Whole-brain temporal (time) variability is high in areas associated with intelligence and low in sensory cortices (credit: Jie Zhang et al./Brain)
A new study of human intelligence by University of Warwick researchers and associates at nine universities in China and NEC Laboratories America has quantified the brain’s dynamic functions, identifying how different parts of the brain interact with each other at different times, they reported in the journal Brain.
The more variable a brain is, and the more its different parts frequently connect with each other, the higher a person’s intelligence and creativity are, the researchers found .
Specifically, using resting-state MRI analysis of 1180 people’s brains in eight datasets around the world, the researchers discovered that the areas of the brain associated with learning and development, such as the hippocampus, show high levels of temporal variability — meaning that they change their neural connections with other parts of the brain more frequently, over a matter of minutes or seconds. But regions of the brain that aren’t associated with intelligence — visual, auditory, and sensory-motor areas — show small variability and adaptability.
This more accurate understanding of human intelligence could be applied to the construction of advanced artificial neural networks for computers, with the ability to learn, grow and adapt, the researchers suggest. Currently, AI systems do not process the functional variability and adaptability that is vital to the human brain for growth and learning, they note.
Improving mental-health treatments
Brain regions showing significant variability differences between patients with mental disorders and matched healthy controls. Blue indicates that the variability of patients is lower than that of controls, and red-to-yellow indicates the opposite. (credit: Jie Zhang et al./Brain)
This study may also have implications for a deeper understanding of another largely misunderstood field: mental health. Altered patterns of variability were observed in the brain’s default network with schizophrenia, autism, and attention deficit hyperactivity disorder (ADHD) patients.
Knowing the root cause of mental-health defects may bring scientists closer to treating and preventing these conditions in the future, according to the researchers.
Abstract of Neural, electrophysiological and anatomical basis of brain-network variability and its characteristic changes in mental disorders
Functional brain networks demonstrate significant temporal variability and dynamic reconfiguration even in the resting state. Currently, most studies investigate temporal variability of brain networks at the scale of single (micro) or whole-brain (macro) connectivity. However, the mechanism underlying time-varying properties remains unclear, as the coupling between brain network variability and neural activity is not readily apparent when analysed at either micro or macroscales. We propose an intermediate (meso) scale analysis and characterize temporal variability of the functional architecture associated with a particular region. This yields a topography of variability that reflects the whole-brain and, most importantly, creates an analytical framework to establish the fundamental relationship between variability of regional functional architecture and its neural activity or structural connectivity. We find that temporal variability reflects the dynamical reconfiguration of a brain region into distinct functional modules at different times and may be indicative of brain flexibility and adaptability. Primary and unimodal sensory-motor cortices demonstrate low temporal variability, while transmodal areas, including heteromodal association areas and limbic system, demonstrate the high variability. In particular, regions with highest variability such as hippocampus/parahippocampus, inferior and middle temporal gyrus, olfactory gyrus and caudate are all related to learning, suggesting that the temporal variability may indicate the level of brain adaptability. With simultaneously recorded electroencephalography/functional magnetic resonance imaging and functional magnetic resonance imaging/diffusion tensor imaging data, we also find that variability of regional functional architecture is modulated by local blood oxygen level-dependent activity and α-band oscillation, and is governed by the ratio of intra- to inter-community structural connectivity. Application of the mesoscale variability measure to multicentre datasets of three mental disorders and matched controls involving 1180 subjects reveals that those regions demonstrating extreme, i.e. highest/lowest variability in controls are most liable to change in mental disorders. Specifically, we draw attention to the identification of diametrically opposing patterns of variability changes between schizophrenia and attention deficit hyperactivity disorder/autism. Regions of the default-mode network demonstrate lower variability in patients with schizophrenia, but high variability in patients with autism/attention deficit hyperactivity disorder, compared with respective controls. In contrast, subcortical regions, especially the thalamus, show higher variability in schizophrenia patients, but lower variability in patients with attention deficit hyperactivity disorder. The changes in variability of these regions are also closely related to symptom scores. Our work provides insights into the dynamic organization of the resting brain and how it changes in brain disorders. The nodal variability measure may also be potentially useful as a predictor for learning and neural rehabilitation.
Prolonged sitting, such as watching a lot of television every day, may increase your risk of dying from a blood clot in the lung, according to a new open-access research letter published July 26 in the American Heart Association’s journal Circulation.
Deep vein thrombosis (credit: Blausen.com staff)
A lung blood clot (pulmonary embolism) usually begins as a clot in the leg or pelvis as a result of inactivity and slowed blood flow (deep vein thrombosis). If the clot breaks free, it can travel to a lung and become lodged in a small blood vessel, where it is especially dangerous.
From 1988 to 1990, Japanese researchers asked 86,024 participants, age 40-79, how many hours they spent watching TV. Over the next 19 years, 59 participants died of a pulmonary embolism*.
The researchers found that compared to participants who watched TV less than 2.5 hours each day, deaths from a pulmonary embolism increased by 70 percent among those who watched TV from 2.5 to 4.9 hours; by 40 percent for each additional 2 hours of daily TV watching; and 2.5 times among those who watched TV 5 or more hours.
“Pulmonary embolism occurs at a lower rate in Japan than it does in Western countries, but it may be on the rise,” said Hiroyasu Iso, M.D., Ph.D., professor of public health at Osaka University Graduate School of Medicine and study corresponding author. “The Japanese people are increasingly adopting sedentary lifestyles, which we believe is putting them at increased risk.”
Apple Watch heart rate measure (credit: Apple)
Authors noted that the risk is likely greater than the findings suggest. Deaths from pulmonary embolism are believed to be underreported because diagnosis is difficult. The most common symptoms of pulmonary embolism — chest pain and shortness of breath — are the same as other life-threatening conditions, and diagnosis requires imaging that many hospitals are not equipped to provide.
Other risks factors studied were obesity (the strongest link after hours sitting), diabetes, cigarette smoking, and hypertension.
The researchers said the findings may be particularly relevant to Americans, since U.S. adults watch more television — especially “binge watching” — than Japanese adults (according to another study).
