanding of how this process occurs on a cellular level. Now, Salk scientists have created wearable microscopes to enable unprecedented insight into the signaling patterns that occur within the spinal cords of mice.
This technological advancement, detailed in two papers published in Nature Communications and Nature Biotechnology, will help researchers better understand the neural basis of sensations and movement in healthy and disease contexts, such as chronic pain, itch, amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS).
“These new wearable microscopes allow us to see nerve activity related to sensations and movement in regions and at speeds inaccessible by other high-resolution technology,” says senior author Axel Nimmerjahn, associate professor and director of the Waitt Advanced Biophotonics Center. “Our wearable microscopes fundamentally change what is possible when studying the central nervous system.”
The wearable microscopes are approximately seven- and fourteen millimeters wide (about the width of a little finger or the human spinal cord) and offer high-resolution, high-contrast, and multicolor imaging in real-time across previously inaccessible regions of the spinal cord. The new technology can be combined with a microprism implant, which is a small reflective glass element placed near the tissue regions of interest.
“The microprism increases the depth of imaging, so previously unreachable cells can be viewed for the first time. It also allows cells at various depths to be imaged simultaneously and with minimal tissue disturbance,” says Erin Carey, co-first author of one of the studies and researcher in Nimmerjahn’s lab.
Pavel Shekhtmeyster, a former postdoctoral fellow in Nimmerjahn’s lab and co-first author on both studies, agrees, “We’ve overcome field-of-view and depth barriers in the context of spinal cord research. Our wearable microscopes are light enough to be carried by mice and allow measurements previously thought impossible.”
With the novel microscopes, Nimmerjahn’s team began applying the technology to gather new information about the central nervous system. In particular, they wanted to image astrocytes, star-shaped non-neuronal glial cells, in the spinal cord because the team’s earlier work suggested the cells’ unexpected involvement in pain processing.
The team found that squeezing the tails of mice activated the astrocytes, sending coordinated signals across spinal cord segments. Prior to the invention of the new microscopes, it was impossible to know what astrocyte activity looked like — or what any cellular activity looked like across those spinal cord regions of moving animals.
“Being able to visualize when and where pain signals occur and what cells participate in this process allows us to test and design therapeutic interventions,” says Daniela Duarte, co-first author of one of the studies and researcher in Nimmerjahn’s lab. “These new microscopes could revolutionize the study of pain.”
Nimmerjahn’s team has already begun investigating how neuronal and non-neuronal activity in the spinal cord is altered in different pain conditions and how various treatments control abnormal cell activity.
HAT: Head-Worn Assistive Teleoperation of Mobile Manipulators
by Carnegie Mellon University researchers
New research from Carnegie Mellon University’s Robotics Institute (RI) aims to increase autonomy for individuals with such motor impairments by introducing a head-worn device that will help them control a mobile manipulator. Teleoperated mobile manipulators can aid individuals in completing daily activities, but many existing technologies like hand-operated joysticks or web interfaces require a user to have substantial fine motor skills to effectively control them. Research offers a new device equipped with a hands-free microphone and head-worn sensor that allows users to control a mobile robot via head motion and speech recognition.
More than five million people in the United States live with some form of paralysis and may encounter difficulties completing everyday tasks, like grabbing a glass of water or putting on clothes. New research from Carnegie Mellon University’s Robotics Institute (RI) aims to increase autonomy for individuals with such motor impairments by introducing a head-worn device that will help them control a mobile manipulator.
Teleoperated mobile manipulators can aid individuals in completing daily activities, but many existing technologies like hand-operated joysticks or web interfaces require a user to have substantial fine motor skills to effectively control them. Research led by robotics Ph.D. student Akhil Padmanabha offers a new device equipped with a hands-free microphone and head-worn sensor that allows users to control a mobile robot via head motion and speech recognition. Head-Worn Assistive Teleoperation (HAT) requires fewer fine motor skills than other interfaces, offering an alternative for users who face constraints with the technology currently on the market.
A mast cell–thermoregulatory neuron circuit axis regulates hypothermia in anaphylaxis
by Chunjing Bao, Ouyang Chen, Huaxin Sheng, Jeffrey Zhang, Yikai Luo, Byron W. Hayes, Han Liang, Wolfgang Liedtke, Ru-Rong Ji, Soman N. Abraham in Science Immunology
A key feature of the severe allergic reaction known as anaphylaxis is an abrupt drop in blood pressure and body temperature, causing people to faint and, if untreated, potentially die.
