Amazon’s first Amazon Go store opened today in Seattle, automating most of the purchase, checkout, and payment steps associated with a retail transaction and replacing cash registers, cashiers, credit cards, self-checkout kiosks, RFID chips — and lines — with hundreds of small cameras, computer vision, deep-learning algorithms, and sensor fusion.
Just walk in (as long as you have the Amazon Go app and an Amazon.com account), scan a QR code at the turnstile, grab, and go.
Meanwhile, the shutdown of the dysfunctional U.S. government continues.* Hmm, what if we created Government Go?
If you visit the store (2131 7th Ave — 7 a.m. to 9 p.m. PT Monday to Friday), let us know about your experience and thoughts in the comments below.
* January 22 at 6:11 PM EST: House votes to end government shutdown, sending legislation to Trump — Washington Post
German researchers created a 55-nm-by-55-nm DNA-based molecular platform with a 25-nm-long robotic arm that can be actuated with externally applied electrical fields, under computer control. (credit: Enzo Kopperger et al./Science)
By powering a self-assembling DNA nanorobotic arm with electric fields, German scientists have achieved precise nanoscale movement that is at least five orders of magnitude (hundreds of thousands times) faster than previously reported DNA-driven robotic systems, they suggest today (Jan. 19) in the journal Science.
DNA origami has emerged as a powerful tool to build precise structures. But now, “Kopperger et al. make an impressive stride in this direction by creating a dynamic DNA origami structure that they can directly control from the macroscale with easily tunable electric fields—similar to a remote-controlled robot,” notes Björn Högberg of Karolinska Institutet in a related Perspective in Science, (p. 279).
The nanorobotic arm resembles the gearshift lever of a car. Controlled by an electric field (comparable to the car driver), short, single-stranded DNA serves as “latches” (yellow) to momentarily grab and lock the 25-nanometer-long arm into predefined “gear” positions. (credit: Enzo Kopperger et al./Science)
The new biohybrid nanorobotic systems could even act as a molecular mechanical memory (a sort of nanoscale version of the Babbage Analytical Engine), he notes. “With the capability to form long filaments with multiple DNA robot arms, the systems could also serve as a platform for new inventions in digital memory, nanoscale cargo transfer, and 3D printing of molecules.”
“The robot-arm system may be scaled up and integrated into larger hybrid systems by a combination of lithographic and self-assembly techniques,” according to the researchers. “Electrically clocked synthesis of molecules with a large number of robot arms in parallel could then be the first step toward the realization of a genuine nanorobotic production factory.”
Taking a different approach to a nanofactory, this “Productive Nanosystems: from Molecules to Superproducts” film — a collaborative project of animator and engineer John Burch and pioneer nanotechnologist K. Eric Drexler in 2005 — demonstrated key steps in a hypothetical process that converts simple molecules into a billion-CPU laptop computer. More here.
Abstract of A self-assembled nanoscale robotic arm controlled by electric fields
The use of dynamic, self-assembled DNA nanostructures in the context of nanorobotics requires fast and reliable actuation mechanisms. We therefore created a 55-nanometer–by–55-nanometer DNA-based molecular platform with an integrated robotic arm of length 25 nanometers, which can be extended to more than 400 nanometers and actuated with externally applied electrical fields. Precise, computer-controlled switching of the arm between arbitrary positions on the platform can be achieved within milliseconds, as demonstrated with single-pair Förster resonance energy transfer experiments and fluorescence microscopy. The arm can be used for electrically driven transport of molecules or nanoparticles over tens of nanometers, which is useful for the control of photonic and plasmonic processes. Application of piconewton forces by the robot arm is demonstrated in force-induced DNA duplex melting experiments.
Repeating a word: as the brain receives (yellow), interpretes (red), and responds (blue) within a second, the prefrontal cortex (red) coordinates all areas of the brain involved. (video credit: Avgusta Shestyuk/UC Berkeley).
Recording the electrical activity of neurons directly from the surface of the brain, using electrocorticograhy (ECoG)*, neuroscientists were able to track the flow of thought across the brain in real time for the first time. They showed clearly how the prefrontal cortex at the front of the brain coordinates activity to help us act in response to a perception.
Here’s what they found.
For a simple task, such as repeating a word seen or heard:
The visual and auditory cortices react first to perceive the word. The prefrontal cortex then kicks in to interpret the meaning, followed by activation of the motor cortex (preparing for a response). During the half-second between stimulus and response, the prefrontal cortex remains active to coordinate all the other brain areas.