The researchers advised a few simple steps to avoid a pulmonary embolism: “After an hour or so, stand up, stretch, walk around, or while you’re watching TV, tense and relax your leg muscles for 5 minutes (similar to that given to travelers on long plane flights), keep hydrated, and shed pounds if overweight.
An hour of moderate exercise a day enough to counter health risks from prolonged sitting
University of Cambridge researchers, in another new study published July 27 in Lancet, noted that recent estimates suggest that more than 5 million people die globally each year as a result of failing to meet recommended daily activity levels.
But they found that 60 to 75 minutes of moderate intensity exercise per day were sufficient to eliminate the increased risk of early death associated with sitting for over eight hours per day, based on an analysis of 16 studies, which included data from more than one million men and women.** (Three out of four people in the study failed to reach this level of daily activity, though.)
The greatest risk of early death was for those individuals who were physically inactive. They were between 28% and 59% more likely to die early compared with those who were in the most active quartile — a risk similar to that associated with smoking and obesity. In other words, lack of physical activity is a greater health risk than prolonged sitting.
The enormous economic burden of physical inactivity — a global pandemic
Another study, also published July 27 in Lancet, revealed that in 2013, physical inactivity cost INT $67.5 billion*** (in international dollars = what U.S. dollars could buy in 2013) globally in healthcare expenditure and lost productivity in 142 countries, representing 93.2 per cent of the world’s population. The study was based on the direct health-care cost, productivity losses, and disability-adjusted life years (DALYs) for five major non-communicable diseases attributable to inactivity: coronary heart disease, stroke, type 2 diabetes, breast cancer and colon cancer.
* The study, which is part of the Japan Collaborative Cohort Study funded by the Ministry of Education, Science, Sports and Culture of Japan, was conducted before computers, tablets and smartphones became popular sources of information and entertainment. The researchers believe new studies are needed to determine the effect of these new technologies on pulmonary embolism risk.
** The researchers acknowledge that there are limitations to the data analyzed, which mainly came from participants aged 45 years and older and living in western Europe, the U.S. and Australia. But the researchers asked all included studies to reanalyze their data in a harmonized manner, an approach that has never before been adopted for a study of this size and therefore also provides much more robust effect estimates compared with previous studies.
*** Cost breakdown:
$67.5bn: Total costs, including $53.8bn in direct cost (healthcare expenditure) and 13.7bn in indirect costs (productivity losses).
$31.2bn: Total loss in tax revenue through public healthcare expenditure
$12.9bn: Total amount in private sector pays for physical inactivity-related diseases (e.g. health insurance companies)
$9.7bn: Total amount households paid out-of-pocket for physical inactivity-related diseases
Type 2 Diabetes was the costliest disease, accounting for $37.6bn (70 percent) of direct costs.
Abstract of Watching Television and Risk of Mortality From Pulmonary Embolism Among Japanese Men and Women
Although case series reporting pulmonary embolism or deep vein thrombosis after prolonged television watching have been published, no prospective study has examined the association between time spent watching television and the risk of mortality from pulmonary embolism. We examined this association in a large cohort study of Japanese men and women.
Abstract of Does physical activity attenuate, or even eliminate, the detrimental association of sitting time with mortality? A harmonised meta-analysis of data from more than 1 million men and women
Background: High amounts of sedentary behaviour have been associated with increased risks of several chronic conditions and mortality. However, it is unclear whether physical activity attenuates or even eliminates the detrimental effects of prolonged sitting. We examined the associations of sedentary behaviour and physical activity with all-cause mortality.
Methods: We did a systematic review, searching six databases (PubMed, PsycINFO, Embase, Web of Science, Sport Discus, and Scopus) from database inception until October, 2015, for prospective cohort studies that had individual level exposure and outcome data, provided data on both daily sitting or TV-viewing time and physical activity, and reported effect estimates for all-cause mortality, cardiovascular disease mortality, or breast, colon, and colorectal cancer mortality. We included data from 16 studies, of which 14 were identified through a systematic review and two were additional unpublished studies where pertinent data were available. All study data were analysed according to a harmonised protocol, which categorised reported daily sitting time and TV-viewing time into four standardised groups each, and physical activity into quartiles (in metabolic equivalent of task [MET]-hours per week). We then combined data across all studies to analyse the association of daily sitting time and physical activity with all-cause mortality, and estimated summary hazard ratios using Cox regression. We repeated these analyses using TV-viewing time instead of daily sitting time.
Findings: Of the 16 studies included in the meta-analysis, 13 studies provided data on sitting time and all-cause mortality. These studies included 1 005 791 individuals who were followed up for 2–18·1 years, during which 84 609 (8·4%) died. Compared with the referent group (ie, those sitting <4 h/day and in the most active quartile [>35·5 MET-h per week]), mortality rates during follow-up were 12–59% higher in the two lowest quartiles of physical activity (from HR=1·12, 95% CI 1·08–1·16, for the second lowest quartile of physical activity [<16 MET-h per week] and sitting <4 h/day; to HR=1·59, 1·52–1·66, for the lowest quartile of physical activity [<2·5 MET-h per week] and sitting >8 h/day). Daily sitting time was not associated with increased all-cause mortality in those in the most active quartile of physical activity. Compared with the referent (<4 h of sitting per day and highest quartile of physical activity [>35·5 MET-h per week]), there was no increased risk of mortality during follow-up in those who sat for more than 8 h/day but who also reported >35·5 MET-h per week of activity (HR=1·04; 95% CI 0·99–1·10). By contrast, those who sat the least (<4 h/day) and were in the lowest activity quartile (<2·5 MET-h per week) had a significantly increased risk of dying during follow-up (HR=1·27, 95% CI 1·22–1·31). Six studies had data on TV-viewing time (N=465 450; 43 740 deaths). Watching TV for 3 h or more per day was associated with increased mortality regardless of physical activity, except in the most active quartile, where mortality was significantly increased only in people who watched TV for 5 h/day or more (HR=1·16, 1·05–1·28).