That response has long been attributed to a sudden dilation and leakage of blood vessels. But in a study using mice, Duke Health researchers have found that this response, especially body temperature drop, requires an additional mechanism — the nervous system.
Appearing online in the journal Science Immunology, the study could point to new targets for therapies to prevent or treat anaphylactic shock, which occurs in up to 5% of people in the U.S. annually in response to food allergies or bites from insects or venomous animals.
“This finding for the first time identifies the nervous system as a key player in the anaphylactic response,” said senior author Soman Abraham, Ph.D., professor in the departments of Pathology, Immunology, and Molecular Genetics and Microbiology at Duke University School of Medicine.
“The sensory nerves involved in thermal regulation — especially the nerves that sense high environmental temperatures — send the brain a false signal during anaphylaxis that the body is exposed to high temperatures even though it is not the case,” Abraham said. “This causes a rapid drop in body temperature as well as blood pressure.”
Abraham and colleagues, including first author Chunjing “Evangeline” Bao, a Ph.D. candidate in Abraham’s lab at Duke, tracked the sequence of events when allergens activate mast cells — the immune cells that trigger the chemical reactions leading to swelling, difficulty breathing, itchiness, low blood pressure and hypothermia.
The researchers found that one of the chemicals mast cells unleash when they are activated is an enzyme that interacts with sensory neurons, notably those involved in the body’s thermoregulatory neural network.
When stimulated as part of an allergic reaction, this neural network gets the signal to immediately shut down the body’s heat generators in the brown fat tissue, causing hypothermia. The activation of this network also causes a sudden drop in blood pressure.
The researchers validated their findings by showing that depriving mice of the specific mast cell enzyme protected them against hypothermia, whereas directly activating the heat-sensing neurons in mice induced anaphylactic reactions such as hypothermia and hypotension.
“By demonstrating that the nervous system is a key player — not just the immune cells — we now have potential targets for prevention or therapy,” Bao said. “This finding could also be important for other conditions, including septic shock, and we are undertaking those studies.”
Cellular composition and circuit organization of the locus coeruleus of adult mice
by Andrew McKinney, Ming Hu, Amber Hoskins, Arian Mohammadyar, Nabeeha Naeem, Junzhan Jing, Saumil S Patel, Bhavin R Sheth, Xiaolong Jiang in Life
A small nucleus in the brainstem called locus coeruleus (literally the “blue spot,”) is the primary source of a major neuromodulator, norepinephrine (NE), an important mediator of the ‘fight or flight’ response in animals. However, very little is known about the local connections of this small albeit critically important group of neurons. A recent pioneering study published in eLife from the laboratory of Dr. Xiaolong Jiang, investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital and assistant professor at Baylor College of Medicine, now reveals the cellular composition and circuit organization of the locus coeruleus in adult mice.
“In this study, we undertook the arduous task of mapping local connections of NE-producing neurons in the locus coeruleus,” Dr. Jiang said. “This is the first study of such an unprecedented magnitude and detail to be performed on the locus coeruleus, and in fact, on any monoamine neurotransmitter system. Our study has revealed that the neurons in the locus coeruleus have an unexpectedly rich cellular heterogeneity and local wiring logic.”
Locus coeruleus (LC) is known to house the vast majority of norepinephrine-releasing neurons in the brain and regulates many fundamental brain functions including the fight and flight response, sleep/wake cycles, and attention control. Present in the pontine region of the brainstem, LC neurons sense any existential dangers or threats in our external environment and send signals to alert other brain regions of the impending danger.
The primary action of LC neurons is to release norepinephrine, a neurotransmitter, and a hormone, that increases alertness and promotes arousal, regulating the sleep/wake cycle and memory. Altered levels of norepinephrine are associated with depression, anxiety, post-traumatic stress disorder, panic attacks, hyperactivity, heart problems, and substance abuse. Thus, a better understanding of how LC neurons function is key to understanding and identifying therapies for many neuropsychiatric and neurodegenerative conditions.