For a particularly hard task, like determining the antonym of a word:
During the time the brain takes several seconds to respond, the prefrontal cortex recruits other areas of the brain — probably including memory networks (not tracked). The prefrontal cortex then hands off to the motor cortex to generate a spoken response.
In both cases, the brain begins to prepare the motor areas to respond very early (during initial stimulus presentation) — suggesting that we get ready to respond even before we know what the response will be.
“This might explain why people sometimes say things before they think,” said Avgusta Shestyuk, a senior researcher in UC Berkeley’s Helen Wills Neuroscience Institute and lead author of a paper reporting the results in the current issue of Nature Human Behavior.
For a more difficult task, like saying a word that is the opposite of another word, people’s brains required 2–3 seconds to detect (yellow), interpret and search for an answer (red), and respond (blue) — with sustained prefrontal lobe activity (red) coordinating all areas of the brain involved. (video credit: Avgusta Shestyuk/UC Berkeley).
The research backs up what neuroscientists have pieced together over the past decades from studies in monkeys and humans.
“These very selective studies have found that the frontal cortex is the orchestrator, linking things together for a final output,” said co-author Robert Knight, a UC Berkeley professor of psychology and neuroscience and a professor of neurology and neurosurgery at UCSF. “Here we have eight different experiments, some where the patients have to talk and others where they have to push a button, where some are visual and others auditory, and all found a universal signature of activity centered in the prefrontal lobe that links perception and action. It’s the glue of cognition.”
Researchers at Johns Hopkins University, California Pacific Medical Center, and Stanford University were also involved. The work was supported by the National Science Foundation, National Institute of Mental Health, and National Institute of Neurological Disorders and Stroke.
* Other neuroscientists have used functional magnetic resonance imaging (fMRI) and electroencephelography (EEG) to record activity in the thinking brain. The UC Berkeley scientists instead employed a much more precise technique, electrocorticograhy (ECoG), which records from several hundred electrodes placed on the brain surface and detects activity in the thin outer region, the cortex, where thinking occurs. ECoG provides better time resolution than fMRI and better spatial resolution than EEG, but requires access to epilepsy patients undergoing highly invasive surgery involving opening the skull to pinpoint the location of seizures. The new study employed 16 epilepsy patients who agreed to participate in experiments while undergoing epilepsy surgery at UC San Francisco and California Pacific Medical Center in San Francisco, Stanford University in Palo Alto and Johns Hopkins University in Baltimore. Once the electrodes were placed on the brains of each patient, the researchers conducted a series of eight tasks that included visual and auditory stimuli. The tasks ranged from simple, such as repeating a word or identifying the gender of a face or a voice, to complex, such as determining a facial emotion, uttering the antonym of a word, or assessing whether an adjective describes the patient’s personality.
Abstract of Persistent neuronal activity in human prefrontal cortex links perception and action
How do humans flexibly respond to changing environmental demands on a subsecond temporal scale? Extensive research has highlighted the key role of the prefrontal cortex in flexible decision-making and adaptive behaviour, yet the core mechanisms that translate sensory information into behaviour remain undefined. Using direct human cortical recordings, we investigated the temporal and spatial evolution of neuronal activity (indexed by the broadband gamma signal) in 16 participants while they performed a broad range of self-paced cognitive tasks. Here we describe a robust domain- and modality-independent pattern of persistent stimulus-to-response neural activation that encodes stimulus features and predicts motor output on a trial-by-trial basis with near-perfect accuracy. Observed across a distributed network of brain areas, this persistent neural activation is centred in the prefrontal cortex and is required for successful response implementation, providing a functional substrate for domain-general transformation of perception into action, critical for flexible behaviour.
Microsoft has developed a deep neural network that scored higher than humans on exact scores in a Stanford University reading and comprehension test Stanford Question Answering Dataset (SQuAD).
Microsoft achieved 82.650 on Jan. 3; Alibaba Group Holding Ltd. came in at second place at 82.440 on Jan. 5. The best human score so far is 82.304.
“SQuAD is a new reading comprehension dataset, consisting of questions posed by crowdworkers on a set of Wikipedia articles, where the answer to every question is a segment of text, or span, from the corresponding reading passage,” according to the Stanford NLP Group. “With 100,000+ question-answer pairs on 500+ articles, SQuAD is significantly larger than previous reading comprehension datasets.”
“The Chinese e-commerce titan has joined the likes of Tencent Holdings Ltd. and Baidu Inc. in a race to develop AI that can enrich social media feeds, target ads and services or even aid in autonomous driving, Bloomberg notes. “Beijing has endorsed the technology in a national-level plan that calls for the country to become the industry leader 2030.”