Interpretation: High levels of moderate intensity physical activity (ie, about 60–75 min per day) seem to eliminate the increased risk of death associated with high sitting time. However, this high activity level attenuates, but does not eliminate the increased risk associated with high TV-viewing time. These results provide further evidence on the benefits of physical activity, particularly in societies where increasing numbers of people have to sit for long hours for work and may also inform future public health recommendations.
Funding: None.
Abstract of The economic burden of physical inactivity: a global analysis of major non-communicable diseases
Background: The pandemic of physical inactivity is associated with a range of chronic diseases and early deaths. Despite the well documented disease burden, the economic burden of physical inactivity remains unquantified at the global level. A better understanding of the economic burden could help to inform resource prioritisation and motivate efforts to increase levels of physical activity worldwide.
Methods: Direct health-care costs, productivity losses, and disability-adjusted life-years (DALYs) attributable to physical inactivity were estimated with standardised methods and the best data available for 142 countries, representing 93·2% of the world’s population. Direct health-care costs and DALYs were estimated for coronary heart disease, stroke, type 2 diabetes, breast cancer, and colon cancer attributable to physical inactivity. Productivity losses were estimated with a friction cost approach for physical inactivity related mortality. Analyses were based on national physical inactivity prevalence from available countries, and adjusted population attributable fractions (PAFs) associated with physical inactivity for each disease outcome and all-cause mortality.
Findings: Conservatively estimated, physical inactivity cost health-care systems international $ (INT$) 53·8 billion worldwide in 2013, of which $31·2 billion was paid by the public sector, $12·9 billion by the private sector, and $9·7 billion by households. In addition, physical inactivity related deaths contribute to $13·7 billion in productivity losses, and physical inactivity was responsible for 13·4 million DALYs worldwide. High-income countries bear a larger proportion of economic burden (80·8% of health-care costs and 60·4% of indirect costs), whereas low-income and middle-income countries have a larger proportion of the disease burden (75·0% of DALYs). Sensitivity analyses based on less conservative assumptions led to much higher estimates.
Interpretation: In addition to morbidity and premature mortality, physical inactivity is responsible for a substantial economic burden. This paper provides further justification to prioritise promotion of regular physical activity worldwide as part of a comprehensive strategy to reduce non-communicable diseases.
Left: the standard approach to the design of automultiscopic 3D displays, which attempts to cover the angular range of all viewer positions, but involves poor spatial/angular resolution or a restricted range of screen distances. Right: an automultiscopic 3D display architecture that only presents a narrow range of angular images across the small set of viewing positions of a single seat, and replicates that narrow-angle content to all seats in the cinema and at all screen distances. (credit: Netalee Efrat et al./ACM Trans.Graph., )
Glasses-free 3-D already exists: Traditional methods for TV sets use a series of slits in front of the screen (a “parallax barrier”) that allows each eye to see a different set of pixels, creating a simulated sense of depth.
But because parallax barriers have to be at a consistent distance from the viewer, this approach isn’t practical for larger spaces like theaters, which have viewers at different angles and distances. Other methods, including one from the MIT Media Lab, involve developing completely new physical projectors that cover the entire angular range of the audience. However, this often comes at a cost of lower image-resolution.
The key insight with Cinema 3D is that people in movie theaters move their heads only over a very small range of angles, limited by the width of their seat. So it’s enough to display images to a narrow range of angles and replicate that to all seats in the theater, using a series of mirrors and lenses. (The team’s prototype requires 50 sets of mirrors and lenses, which is currently expensive and impractical, the researchers say.)
The team presented Cinema 3D in an open-access paper at last week’s SIGGRAPH computer-graphics conference in Anaheim, California. The work was funded by the Israel Science Foundation and the European Research Council.
MITCSAIL | Cinema 3D: A movie screen for glasses-free 3D
Abstract of Cinema 3D: large scale automultiscopic display
While 3D movies are gaining popularity, viewers in a 3D cinema still need to wear cumbersome glasses in order to enjoy them. Automultiscopic displays provide a better alternative to the display of 3D content, as they present multiple angular images of the same scene without the need for special eyewear. However, automultiscopic displays cannot be directly implemented in a wide cinema setting due to variants of two main problems: (i) The range of angles at which the screen is observed in a large cinema is usually very wide, and there is an unavoidable tradeoff between the range of angular images supported by the display and its spatial or angular resolutions. (ii) Parallax is usually observed only when a viewer is positioned at a limited range of distances from the screen. This work proposes a new display concept, which supports automultiscopic content in a wide cinema setting. It builds on the typical structure of cinemas, such as the fixed seat positions and the fact that different rows are located on a slope at different heights. Rather than attempting to display many angular images spanning the full range of viewing angles in a wide cinema, our design only displays the narrow angular range observed within the limited width of a single seat. The same narrow range content is then replicated to all rows and seats in the cinema. To achieve this, it uses an optical construction based on two sets of parallax barriers, or lenslets, placed in front of a standard screen. This paper derives the geometry of such a display, analyzes its limitations, and demonstrates a proof-of-concept prototype.
UNC Health Care | UNC Science Short: Sleep Spindles
University of North Carolina (UNC) School of Medicine scientists report using transcranial alternating current stimulation (tACS) to enhance memory during sleep, laying the groundwork for a new treatment paradigm for neurological and psychiatric disorders.
The findings, published in the journal Current Biology, offer a non-invasive method to potentially help millions of people with conditions such as autism, Alzheimer’s disease, schizophrenia, and major depressive disorder.
Do sleep spindles cause memory consolidation? The experiment.
For years, researchers have recorded electrical brain activity that oscillates or alternates during sleep on an electroencephalogram (EEG) as waves called sleep spindles. And scientists have suspected their involvement in cataloging and storing memories as we sleep.
Sleep spindle and associated K-Complex (credit: Neocadre/public domain)
“But we didn’t know if sleep spindles enable or even cause memories to be stored and consolidated,” said senior author UNC neuroscientist Flavio Frohlich, PhD, assistant professor of psychiatry and member of the UNC Neuroscience Center. “They could’ve been merely byproducts of other brain processes that enabled what we learn to be stored as a memory. But our study shows that, indeed, the spindles are crucial for the process of creating memories we need for everyday life. And we can target them to enhance memory.”