Once viewed as a homogenous group of neurons that exert global, uniform influence over the entire brain, recent studies suggest LC neurons are a heterogeneous population of noradrenergic cells that exhibit both spatial and temporal modularity. These findings piqued the interest of Dr. Jiang and his team to investigate the cellular and circuit mechanisms underlying the functional diversity of LC neurons.
To do that, the team had to overcome a few technical barriers to be able to measure the activity of several LC neurons simultaneously from the brain slices of adult mice. For instance, while the technique of intracellular recordings of more than two neurons simultaneously has been used to study cortical circuits for the past few decades, it has been challenging to use this technique to record small nuclei in the brainstem such as the LC due to the space restraint and limited cell number in each brain slice. In this study, by optimizing slice quality and adapting their recording system to small brainstem slices, Andrew McKinney, a graduate student in the Jiang lab and the first author of the paper, successfully managed to record up to eight LC neurons simultaneously for the first time.
This technical development led Andrew and others in the team to make several unexpected observations about how LC neurons are organized and how they function.
First, consistent with emerging views in the field they found that norepinephrine-producing neurons in the LC are diverse. Further, they found that these can be classified into at least two major cell types based on their morphology and electrical properties and these subtypes occupy different spatial locations (anatomical niches) within LC. This finding provided a solid and much-needed basis for further in-depth studies of LC in adult animals.
Second, they found that LC neurons do not form chemical synapses, the most common type of connection between neurons. Instead, they form electrical synapses and connect to one another via gap junctions. This was an unexpected discovery because the conventional thinking is that electrical coupling via gap junctions is primarily present in developing LC and not in the LC of adult animals.
Third, they found that LC neurons of the same subtype electrically connected with one another but did not connect with the neurons of the other kind, providing the first cellular and circuit clue for the functional modularity of the LC and opening up avenues to understand how functional modularity arises within the noradrenergic system and dynamically controls diverse processes. These findings indicate that given that each cell type has preferential anatomical locations in LC and different projection targets, each electrically coupled within-cell-type homotypic network may coordinate or synergize their input or output as a whole to engage in distinct functions of the circuits as they carry information from the brain to various targets such as muscles or glands.
Finally, unlike the web-like connections that are typical of chemical synapses between neurons in the central nervous system, LC neurons of a single subtype were discovered to form unique linear chain-like electrical connections with one another. This provides the first experimental clue into how electrically-coupled neuronal networks are organized in the brain.
“This study sheds light on several unexplored questions about the cellular and circuit organization of the locus coeruleus in particular and also offers several new insights into other broader aspects of brain physiology,” Dr. Jiang said. “We anticipate these novel findings will be of broad interest to cellular, systems, and computational neuroscientists and will inspire several future studies to understand how each neuron within LC interacts with one another to give rise to a synchronized network,” Dr. Jiang added. “In addition, given that the dysregulation of the LC has been implicated in many neuropsychiatric and neurodegenerative disorders including autism and Alzheimer’s disease, these findings provide an essential knowledge base to decipher cellular and circuit mechanisms of these diseases.”
Muscarinic acetylcholine receptor-dependent and NMDA receptor-dependent LTP and LTD share the common AMPAR trafficking pathway
by Tomonari Sumi, Kouji Harada in iScience
Scientific evidence shows how the cognitive decline in Alzheimer’s disease (AD) is caused by the buildup of amyloid beta proteins, which promote synaptic malfunction. One of the neuropathological features in the brains of patients with AD is the degeneration of the basal forebrain cholinergic neurons, leading to a decrease in the number of cholinergic projections to the hippocampus. As a symptomatic treatment of AD, cholinergic neurotransmission is enhanced by the use of certain drugs, known as acetylcholinesterase inhibitors. For better prevention and treatment of cognitive disorders like AD and schizophrenia, it is necessary to understand how acetylcholine regulates synaptic transmissions.
Higher brain functions, like learning and memory, are partly regulated by signaling through the M1 muscarinic acetylcholine receptor (mAChR). The mAChR also induces long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission in the hippocampus. During hippocampus-controlled learning activities, extracellular levels of acetylcholine (Ach) increase by 4 times in the hippocampus, driven by mAChR signal transmission. Activation of the mAChR by agonists (activator chemicals) is known to induce LTP and LTD in the hippocampus, but the underlying molecular mechanisms are not well understood.