Microsoft and Alibaba have developed deep neural network models that scored higher than humans in a Stanford University reading and comprehension test, Stanford Question Answering Dataset (SQuAD).
Microsoft achieved 82.650 on the ExactMatch (EM) metric* on Jan. 3, and Alibaba Group Holding Ltd. scored 82.440 on Jan. 5. The best human score so far is 82.304.
“SQuAD is a new reading comprehension dataset, consisting of questions posed by crowdworkers on a set of Wikipedia articles, where the answer to every question is a segment of text, or span, from the corresponding reading passage,” according to the Stanford NLP Group. “With 100,000+ question-answer pairs on 500+ articles, SQuAD is significantly larger than previous reading comprehension datasets.”
However, challenging the “comprehension” description, Gary Marcus, PhD, a Professor of Psychology and Neural Science at NYU, notes in a tweet that “the SQUAD test shows that machines can highlight relevant passages in text, not that they understand those passages.”
“The Chinese e-commerce titan has joined the likes of Tencent Holdings Ltd. and Baidu Inc. in a race to develop AI that can enrich social media feeds, target ads and services or even aid in autonomous driving, Bloomberg notes. “Beijing has endorsed the technology in a national-level plan that calls for the country to become the industry leader 2030.”
*”The ExactMatch metric measures the percentage of predictions that match any one of the ground truth answers exactly. The F1 score metric measures the average overlap between the prediction and ground truth answer.” – Pranav Rajpurkar et al., ArXiv
Nanoengineered electroporation microelectrodes (NEMs) allow for improved current distribution and electroporation effectiveness by reducing peak voltage regions (to avoid damaging tissue). (left) Cross-section of NEM model, illustrating the total effective electroporation volume and its distribution of the voltage around the pipette tip, at a safe current of 50 microamperes. (Scale bar = 5 micrometers.) (right) A five-hole NEM after successful insertion into brain tissue, imaged with high-resolution focused ion beam (FIB). (Scale bar = 2 micrometers) (credit: D. Schwartz et al./Nature Communications)
Neuroscientists at the Francis Crick Institute have developed a new technique to map electrical microcircuits* in the brain at far more detail than existing techniques*, which are limited to tiny sections of the brain (or remain confined to simpler model organisms, like zebrafish).
In the brain, groups of neurons that connect up in microcircuits help us process information about things we see, smell and taste. Knowing how many neurons and other types of cells make up these microcircuits would give scientists a deeper understanding of how the brain computes complex information.
Nanoengineered microelectrodes
The researchers developed a new design called “nanoengineered electroporation** microelectrodes” (NEMs). They were able to use an NEM to map out all 250 cells that make up a specific microcircuit in a part of a mouse brain that processes smell (known as the “olfactory bulb glomerulus”) in a horizontal slice of the olfactory bulb — something never before achieved.
To do that, the team created a series of tiny pores (holes) near the end of a micropipette using nano-engineering tools. The new design distributes the electrical current uniformly over a wider area (up to a radius of about 50 micrometers — the size of a typical neural microcircuit), with minimal cell damage.
The researchers tested the NEM technique with a specific microcircuit, the olfactory bulb glomerulus (which detects smells). They were able to identify detailed, long-range, complex anatomical features (scale bar = 100 micrometers). (White arrows identify parallel staining of vascular structures.) (credit: D. Schwartz et al./Nature Communications)
Seeing 100% of the cells in a brain microcircuit for the first time
Unlike current methods, the team was able to stain up to 100% of the cells in the microcircuit they were investigating, according to Andreas Schaefer, who led the research, which was published in open-access Nature Communications today (Jan. 12, 2018).
“As the brain is made up of repeating units, we can learn a lot about how the brain works as a computational machine by studying it at this [microscopic] level,” he said. “Now that we have a tool of mapping these tiny units, we can start to interfere with specific cell types to see how they directly control behavior and sensory processing.”
The work was conducted in collaboration with researchers at the Max-Planck-Institute for Medical Research in Heidelberg, Heidelberg University, Heidelberg University Hospital, University College London, the MRC National Institute for Medical Research, and Columbia University Medical Center.
* Scientists currently use color-tagged viruses or charged dyes with applied electroporation current to stain brain cells. These methods, using a glass capillary with a single hole,are limited to low current (higher current could damage tissue), so they can only allow for identifying a limited area of a microcircuit.