Feedback-Controlled Spindle tACS (A) Graphical representation of real-time spindle detection and feedback-controlled transcranial current stimulation. (B) Schematic of tACS current source and stimulation electrode configuration; stimulation electrode placement according to International 10-20 locations. (credit: Caroline Lustenberger et al./Current Biology)
During Frohlich’s study, 16 male participants underwent a screening night of sleep before completing two nights of sleep for the study.
Before going to sleep each night, all participants performed two common memory exercises — associative word-pairing tests and motor sequence tapping tasks, which involved repeatedly finger-tapping a specific sequence. During both study nights, each participant had electrodes placed at specific spots on their scalps. During sleep one of the nights, each person received tACS — an alternating current of weak electricity synchronized with the brain’s natural sleep spindles. During sleep the other night, each person received sham stimulation as placebo.
Direct causal link
Each morning, researchers had participants perform the same standard memory tests. Frohlich’s team found no improvement in test scores for associative word-pairing but a significant improvement in the motor tasks when comparing the results between the stimulation and placebo night.
“This demonstrated a direct causal link between the electric activity pattern of sleep spindles and the process of motor memory consolidation.” Frohlich said.
“We’re excited about this because we know sleep spindles, along with memory formation, are impaired in a number of disorders, such as schizophrenia and Alzheimer’s,” said Caroline Lustenberger, PhD, first author and postdoctoral fellow in the Frohlich lab. “We hope that targeting these sleep spindles could be a new type of treatment for memory impairment and cognitive deficits.”
The challenging research ahead
Frohlich said the next step is to try the same type of non-invasive brain stimulation in patients that have known deficits in these spindle activity patterns.
Based on the Current Biology paper, it’s clear the team is just getting started, with a lot of interesting possibilities to explore. For example, they note that “it is still unclear which specific cortical regions might be involved in sleep-dependent memory consolidation.”
It’s a sort of jungle in there, one with unknown species. The researchers say they may target posterior brain regions using faster frequencies (e.g., 15 Hz tACS) to optimally benefit motor memory consolidation, for example, and that maybe they should try synchronization of frontal oscillatory activity. And they want to find out if spindles synchronized across cortical regions are “essential for memory consolidation to occur” or are only spindles localized to brain regions necessary for performing the task?
Future studies will also be needed to investigate more complex ‘‘real-life’’ motor tasks that benefit from sleep and to relate those findings to sleep spindles, they add. “Future studies are also needed to further find optimized stimulation parameters by means of ideal stimulation location (centro-parietal instead of frontal) and (spindle) frequency applied.”
And when it comes to developing neuro-therapeutics, things will get even wilder. Will anomalous spindle patterns need to be reconstructed and reinforced, or will whole new customized patterns be needed? And if so, would this be some kind of reconstruction of a person’s memory (at least, their motor memory, for starters)? and what about dealing with circadian desynchronization and its possible disruptive effects on spindle patterns? And does it makes sense to look at phase patterns, in addition to frequency?
And perhaps most interesting to Kurzweilians, could the ability to improve spindle patterns, using machine learning, lead one day to cyborg minds and merged human-machine superintelligence?
KurzweilAI will be closely following this fascinating research.
The study was funded by the National Institutes of Health, UNC Department of Psychiatry, UNC School of Medicine, and Swiss National Science Foundation.
* We asked Frohlich to comment on possible risks similar to those reported with tDCS. “So far, tACS used in laboratory studies (i.e., in a well-controlled environment) has been very safe and we have never experienced serious side effects in any of our tACS studies,” he said. “However, unregulated DIY use of tACS could indeed theoretically carry risks, albeit we do not know at this point.”
Abstract of Feedback-Controlled Transcranial Alternating Current Stimulation Reveals a Functional Role of Sleep Spindles in Motor Memory Consolidation
Transient episodes of brain oscillations are a common feature of both the waking and the sleeping brain. Sleep spindles represent a prominent example of a poorly understood transient brain oscillation that is impaired in disorders such as Alzheimer’s disease and schizophrenia. However, the causal role of these bouts of thalamo-cortical oscillations remains unknown. Demonstrating a functional role of sleep spindles in cognitive processes has, so far, been hindered by the lack of a tool to target transient brain oscillations in real time. Here, we show, for the first time, selective enhancement of sleep spindles with non-invasive brain stimulation in humans. We developed a system that detects sleep spindles in real time and applies oscillatory stimulation. Our stimulation selectively enhanced spindle activity as determined by increased sigma activity after transcranial alternating current stimulation (tACS) application. This targeted modulation caused significant enhancement of motor memory consolidation that correlated with the stimulation-induced change in fast spindle activity. Strikingly, we found a similar correlation between motor memory and spindle characteristics during the sham night for the same spindle frequencies and electrode locations. Therefore, our results directly demonstrate a functional relationship between oscillatory spindle activity and cognition.
A new technique called “magnified analysis of proteome” (MAP) developed at MIT allows researchers to peer at molecules within cells or take a wider view of the long-range connections between neurons. (credit: Courtesy of the researchers)
MIT researchers have developed a new technique for imaging brain tissue at multiple scales, allowing them to peer at molecules within cells or take a wider view of the long-range connections between neurons.
This technique, known as “magnified analysis of proteome” (MAP), should help scientists in their ongoing efforts to chart the connectivity and functions of neurons in the human brain, says Kwanghun Chung, the Samuel A. Goldblith Assistant Professor in the Department of Chemical Engineering, extending the work of Sebastian Seung and colleagues on the Human Connectome Project.
“We use a chemical process to make the whole brain size-adjustable, while preserving pretty much everything. We preserve the proteome (the collection of proteins found in a biological sample), we preserve nanoscopic details, and we also preserve brain-wide connectivity,” says Chung, the senior author of a paper describing the method in the July 25 issue of Nature Biotechnology.
The researchers also showed that the technique is applicable to other organs such as the heart, lungs, liver, and kidneys.