To study these molecular mechanisms, scientists from Japan have recently designed a model to track hippocampal synaptic plasticity. Their study has been published in volume 26 issue 3 of Science.
Associate Professor Tomonari Sumi from Okayama University, Japan, who led the study, explains, “Here, we propose the hypothesis that M1 mAChR-dependent LTP and LTD share the common a-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking pathway associated with NMDAR dependent LTP and LTD.”
For the hippocampal neurons, an AMPA receptor (AMPAR) trafficking model was proposed to simulate N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity. The findings of this study prove the validity of the hypothesis that the mAChR-dependent LTP and LTD share a common AMPAR trafficking pathway.
The difference between the two pathways is that in the M1-mAChR activation, Ca2+ ions stored in the endoplasmic reticulum of the neurons are released into the spine cytosol. A competition between Ca2+ dependent exocytosis and endocytosis regulates LTP and LPD.
“Therefore, it can be concluded that the M1 mAChR-dependent induction of LTP and LTD shares the common AMPAR trafficking pathway with NMDAR-dependent synaptic plasticity, and new gene expression is not necessary, at least in the early stages of LTP and LTD.” says Kouji Harada from the Center for IT-Based Education, Toyohashi University of Technology.
These findings show how the reduction in the number of AMPARs due to varying gene expression levels affects the induction of LTP and LTD. These results will be useful to understand the dominant factors resulting in alterations of LTP and LTD in animal models of AD, which can ultimately be greatly helpful for the development of AD therapy targeting synaptic plasticity for humans.
Aging of the human brain causes a marked reduction in the expression of a number of neurotransmitter receptors, like GluA1, which induces the integration of AMPA receptors inside synaptic membranes. The AMPAR trafficking model shows that alterations in LTP and LTD observed in AD could be due to age-related reduction in AMPAR expression levels.
“Taken together, these observations suggest that either upregulation of neurotransmitter receptor genes or suppression of the downregulation could improve synaptic dysfunction during AD.” says Dr. Sumi.
Human brain effects of DMT assessed via EEG-fMRI
by Christopher Timmermann, Leor Roseman, Sharad Haridas, Fernando E. Rosas, Lisa Luan, Hannes Kettner, Jonny Martell, David Erritzoe, Enzo Tagliazucchi, Carla Pallavicini, Manesh Girn, Andrea Alamia, Robert Leech, David J. Nutt, Robin L. Carhart-Harris in Proceedings of the National Academy of Sciences
Scientists have gleaned new insights into how psychedelics alter conscious experience via their action on brain activity.
In a study at Imperial College London, detailed brain imaging data from 20 healthy volunteers revealed how the potent psychedelic compound, DMT (dimethyltryptamine), alters brain function. During the immersive DMT experience, there was increased connectivity across the brain, with more communication between different areas and systems. The changes to brain activity were most prominent in areas linked with ‘higher level’ functions, such as imagination.
DMT is a potent psychedelic found naturally in certain plants and animals. It occurs in trace amounts in the human body and is the major psychoactive compound in ayahuasca — the psychedelic brew prepared from vines and leaves and used in ceremonies in the south and central America.
The study, published in the journal PNAS, is the first to track brain activity before, during, and after the DMT experience in such detail.
Dr. Chris Timmerman, from the Centre for Psychedelic Research at Imperial College London, and the first author of the study, said:
“This work is exciting as it provides the most advanced human neuroimaging view of the psychedelic state to-date.
“One increasingly popular view is that much of brain function is concerned with modelling or predicting its environment. Humans have unusually big brains and model an unusually large amount of the world. For example, like with optical illusions, when we’re looking at something, some of what we’re actually seeing is our brain filling in the blanks based on what we already know. What we have seen with DMT is that activity in highly evolved areas and systems of the brain that encode especially high-level models becomes highly dysregulated under the drug, and this relates to the intense drug ‘trip’.”
Unlike other classic psychedelics, such as LSD or psilocybin, DMT’s effects on the brain are relatively brief, lasting a matter of minutes, rather than hours. DMT can produce intense and immersive altered states of consciousness, with the experience characterized by vivid and bizarre visions, a sense of ‘visiting’ alternative realities or dimensions, and similarities with near-death experiences. But exactly how the compound alters brain function to account for such effects has been unclear.