** Electroporation is a microbiology technique that applies an electrical field to cells to increase the permeability (ease of penetration) of the cell membrane, allowing (in this case) fluorophores (fluorescent, or glowing dyes) to penetrate into the cells to label (identify parts of) the neural microcircuits (including the “inputs” and “outputs”) under a microscope.
Abstract of Architecture of a mammalian glomerular domain revealed by novel volume electroporation using nanoengineered microelectrodes
Dense microcircuit reconstruction techniques have begun to provide ultrafine insight into the architecture of small-scale networks. However, identifying the totality of cells belonging to such neuronal modules, the “inputs” and “outputs,” remains a major challenge. Here, we present the development of nanoengineered electroporation microelectrodes (NEMs) for comprehensive manipulation of a substantial volume of neuronal tissue. Combining finite element modeling and focused ion beam milling, NEMs permit substantially higher stimulation intensities compared to conventional glass capillaries, allowing for larger volumes configurable to the geometry of the target circuit. We apply NEMs to achieve near-complete labeling of the neuronal network associated with a genetically identified olfactory glomerulus. This allows us to detect sparse higher-order features of the wiring architecture that are inaccessible to statistical labeling approaches. Thus, NEM labeling provides crucial complementary information to dense circuit reconstruction techniques. Relying solely on targeting an electrode to the region of interest and passive biophysical properties largely common across cell types, this can easily be employed anywhere in the CNS.
A cross section of a muscle fiber grown from induced pluripotent stem cells, showing muscle cells (green), cell nuclei (blue), and the surrounding support matrix for the cells (credit: Duke University)
Biomedical engineers at Duke University have grown the first functioning human skeletal muscle from human induced pluripotent stem cells (iPSCs). (Pluripotent stem cells are important in regenerative medicine because they can generate any type of cell in the body and can propagate indefinitely; the induced version can be generated from adult cells instead of embryos.)
The engineers say the new technique is promising for cellular therapies, drug discovery, and studying rare diseases. “When a child’s muscles are already withering away from something like Duchenne muscular dystrophy, it would not be ethical to take muscle samples from them and do further damage,” explained Nenad Bursac, professor of biomedical engineering at Duke University and senior author of an open-access paper on the research published Tuesday, January 9, in Nature Communications.
How to grow a muscle
In the study, the researchers started with human induced pluripotent stem cells. These are cells taken from adult non-muscle tissues, such as skin or blood, and reprogrammed to revert to a primordial state. The pluripotent stem cells are then grown while being flooded with a molecule called Pax7 — which signals the cells to start becoming muscle.
After two to four weeks of 3-D culture, the resulting muscle cells form muscle fibers that contract and react to external stimuli such as electrical pulses and biochemical signals — mimicking neuronal inputs just like native muscle tissue. The researchers also implanted the newly grown muscle fibers into adult mice. The muscles survived and functions for at least three weeks, while progressively integrating into the native tissue through vascularization (growing blood vessels).
A stained cross section of the new muscle fibers, showing muscle cells (red), receptors for neuronal input (green), and cell nuclei (blue) (credit: Duke University)
Once the cells were well on their way to becoming muscle, the researchers stopped providing the Pax7 signaling molecule and started giving the cells the support and nourishment they needed to fully mature. (At this point in the research, the resulting muscle is not as strong as native muscle tissue, and also falls short of the muscle grown in a previous study*, which started from muscle biopsies.)
However, the pluripotent stem cell-derived muscle fibers develop reservoirs of “satellite-like cells” that are necessary for normal adult muscles to repair damage, while the muscle from the previous study had much fewer of these cells. The stem cell method is also capable of growing many more cells from a smaller starting batch than the previous biopsy method.
“With this technique, we can just take a small sample of non-muscle tissue, like skin or blood, revert the obtained cells to a pluripotent state, and eventually grow an endless amount of functioning muscle fibers to test,” said Bursac.
The researchers could also, in theory, fix genetic malfunctions in the induced pluripotent stem cells derived from a patient, he added. Then they could grow small patches of completely healthy muscle. This could not heal or replace an entire body’s worth of diseased muscle, but it could be used in tandem with more widely targeted genetic therapies or to heal more localized problems.
The researchers are now refining their technique to grow more robust muscles and beginning work to develop new models of rare muscle diseases. This work was supported by the National Institutes of Health.