Multiscale imaging
A 3-dimensional image taken via the CLARITY technique showing a 1 millimeter slice of mouse hippocampus. The different colors represent proteins stained with fluorescent antibodies. Excitatory neurons are labeled in green, Inhibitory neurons in red, and astrocytes in blue. (credit: Kwanghun Chung and Karl Deisseroth)
The new MAP technique builds on a tissue transformation method known as CLARITY, which Chung developed as a postdoc at Stanford University. CLARITY preserves cells and molecules in brain tissue and makes them transparent so the molecules inside the cell can be imaged in 3-D. In the new study, Chung sought a way to image the brain at multiple scales, within the same tissue sample.*
There are hundreds of thousands of commercially available antibodies that can be used to fluorescently tag specific proteins. In this study, the researchers imaged neuronal structures such as axons and synapses by labeling proteins found in those structures, and they also labeled proteins that allow them to distinguish neurons from glial cells.
“We can use these antibodies to visualize any target structures or molecules,” Chung says. “We can visualize different neuron types and their projections to see their connectivity. We can also visualize signaling molecules or functionally important proteins.”
High resolution
Once the tissue is expanded, the researchers can use any of several common microscopes to obtain images with a resolution as high as 60 nanometers — much better than the usual 200 to 250-nanometer limit of light microscopes, which are constrained by the wavelength of visible light. The researchers also demonstrated that this approach works with relatively large tissue samples, up to 2 millimeters thick.
“This is, as far as I know, the first demonstration of super-resolution proteomic imaging of millimeter-scale samples,” Chung says.
“This is an exciting advance for brain mapping, a technique that reveals the molecular and connectional architecture of the brain with unprecedented detail,” says Seung, a professor of computer science at the Princeton Neuroscience Institute, who was not involved in the research.
Currently, efforts to map the connections of the human brain rely on electron microscopy, but Chung and colleagues demonstrated that the higher-resolution MAP imaging technique can trace those connections more accurately.
Chung’s lab is now working on speeding up the imaging and the image processing, which is challenging because there is so much data generated from imaging the expanded tissue samples. “It’s already easier than other techniques because the process is really simple and you can use off-the-shelf molecular markers, but we are trying to make it even simpler,” Chung says.
* To achieve that, the researchers developed a method to reversibly expand tissue samples in a way that preserves nearly all of the proteins within the cells. Those proteins can then be labeled with fluorescent molecules and imaged.
The technique relies on flooding the brain tissue with acrylamide polymers, which can form a dense gel. In this case, the gel is 10 times denser than the one used for the CLARITY technique, which gives the sample much more stability. This stability allows the researchers to denature and dissociate the proteins inside the cells without destroying the structural integrity of the tissue sample.
Before denaturing the proteins, the researchers attach them to the gel using formaldehyde, as Chung did in the CLARITY method. Once the proteins are attached and denatured, the gel expands the tissue sample to four or five times its original size.
“It is reversible and you can do it many times,” Chung says. “You can then use off-the-shelf molecular markers like antibodies to label and visualize the distribution of all these preserved biomolecules.”
Melanie Gonick/MIT | MIT researchers have developed a new technique for imaging brain tissue at multiple scales, allowing them to peer at molecules within cells or take a wider view of the long-range connections between neurons.
More on this News Release
Imaging the brain at multiple size scales
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
JOURNAL
Nature Biotechnology
Abstract of Multiplexed and scalable super-resolution imaging of three-dimensional protein localization in size-adjustable tissues
The biology of multicellular organisms is coordinated across multiple size scales, from the subnanoscale of molecules to the macroscale, tissue-wide interconnectivity of cell populations. Here we introduce a method for super-resolution imaging of the multiscale organization of intact tissues. The method, called magnified analysis of the proteome (MAP), linearly expands entire organs fourfold while preserving their overall architecture and three-dimensional proteome organization. MAP is based on the observation that preventing crosslinking within and between endogenous proteins during hydrogel-tissue hybridization allows for natural expansion upon protein denaturation and dissociation. The expanded tissue preserves its protein content, its fine subcellular details, and its organ-scale intercellular connectivity. We use off-the-shelf antibodies for multiple rounds of immunolabeling and imaging of a tissue’s magnified proteome, and our experiments demonstrate a success rate of 82% (100/122 antibodies tested). We show that specimen size can be reversibly modulated to image both inter-regional connections and fine synaptic architectures in the mouse brain.
“Do-it-yourself” users of transcranial direct current stimulation (tDCS) seeking cognitive enhancement are exposing themselves to hidden risks, neuroscientists warn in an open-access Open Letter in the journal Annals of Neurology.
tDCS devices are made up of a band that wraps around one’s head with electrodes placed at specific scalp locations to target specific brain regions. The devices transmit varying levels of electrical current to the brain to achieve the desired result, such as an enhanced state of relaxation, energy, focus, creativity, or a variety of other goals.
Cognitive neuroscience research suggests that tDCS can enhance cognition, and relieve symptoms of anxiety, depression, and other conditions. “Published results of these studies might lead DIY tDCS users to believe that they can achieve the same results if they mimic the way stimulation is delivered in research studies. However, there are many reasons why this simply isn’t true,” said first author, Rachel Wurzman, PhD, a postdoctoral research fellow in the Laboratory for Cognition and Neural Stimulation at Perelman School of Medicine at the University of Pennsylvania.
“It is important for people to understand why outcomes of tDCS can be unpredictable, because we know that in some cases, the benefits that are seen after tDCS in certain mental abilities may come at the expense of others.”
The “Open Letter” is signed by 39 researchers who share this sentiment, representing an unprecedented consensus among tDCS experts. “Given the possibility that the improper use of our articles might cause harm, as a community we felt it necessary — an ethical obligation — to explain in a peer-reviewed journal why it is that we generally do not encourage do-it-yourself use of tDCS,” she said.
tDCS risks
Among the concerns explained in the paper:
It is not yet known whether stimulation extends beyond the specific brain regions targeted. These indirect effects may alter unintended brain functions. Stimulating one region could improve one’s ability to perform one task but hurt the ability to perform another.