In the latest study, 20 healthy volunteers were given an injection of the drug while researchers from Imperial’s Centre for Psychedelic Research captured detailed imagery of their brains, enabling the team to study how activity changes before, during and after the trip.
Volunteers received a high dose of DMT (20mg, given intravenously), while simultaneously undergoing two types of brain imaging: functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). The total psychedelic experience lasted about 20 minutes, and at regular intervals, volunteers provided a rating of the subjective intensity of their experience (on a 1 to 10 scale).
The fMRI scans found changes to activity within and between brain regions in volunteers under the influence of DMT. Effects included increased connectivity across the brain, with more communication between different areas and systems. These phenomena, termed ‘network disintegration and desegregation’ and increased ‘global functional connectivity’, align with previous studies with other psychedelics. The changes to activity were most prominent in brain areas linked with ‘higher level’, human-specific functions, such as imagination.
The researchers highlight that while their study is not the first to image the brain under the influence of psychedelics or the first to show the signatures of brain activity linked to psychedelics, it is the first to combine imaging techniques to study the brain during a highly immersive psychedelic experience. They explain the work provides further evidence of how DMT, and psychedelics more generally, exert their effects by disrupting high level brain systems.
Prof Robin Carhart-Harris, founder of the Centre for Psychedelic Research at Imperial College London, and senior author on the paper (now working at the University of California, San Francisco), commented: “Motivated by, and building on our previous research with psychedelics, the present work combined two complementary methods for imaging the brain imaging. fMRI allowed us to see the whole of the brain, including its deepest structures, and EEG helped us view the brain’s fine-grained rhythmic activity.
“Our results revealed that when a volunteer was on DMT there was a marked dysregulation of some of the brain rhythms that would ordinarily be dominant. The brain switched in its mode of functioning to something altogether more anarchic. It will be fascinating to follow-up on these insights in the years to come. Psychedelics are proving to be extremely powerful scientific tools for furthering our understanding of how brain activity relates to conscious experience.”
The Imperial team is now exploring how to prolong the peak of the psychedelic experience through continuous infusion with DMT, and some are also advising on a commercially run trial to assess DMT for patients with depression.
The occipital place area represents visual information about walking, not crawling
by Christopher M Jones, Joshua Byland, Daniel D Dilks in Cerebral Cortex
Using vision to efficiently move through an area by foot uses a unique region of the brain’s cortex, according to a small study funded by the National Eye Institute (NEI). The region, called the occipital place area (OPA), fails to activate during other modes of moving, such as crawling. The finding may help explain developmental milestones as children learn to interact with and navigate their near environments. The study published in the journal Cerebral Cortex. NEI is part of the National Institutes of Health.
Navigating through a physical environment — anything from a small room to a city — requires the brain to process several classes of information. Each class of information is processed in its own region of the brain’s cortex, which then work together to support navigation behavior, such as walking. Loss of any one of these regions can affect how or whether someone can successfully navigate.
Two main areas of the cortex are activated as people navigate through an environment: the OPA and the retrosplenial complex (RSC). Daniel Dilks, Ph.D., Emory University, Atlanta, theorizes that each of these areas supports a different kind of navigation. The RSC supports map-based navigation, which involves finding our way from a specific place to some distant, out-of-sight place (for example, finding our way from your house to your favorite restaurant). By contrast, he believes the OPA supports visually guided navigation, which involves finding our way through near environment, avoiding boundaries and obstacles (for example, moving through your kitchen without bumping into things).
However, his theory has been controversial, in part because the OPA doesn’t appear to support visually guided navigation until around 8 years of age. Yet children somehow manage to get around their homes and schools long before that time — even from the earliest ages, when they crawl rather than walk.
“We asked ourselves, does the OPA come on early but just mature slowly?” Dilks said. “Or does crawling use an entirely different system?”
While most adults and older children primarily navigate environments by walking, we retain the ability to crawl as we did in infancy. If OPA just matured slowly, then it should be activated by both modes of movement, Dilks reasoned. So, he and students Christopher Jones and Joshua Byland set out to discover whether the OPA would activate in adults when crawling.
To test this, the scientists recorded videos from the perspective of someone walking through an environment, and then similar videos from the perspective of someone crawling through that same environment. They also patched together random shots of the videos (scrambled) and took videos from a flying-over-the-environment perspective, to include a mode of navigation not accessible to humans.