Duke Engineering | Human Muscle Grown from Skin Cells
Muscles for future microscale robot exoskeletons
Meanwhile, physicists at Cornell University are exploring ways to create muscles for future microscale robot exoskeletons — rapidly changing their shape upon sensing chemical or thermal changes in their environment. The new designs are compatible with semiconductor manufacturing, making them useful for future microscale robotics.
The microscale robot exoskeleton muscles move using a motor called a bimorph. (A bimorph is an assembly of two materials — in this case, graphene and glass — that bends when driven by a stimulus like heat, a chemical reaction or an applied voltage.) The shape change happens because, in the case of heat, two materials with different thermal responses expand by different amounts over the same temperature change. The bimorph bends to relieve some of this strain, allowing one layer to stretch out longer than the other. By adding rigid flat panels that cannot be bent by bimorphs, the researchers localize bending to take place only in specific places, creating folds. With this concept, they are able to make a variety of folding structures ranging from tetrahedra (triangular pyramids) to cubes. The bimorphs also fold in response to chemical stimuli by driving large ions into the glass, causing it to expand. (credit: Marc Z. Miskin et al./PNAS)
Their work is outlined in a paper published Jan. 2 in Proceedings of the National Academy of Sciences.
* The advance builds on work published in 2015, when the Duke engineers grew the first functioning human muscle tissue from cells obtained from muscle biopsies. In that research, Bursac and his team started with small samples of human cells obtained from muscle biopsies, called “myoblasts,” that had already progressed beyond the stem cell stage but hadn’t yet become mature muscle fibers. The engineers grew these myoblasts by many folds and then put them into a supportive 3-D scaffolding filled with a nourishing gel that allowed them to form aligned and functioning human muscle fibers.
Abstract of Engineering human pluripotent stem cells into a functional skeletal muscle tissue
The generation of functional skeletal muscle tissues from human pluripotent stem cells (hPSCs) has not been reported. Here, we derive induced myogenic progenitor cells (iMPCs) via transient overexpression of Pax7 in paraxial mesoderm cells differentiated from hPSCs. In 2D culture, iMPCs readily differentiate into spontaneously contracting multinucleated myotubes and a pool of satellite-like cells endogenously expressing Pax7. Under optimized 3D culture conditions, iMPCs derived from multiple hPSC lines reproducibly form functional skeletal muscle tissues (iSKM bundles) containing aligned multi-nucleated myotubes that exhibit positive force–frequency relationship and robust calcium transients in response to electrical or acetylcholine stimulation. During 1-month culture, the iSKM bundles undergo increased structural and molecular maturation, hypertrophy, and force generation. When implanted into dorsal window chamber or hindlimb muscle in immunocompromised mice, the iSKM bundles survive, progressively vascularize, and maintain functionality. iSKM bundles hold promise as a microphysiological platform for human muscle disease modeling and drug development.
Abstract of Graphene-based bimorphs for micron-sized, autonomous origami machines
Origami-inspired fabrication presents an attractive platform for miniaturizing machines: thinner layers of folding material lead to smaller devices, provided that key functional aspects, such as conductivity, stiffness, and flexibility, are persevered. Here, we show origami fabrication at its ultimate limit by using 2D atomic membranes as a folding material. As a prototype, we bond graphene sheets to nanometer-thick layers of glass to make ultrathin bimorph actuators that bend to micrometer radii of curvature in response to small strain differentials. These strains are two orders of magnitude lower than the fracture threshold for the device, thus maintaining conductivity across the structure. By patterning 2-<mml:math><mml:mi>
A University of Michigan (U-M) team has announced plans to develop an “unhackable” computer, funded by a new $3.6 million grant from the Defense Advanced Research Projects Agency (DARPA).
The goal of the project, called MORPHEUS, is to design computers that avoid the vulnerabilities of most current microprocessors, such as the Spectre and Meltdown flaws announced last week.*
The U-M grant is one of nine that DARPA has recently funded through SSITH.
Future-proofing
The idea is to protect against future threats that have yet to be identified. “Instead of relying on software Band-Aids to hardware-based security issues, we are aiming to remove those hardware vulnerabilities in ways that will disarm a large proportion of today’s software attacks,” said Linton Salmon, manager of DARPA’s System Security Integrated Through Hardware and Firmware program.
Under MORPHEUS, the location of passwords would constantly change, for example. And even if an attacker were quick enough to locate the data, secondary defenses in the form of encryption and domain enforcement would throw up additional roadblocks.
More than 40 percent of the “software doors” that hackers have available to them today would be closed if researchers could eliminate seven classes of hardware weaknesses**, according to DARPA.