What a person is doing during tDCS — reading a book, watching TV, sleeping — can change its effects. Which activity is best to achieve a certain change in brain function is not yet known.
The researchers have never performed tDCS at the frequency levels some home users experiment with, such as stimulating daily for months or longer. “We know that stimulation from a few sessions can be quite lasting, but we do not yet know the possible risks of a larger cumulative dose over several years or a lifetime,” they wrote.
Small changes in tDCS settings, including the current’s amplitude, stimulation duration and electrode placement, can have large and unexpected effects; more stimulation is not necessarily better.
The effects of tDCS vary across different people. Up to 30 percent of experimental subjects respond with changes in brain excitability in the opposite direction from other subjects using identical tDCS settings. Factors such as gender, handedness, hormones, medication, etc. could impact and potentially reverse a given tDCS effect.
Most research is conducted for the purpose of treating disease, with the goal of alleviating symptoms, with a detailed disclosure or risks as required of studies of human research subjects. The level of risk is quite different for healthy subjects performing tDCS at home.
The two companies plan to expand drone delivery tests in Reno and expect drone packages to include “everyday essentials” such as batteries and sunscreen in the future, according to 7‑Eleven EVP Jesus H. Delgado-Jenkins.
Flirtey previously conducted the first FAA-approved drone delivery last July, a series of urgent medical deliveries to a rural healthcare clinic. The company also completed the first fully autonomous, FAA-approved urban drone delivery in the U.S. on March 25 to an uninhabited residential setting in Hawthorne, Nevada. The package included bottled water, emergency food, and a first aid kit.
And in June, Flirtey performed the first drone delivery of stool, blood, and urine samples from land to a medical testing facility on a barge in New Jersey’s Delaware Bay. Johns Hopkins University researchers on the barge sent back water purification tablets, insulin and a First Aid kit back to shore.
Amazon Prime Air testing moves to the UK
Amazon Prime Air’s new drone design, now being tested in the UK (credit: Amazon)
Meanwhile, hampered by the FAA’s strict new requirement* that commercially operated drones must fly within the operator’s line of sight at all times, on Monday July 25, Amazon.com Inc. announced plans for a partnership with the UK Government to make the delivery of parcels (up to 5 pounds to customers in 30 minutes or less) by Amazon’s planned Prime Air delivery service a reality.
Supported by the UK Civil Aviation Authority (CAA), Amazon now has UK permissions to “explore beyond line of sight operations in rural and suburban areas, test sensor performance to make sure the drones can identify and avoid obstacles, and [for] flights where one person operates multiple highly-automated drones.”
* According to an FAA announcement June 21 of the first operational rules for “unmanned aircraft drones weighing less than 55 pounds that are conducting non-hobbyist operations … pilots must “keep an unmanned aircraft within visual line of sight. Operations are allowed during daylight and during twilight if the drone has anti-collision lights. The new regulations also address height and speed restrictions and other operational limits, such as prohibiting flights over unprotected people on the ground who aren’t directly participating in the UAS operation.”
The FAA notes that “according to industry estimates, the [new] rule could generate more than $82 billion for the U.S. economy and create more than 100,000 new jobs over the next 10 years.”
Flirity | Flirtey making history with the first U.S. drone delivery (demo)
The flash-drive-sized device contains two layers of human cells that model the interface between mother and fetus. Microfluidic channels on both sides of those layers allow researchers to study how molecules are transported through, or are blocked by, that interface. (credit: University of Pennsylvania)
Researchers at the University of Pennsylvania have developed the first placenta-on-a-chip that can fully model the transport of nutrients across the placental barrier — part of a nationwide effort sponsored by the March of Dimes to identify causes of preterm birth and ways to prevent it.
Prematurely born babies may experience lifelong, debilitating consequences, but the underlying mechanisms of this condition are not well understood due in part to the difficulties of experimenting with intact, living human placentae.
Like other organs-on-chips, such as ones developed to simulate lungs, intestines, and eyes, the placenta-on-a-chip provides a unique capability to mimic and study the function of that human organ in ways that have not been possible using traditional tools, which are limited by complexity, the scarcity of samples, and the limited lifespan of how long the tissue remains viable (for only a few hours after delivery), according to the researchers.
Modeling the vital placental barrier
The flash-drive-sized device contains two layers of human cells that model the interface between mother and fetus. Microfluidic channels on either side of those layers allow researchers to study how molecules are transported through, or are blocked by, that interface.
(A) Schematic of a human fetus and placenta within the uterine cavity. (B) Cross-sectional view of the placenta showing villi (vascular projections that increase the surface area of a membrane) in direct contact with maternal blood in (C),where the maternal intervillous space is separated from the fetal capillary by the maternal–fetal interface, which is composed of the syncytiotrophoblast, basal lamina, and villous endothelial cells. (D) 3-D microarchitecture of the placental barrier reconstituted within the placenta-on-a-chip, which consists of upper and lower microchannels separated by a thin, semipermeable membrane. Trophoblast cells are cultured in the upper microchannel layer and villous endothelial cells are grown in the lower microchannel layer. (credit: Cassidy Blundell et al./Lab on a Chip)
The researchers’ placenta-on-a-chip is a clear silicone device with two parallel microfluidic channels separated by a porous membrane. On one side of those pores, trophoblast cells, which are found at the placental interface with maternal blood, are grown. On the other side are endothelial cells, found on the interior of fetal blood vessels.
The layers of those two cell types mimic the placental barrier, the gatekeeper (or filter) that controls flow between the maternal and fetal circulatory systems, including nutrients that must pass, but also foreign agents like viruses that must be blocked.
A concentration gradient of glucose (green dots) is generated across the microengineered placental barrier to drive glucose transport from the maternal to fetal compartments. (credit: Cassidy Blundell et al./Lab on a Chip)
In their new study, the Penn researchers have demonstrated that the two layers of cells continue to grow and develop while inside the chip, undergoing a process known as “syncytialization.”