When viewing videos, our brains often activate as if we were performing the activity ourselves — a sympathetic response that made Dilks’ experiment possible. Using functional magnetic resonance imaging (fMRI), the researchers were able to monitor the activation of brain regions in 15 adult study participants as they were viewing each video and imagining themselves moving through the environment.
When the participants viewed the walking video, the region of the brain corresponding to the OPA was activated. But when they viewed the other videos — crawling, flying, or scrambled, OPA was not activated. In contrast, the RSC was activated when viewing all the videos, suggesting that only OPA is specific for walking, as opposed to other modes of visual navigation.
In addition, several other brain areas were activated when the participants viewed the crawling videos, suggesting additional regions that may be involved in navigation early in life.
“Not only does this study suggest that there’s a completely different brain system managing navigation in early versus late childhood, but it suggests that each of these pieces of the navigation system come on at different stages of development,” Dilks said. “Based on our study, we think OPA is specifically tied to mature, efficient walking.”
Multivariate BWAS can be replicable with moderate sample sizes
by Tamas Spisak, Ulrike Bingel, Tor D. Wager in Nature
Since the development of functional magnetic resonance imaging in the 1990s, the reliance on neuroimaging has skyrocketed as researchers investigate how fMRI data from the brain at rest, and anatomical brain structure itself, can be used to predict individual traits, such as depression, cognitive decline, and brain disorders.
Brain imaging has the potential to reveal the neural underpinnings of many traits, from disorders like depression and chronic widespread pain to why one person has a better memory than another, and why some people’s memories are resilient as they age. But how reliable brain imaging is for detecting traits has been a subject of wide debate.
Prior research on brain-wide associated studies (termed ‘BWAS’) has shown that links between brain function and structure and traits are so weak that thousands of participants are needed to detect replicable effects. Research of this scale requires millions of dollars in investment in each study, limiting which traits and brain disorders can be studied.
However, according to a new commentary published in Nature, stronger links between brain measures and traits can be obtained when state-of-the-art pattern recognition (or ‘machine learning’) algorithms are utilized, which can garner high-powered results from moderate sample sizes.
In their article, researchers from Dartmouth and University Medicine Essen provide a response to an earlier analysis of brain-wide association studies led by Scott Marek at Washington University School of Medicine in St. Louis, Brenden Tervo-Clemmens at Massachusetts General Hospital/Harvard Medical School, and colleagues. The earlier study found very weak associations across a range of traits in several large brain imaging studies, concluding that thousands of participants would be needed to detect these associations.
The new article explains that the very weak effects found in the earlier paper do not apply to all brain images and all traits, but rather are limited to specific cases. It outlines how fMRI data from hundreds of participants, as opposed to thousands, can be better leveraged to yield important diagnostic information about individuals.
One key to stronger associations between brain images and traits such as memory and intelligence is the use of state-of-the-art pattern recognition algorithms.
“Given that there’s virtually no mental function performed entirely by one area of the brain, we recommend using pattern recognition to develop models of how multiple brain areas contribute to predicting traits, rather than testing brain areas individually,” says senior author Tor Wager, the Diana L. Taylor Distinguished Professor of Psychological and Brain Sciences and director of the Brain Imaging Center at Dartmouth.
“If models of multiple brain areas working together rather than in isolation are applied, this provides for a much more powerful approach in neuroimaging studies, yielding predictive effects that are four times larger than when testing brain areas in isolation,” says lead author Tamas Spisak, head of the Predictive Neuroimaging Lab at the Institute of Diagnostic and Interventional Radiology and Neuroradiology at University Medicine Essen.
However, not all pattern recognition algorithms are equal and finding the algorithms that work best for specific types of brain imaging data is an active area of research. The earlier paper by Marek, Tervo-Clemmens et al. also tested whether pattern recognition can be used to predict traits from brain images, but Spisak and colleagues found that the algorithm they used is suboptimal.
When the researchers applied a more powerful algorithm, the effects got even larger and reliable associations could be detected in much smaller samples.
“When you do the power calculations on how many participants are needed to detect replicable effects, the number drops to below 500 people,” Spisak says.
“This opens the field to studies of many traits and clinical conditions for which obtaining thousands of patients is not possible, including rare brain disorders,” says co-author Ulrike Bingel at University Medicine Essen, who is the head of the University Centre for Pain Medicine. “Identifying markers, including those involving the central nervous system, are urgently needed, as they are critical to improve diagnostics and individually tailored treatment approaches. We need to move towards a personalized medicine approach grounded in neuroscience. The potential for multivariate BWAS to move us towards this goal should not be underestimated.”
The team explains that the weak associations found in the earlier analysis, particularly through brain images, were collected while people were simply resting in the scanner, rather than performing tasks. But fMRI can also capture brain activity linked to specific moment-by-moment thoughts and experiences.
Wager believes that linking brain patterns to these experiences may be a key to understanding and predicting differences among individuals.
“One of the challenges associated with using brain imaging to predict traits is that many traits aren’t stable or reliable. If we use brain imaging to focus on studying mental states and experiences, such as pain, empathy, and drug craving, the effects can be much larger and more reliable,” says Wager. “The key is finding the right task to capture the state.”
“For example, showing images of drugs to people with substance use disorders can elicit drug cravings, according to an earlier study revealing a neuromarker for cravings,” says Wager.
“Identifying which approaches to understanding the brain and mind are most likely to succeed is important, as this affects how stakeholders view and ultimately fund translational research in neuroimaging,” says Bingel. “Finding the limitations and working together to overcome them is key to developing new ways of diagnosing and caring for patients with brain and mental health disorders.”
Point-of-Care Testing of Enzyme Polymorphisms for Predicting Hypnotizability and Postoperative Pain
by Dana L. Cortade, Jessie Markovits, David Spiegel, Shan X. Wang in The Journal of Molecular Diagnostics
Hypnosis is an effective treatment for pain for many individuals but determining which patients will benefit most can be challenging. Hypnotizability testing requires special training and in-person evaluation rarely available in the clinical setting. Now, investigators have developed a fast, point-of-care molecular diagnostic test that identifies a subset of individuals who are most likely to benefit from hypnosis interventions for pain treatment. Their study, in The Journal of Molecular Diagnostics, published by Elsevier, also found that a subset of highly hypnotizable individuals may be more likely to experience high levels of postoperative pain.
“Since hypnotizability is a stable cognitive trait with a genetic basis, our goal was to create a molecular diagnostic tool for objectively identifying individuals who would benefit from hypnosis by determining ‘treatability’ at the point-of-care,” explained co-lead investigator Dana L. Cortade, a recently graduated PhD in Materials Science and Engineering, School of Engineering, Stanford University, Stanford, CA, USA. “The advancement of nonpharmacological adjuvant treatments for pain is of the utmost importance in light of the opioid epidemic.”
Prior research established that the genetic basis for hypnotizability includes four specific single-nucleotide polymorphisms (SNPs), or genetic variations, found in the catechol-o-methyltransferase (COMT) gene for an enzyme in the brain that is responsible for dopamine metabolism in the prefrontal cortex. Although SNPs can contain valuable information on disease risk and treatment response, widespread use in clinical practice is limited because of the complexities, costs, and time delays involved in sending samples to laboratories for testing.
The investigators developed an SNP genotyping assay on a giant magnetoresistive (GMR) biosensor array to detect the optimal combination of the COMT SNPs in patient DNA samples. GMR biosensor arrays are reliable, cheaper, sensitive, and can be easily deployed in point-of-care settings using saliva or blood samples.
The study investigated the association between COMT diplotypes and hypnotizability using a clinical hypnotizability scale called the Hypnotic Induction Profile (HIP) in individuals who had participated in one of the three previous clinical trials in which an HIP was administered. An additional exploratory study of the association between perioperative pain, COMT genotypes, and HIP scores was conducted with the patients in the third cohort, who had undergone total knee arthroplasty (TKA). DNA was extracted from blood samples previously collected in the first cohort, and saliva samples were collected by mail from participants in the other two trials. Participants were considered treatable by hypnosis if they had HIP scores of 3 or higher on a scale of zero to 10.
For participants identified with the optimal COMT diplotypes by the GMR biosensor array, 89.5% scored highly on the HIP, which identified 40.5% of the treatable population. The optimal COMT group mean HIP score was significantly higher than that in the suboptimal COMT group. Interestingly, further analysis revealed that the difference was observed only in women.