“The placental cells change over the course of pregnancy,” explained Dan Huh, the Wilf Family Term Assistant Professor of Bioengineering in Penn’s School of Engineering and Applied Science. “During pregnancy, the placental trophoblast cells actually fuse with one another to form an interesting tissue called syncytium. The barrier also becomes thinner as the pregnancy progresses, and with our new model we’re able to reproduce this change.
“This process is very important because it affects placental transport and was a critical aspect not represented in our previous model.”
The Penn team validated the new model by showing glucose transfer rates across this syncytialized barrier matched those measured in perfusion studies of donated human placentae.
“The placenta is arguably the least understood organ in the human body,” Huh said, “and much remains to be learned about how transport between mother and fetus works at the tissue, cellular and molecular levels. An isolated whole organ is an not ideal platform for these types of mechanistic studies.”
Studies of preterm birth
While the placenta-on-a-chip is still in the early stages of testing, researchers at Penn and beyond are already planning to use it in studies on preterm birth. The rate of preterm birth is still about 10 to 11 percent of all pregnancies.
“Eventually,” Huh said, “we hope to leverage the unique capabilities of our model to demonstrate the potential of organ-on-a-chip technology as a new strategy to innovate basic and translational research in reproductive biology and medicine.”
Abstract of A microphysiological model of the human placental barrier
During human pregnancy, the fetal circulation is separated from maternal blood in the placenta by two cell layers – the fetal capillary endothelium and placental trophoblast. This placental barrier plays an essential role in fetal development and health by tightly regulating the exchange of endogenous and exogenous materials between the mother and the fetus. Here we present a microengineered device that provides a novel platform to mimic the structural and functional complexity of this specialized tissue in vitro. Our model is created in a multilayered microfluidic system that enables co-culture of human trophoblast cells and human fetal endothelial cells in a physiologically relevant spatial arrangement to replicate the characteristic architecture of the human placental barrier. We have engineered this co-culture model to induce progressive fusion of trophoblast cells and to form a syncytialized epithelium that resembles the syncytiotrophoblast in vivo. Our system also allows the cultured trophoblasts to form dense microvilli under dynamic flow conditions and to reconstitute expression and physiological localization of membrane transport proteins, such as glucose transporters (GLUTs), critical to the barrier function of the placenta. To provide a proof-of-principle for using this microdevice to recapitulate native function of the placental barrier, we demonstrated physiological transport of glucose across the microengineered maternal–fetal interface. Importantly, the rate of maternal-to-fetal glucose transfer in this system closely approximated that measured in ex vivo perfused human placentas. Our “placenta-on-a-chip” platform represents an important advance in the development of new technologies to model and study the physiological complexity of the human placenta for a wide variety of applications.
His group published their latest findings online June 24, 2016, in the Journal of Neuroimmune Pharmacology.
“The increase in learning in poor-learning mice after cinnamon treatment was significant,” says Pahan. “For example, poor-learning mice took about 150 seconds to find the right hole in the Barnes maze test. On the other hand, after one month of cinnamon treatment, poor-learning mice were finding the right hole within 60 seconds.”
Acts as slow-release form of sodium benzoate
Pahan’s research shows that the effect appears to be due mainly to sodium benzoate, a chemical produced as cinnamon is broken down in the body. Food makers use a synthetic form of it as a preservative. It is also an FDA-approved drug used to treat hyperammonemia — too much ammonia in the blood.
Though some health concerns exist regarding sodium benzoate, most experts agree it’s perfectly safe in the amounts generally consumed. One reassuring point is that it’s water-soluble and easily excreted in the urine.
Cinnamon acts as a slow-release form of sodium benzoate, says Pahan. His lab studies show that different compounds within cinnamon—including cinnamaldehyde, which gives the spice is distinctive flavor and aroma—are “metabolized into sodium benzoate in the liver. Sodium benzoate then becomes the active compound, which readily enters the brain and stimulates hippocampal plasticity.”
Those changes in the hippocampus—the brain’s main memory center—appear to be the mechanism by which cinnamon and sodium benzoate exert their benefits.
In their study, Pahan’s group first tested mice in mazes to separate the good and poor learners. Good learners made fewer wrong turns and took less time to find food. In analyzing baseline disparities between the good and poor learners, Pahan’s team found differences in two brain proteins. The gap was all but erased when cinnamon was given.
“Little is known about the changes that occur in the brains of poor learners,” says Pahan. “We saw increases in GABRA5 and a decrease in CREB in the hippocampus of poor learners. Interestingly, these particular changes were reversed by one month of cinnamon treatment.”
The researchers also examined brain cells taken from the mice. They found that sodium benzoate enhanced the structural integrity of the dendrites, the tree-like extensions of neurons that enable them to communicate with other brain cells.
High-quality clinical evidence on cinnamon is limited
Cinnamon, like many spices, has antioxidant and anti-inflammatory properties. So it could be expected to exert a range of health-boosting actions, and it does have a centuries-long history of medicinal use around the world.
But the U.S. National Center for Complementary and Integrative Health says that “high-quality clinical evidence to support the use of cinnamon for any medical condition is generally lacking.” Most of the clinical trials that have taken place have focused on the spice’s possible effect on blood sugar for people with diabetes. Little if any clinical research has been done on the spice’s possible brain-boosting properties.
Pahan hopes to change that. Based on the promising results from his group’s preclinical studies, he believes that “besides general memory improvement, cinnamon may target Alzheimer’s disease, mild cognitive impairment [a precursor to Alzheimer's], and Parkinson’s disease as well.” He is now talking with neurologists about planning a clinical trial on Alzheimer’s.
But Pahan warns that most cinnamon found in the store is the Chinese variety, which contains a compound called coumarin that may be toxic to the liver in high amounts. A person would likely have to eat tons of cinnamon to run into a problem, but just the same, Pahan recommends the Ceylon or Sri Lanka type, which is coumarin-free.
“Simply smelling the spice may not help because cinnamaldehyde should be metabolized into cinnamic acid and then sodium benzoate,” explains Pahan. “For metabolism [to occur], cinnamaldehyde should be within the cell.”
As for himself, Pahan isn’t waiting for clinical trials. He takes about a teaspoonful—about 3.5 grams—of cinnamon powder mixed with honey as a supplement every night.