“Although we had expected some difference in effect between females and males, the association between hypnotizability and COMT genotypes was strongest in the females in the cohort,” said co-lead investigator Jessie Markovits, MD, Department of Internal Medicine, Stanford School of Medicine, Stanford, CA, USA. “The difference may be due to lower numbers of males in the cohort, or because COMT is known to have interactions with estrogen and to differ in activity by sex. Additional gene targets including COMT, with stratification by sex, could be the focus of future study.”
In the exploratory analysis of the relationship between COMT genotypes and pain after TKA surgery, the same optimal COMT individuals had significantly higher postoperative pain scores than the suboptimal group, indicating a greater need for treatment.
“This supports the body of evidence that COMT genotypes impact pain, and it is also known that COMT genotypes affect opioid use after surgery. Pain researchers can use this technology to correlate genetic predisposition to pain sensitivity and opioid use with response to an evidence-based, alternative remedy: hypnosis,” Dr. Cortade said.
COMT SNPs alone are not a complete biomarker for identifying all individuals who will score highly on a hypnotizability scale and experience high pain sensitivity. The GMR sensor nanoarray can accommodate up to 80 SNPs, and it is possible that other SNPs, such as those for dopamine receptors, are needed to further stratify individuals.
The investigators observe that this study highlights the utility and potential of the evolving applications of precision medicine.
“It is a step towards enabling researchers and healthcare professionals to identify a subset of patients who are most likely to benefit from hypnotic analgesia,” Dr. Markovits said. “Precision medicine has made great strides in identifying differences in drug metabolism that can impact medication decisions for perioperative pain. We hope to provide similar precision in offering hypnosis as an effective, non-pharmacological treatment that can improve patient comfort while reducing opioid use.”
Augmenting hematoma-scavenging capacity of innate immune cells by CDNF reduces brain injury and promotes functional recovery after intracerebral hemorrhage
by Kuan-Yin Tseng, Vassilis Stratoulias, Wei-Fen Hu, Jui-Sheng Wu, Vicki Wang, Yuan-Hao Chen, Anna Seelbach, Henri J. Huttunen, Natalia Kulesskaya, Cheng-Yoong Pang, Jian-Liang Chou, Maria Lindahl, Mart Saarma, Li-Chuan Huang, Mikko Airavaara, Hock-Kean Liew in Cell Death & Disease
University of Helsinki and Taiwanese researchers have found a new way to remove waste from the brain after haemorrhage.
Intracerebral haemorrhage, and bleeding into the brain tissue, is a devastating neurological condition affecting millions of people annually. It has a high mortality rate, while survivors are affected by long-term neurological deficits. No medication has been found to support brain recovery following hemorrhage.
In an international collaboration, researchers from the Brain Repair laboratory, University of Helsinki, together with their Taiwanese colleagues investigated whether a protein called cerebral dopamine neurotrophic factor (CDNF) has potential as a treatment for brain hemorrhage.
Researchers suggest that cerebral dopamine neurotrophic factor, a protein being currently tested for Parkinson’s disease treatment, also has therapeutic effects and enhances immune cell’s response after a brain haemorrhage.
The authors found that the administration of cerebral dopamine neurotrophic factor accelerates hemorrhagic lesion resolution, reduces brain swelling, and improves functional outcomes in an animal model of a brain hemorrhage.
“Surprisingly, we found that cerebral dopamine neurotrophic factor acts on immune cells in the bleeding brain, by increasing anti-inflammatory mediators and suppressing the production of the pro-inflammatory cytokines that are responsible for cell signalling. This is a significant step towards the treatment of injuries caused by brain haemorrhage, for which we currently have no cure,” says Professor Mikko Airavaara, from University of Helsinki.
Dr. Vassileios Stratouliasfrom the Brain Repair laboratory comments, “It’s interesting to note that after a bleeding episode, the brain contains a lot of waste and debris. Cerebral dopamine neurotrophic factor encourages immune cells in the brain to consume and remove the waste and debris, which is essential for the brain’s recovery!”
The administration of cerebral dopamine neurotrophic factor also resulted in the alleviation of cell stress in the area that surrounds the hematoma.
Finally, the researchers demonstrated that systemic administration of cerebral dopamine neurotrophic factor promotes scavenging by the brain’s immune cells after brain haemorrhage and has beneficial effects in an animal model of a brain haemorrhage.
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