Should the research on cinnamon continue to move forward, he envisions a similar remedy being adopted by struggling students worldwide.
Pahan’s study was funded by VA, the National Institutes of Health, and the Alzheimer’s Association.
Abstract of Cinnamon Converts Poor Learning Mice to Good Learners: Implications for Memory Improvement
This study underlines the importance of cinnamon, a commonly used natural spice and flavoring material, and its metabolite sodium benzoate (NaB) in converting poor learning mice to good learning ones. NaB, but not sodium formate, was found to upregulate plasticity-related molecules, stimulate NMDA- and AMPA-sensitive calcium influx and increase of spine density in cultured hippocampal neurons. NaB induced the activation of CREB in hippocampal neurons via protein kinase A (PKA), which was responsible for the upregulation of plasticity-related molecules. Finally, spatial memory consolidation-induced activation of CREB and expression of different plasticity-related molecules were less in the hippocampus of poor learning mice as compared to good learning ones. However, oral treatment of cinnamon and NaB increased spatial memory consolidation-induced activation of CREB and expression of plasticity-related molecules in the hippocampus of poor-learning mice and converted poor learners into good learners. These results describe a novel property of cinnamon in switching poor learners to good learners via stimulating hippocampal plasticity.
His group published their latest findings online June 24, 2016, in the Journal of Neuroimmune Pharmacology.
“The increase in learning in poor-learning mice after cinnamon treatment was significant,” says Pahan. “For example, poor-learning mice took about 150 seconds to find the right hole in the Barnes maze test. On the other hand, after one month of cinnamon treatment, poor-learning mice were finding the right hole within 60 seconds.”
Acts as slow-release form of sodium benzoate
Pahan’s research shows that the effect appears to be due mainly to sodium benzoate, a chemical produced as cinnamon is broken down in the body. Food makers use a synthetic form of it as a preservative. It is also an FDA-approved drug used to treat hyperammonemia — too much ammonia in the blood.
Though some health concerns exist regarding sodium benzoate, most experts agree it’s perfectly safe in the amounts generally consumed. One reassuring point is that it’s water-soluble and easily excreted in the urine.
Cinnamon acts as a slow-release form of sodium benzoate, says Pahan. His lab studies show that different compounds within cinnamon—including cinnamaldehyde, which gives the spice is distinctive flavor and aroma—are “metabolized into sodium benzoate in the liver. Sodium benzoate then becomes the active compound, which readily enters the brain and stimulates hippocampal plasticity.”
Those changes in the hippocampus—the brain’s main memory center—appear to be the mechanism by which cinnamon and sodium benzoate exert their benefits.
In their study, Pahan’s group first tested mice in mazes to separate the good and poor learners. Good learners made fewer wrong turns and took less time to find food. In analyzing baseline disparities between the good and poor learners, Pahan’s team found differences in two brain proteins. The gap was all but erased when cinnamon was given.
“Little is known about the changes that occur in the brains of poor learners,” says Pahan. “We saw increases in GABRA5 and a decrease in CREB in the hippocampus of poor learners. Interestingly, these particular changes were reversed by one month of cinnamon treatment.”
The researchers also examined brain cells taken from the mice. They found that sodium benzoate enhanced the structural integrity of the dendrites, the tree-like extensions of neurons that enable them to communicate with other brain cells.
High-quality clinical evidence on cinnamon is limited
Cinnamon, like many spices, has antioxidant and anti-inflammatory properties. So it could be expected to exert a range of health-boosting actions, and it does have a centuries-long history of medicinal use around the world.
But the U.S. National Center for Complementary and Integrative Health says that “high-quality clinical evidence to support the use of cinnamon for any medical condition is generally lacking.” Most of the clinical trials that have taken place have focused on the spice’s possible effect on blood sugar for people with diabetes. Little if any clinical research has been done on the spice’s possible brain-boosting properties.
Pahan hopes to change that. Based on the promising results from his group’s preclinical studies, he believes that “besides general memory improvement, cinnamon may target Alzheimer’s disease, mild cognitive impairment [a precursor to Alzheimer's], and Parkinson’s disease as well.” He is now talking with neurologists about planning a clinical trial on Alzheimer’s.
But Pahan warns that most cinnamon found in the store is the Chinese variety, which contains a compound called coumarin that may be toxic to the liver in high amounts. A person would likely have to eat tons of cinnamon to run into a problem, but just the same, Pahan recommends the Ceylon or Sri Lanka type, which is coumarin-free.
“Simply smelling the spice may not help because cinnamaldehyde should be metabolized into cinnamic acid and then sodium benzoate,” explains Pahan. “For metabolism [to occur], cinnamaldehyde should be within the cell.”
As for himself, Pahan isn’t waiting for clinical trials. He takes about a teaspoonful—about 3.5 grams—of cinnamon powder mixed with honey as a supplement every night.
Should the research on cinnamon continue to move forward, he envisions a similar remedy being adopted by struggling students worldwide.
Pahan’s study was funded by VA, the National Institutes of Health, and the Alzheimer’s Association.
Abstract of Cinnamon Converts Poor Learning Mice to Good Learners: Implications for Memory Improvement
This study underlines the importance of cinnamon, a commonly used natural spice and flavoring material, and its metabolite sodium benzoate (NaB) in converting poor learning mice to good learning ones. NaB, but not sodium formate, was found to upregulate plasticity-related molecules, stimulate NMDA- and AMPA-sensitive calcium influx and increase of spine density in cultured hippocampal neurons. NaB induced the activation of CREB in hippocampal neurons via protein kinase A (PKA), which was responsible for the upregulation of plasticity-related molecules. Finally, spatial memory consolidation-induced activation of CREB and expression of different plasticity-related molecules were less in the hippocampus of poor learning mice as compared to good learning ones. However, oral treatment of cinnamon and NaB increased spatial memory consolidation-induced activation of CREB and expression of plasticity-related molecules in the hippocampus of poor-learning mice and converted poor learners into good learners. These results describe a novel property of cinnamon in switching poor learners to good learners via stimulating hippocampal plasticity.