DARPA is aiming to render these attacks impossible within five years. “If developed, MORPHEUS could do it now,” said Todd Austin, U-M professor of computer science and engineering, who leads the project. Researchers at The University of Texas and Princeton University are also working with U-M.
* Apple released today (Jan. 8) iOS 11.2.2 and macOS 10.13.2 updates with Spectre fix for Safari and WebKit, according to MacWorld. Threatpost has an update (as of Jan. 7) on efforts by Intel and others in dealing with Meltdown and Spectre processor vulnerabilities .
** Permissions and privileges, buffer errors, resource management, information leakage, numeric errors, crypto errors, and code injection.
UPDATE 1/9/2018: BLUE-SCREEN ALERT: Read this if you have a Windows computer with an AMD processor: Microsoft announced today it has temporarily paused sending some Windows operating system updates (intended to protect against Spectre and Meltdown chipset vulnerabilities) to devices that have impacted AMD processors. “Microsoft has received reports of some AMD devices getting into an unbootable state after installation of recent Windows operating system security updates.”
This image shows the shapes made of living tissue, engineered by the researchers. By patterning mechanically active mouse or human cells to thin layers of extracellular fibers, the researchers could create bowls, coils, and ripple shapes. (credit: Alex Hughes)
Many of the complex folded and curved shapes that form human tissues can now be programmatically recreated with very simple instructions, UC San Francisco (UCSF) bioengineers report December 28 in the journal Developmental Cell.
The researchers used 3D cell-patterning to shape active mouse and human embryonic cells into thin layers of extracellular matrix fibers (a structural material produced by human cells that make up our connective tissue) to create bowls, coils, and ripples out of living tissue. A web of these fibers folded themselves up in predictable ways, mimicking developmental processes in natural human body tissue.
Beyond 3D-printing and molds
As KurzweilAI has reported, labs have already used modified 3D printers to pioneer 3D shapes for tissue engineering (such as this research in creating an ear and jawbone structure). They have also used micro-molding for creating variously shaped objects using plastic material in a mold (frame). But the final product often misses key structural features of normal tissues.
Engineered tissue curvature using DNA-programmed assembly of cells (credit: Alex J. Hughes et al./ Developmental Cell)
The UCSF lab approach instead used a precision 3D cell-patterning technology called DNA-programmed assembly of cells (DPAC). It provides an initial template (pattern) for tissue to later develop in vitro (in a test tube or other lab container). That tissue automatically folds itself into complex shapes in ways that replicate how in vivo (body) tissues normally assemble themselves hierarchically during development.
“This approach could significantly improve the structure, maturation, and vascularization” of tissues in organoids” (miniature models of human parts, such as brains, used for drug testing) “and 3D-printed tissues in general,” the researchers note in the paper.
“We believe these efforts have important implications for the engineering of in vitro models of disease, for regenerative medicine, and for future applications of living active materials such as in soft robotics. … These mechanisms can be integrated with top-down patterning technologies such as optogenetics, micromolding, and printing approaches that control cellular and [extracellular matrix] tissue composition at specific locations.”
This work was funded by a Jane Coffin Childs postdoctoral fellowship, the National Institutes of Health, the Department of Defense Breast Cancer Research Program, the NIH Common Fund, the Chan-Zuckerberg Biohub Investigator Program, the National Science Foundation, the UCSF Program in Breakthrough Biomedical Research, and the UCSF Center for Cellular Construction.
Abstract of Engineered Tissue Folding by Mechanical Compaction of the Mesenchyme
Many tissues fold into complex shapes during development. Controlling this process in vitro would represent an important advance for tissue engineering. We use embryonic tissue explants, finite element modeling, and 3D cell-patterning techniques to show that mechanical compaction of the extracellular matrix during mesenchymal condensation is sufficient to drive tissue folding along programmed trajectories. The process requires cell contractility, generates strains at tissue interfaces, and causes patterns of collagen alignment around and between condensates. Aligned collagen fibers support elevated tensions that promote the folding of interfaces along paths that can be predicted by modeling. We demonstrate the robustness and versatility of this strategy for sculpting tissue interfaces by directing the morphogenesis of a variety of folded tissue forms from patterns of mesenchymal condensates. These studies provide insight into the active mechanical properties of the embryonic mesenchyme and establish engineering strategies for more robustly directing tissue morphogenesis ex vivo.
Patient receiving a real-time reflection of her frontal-lobe brainwave activity as a stream of audio tones through earbuds. (credit: Brain State Technologies)
You are relaxing comfortably, eyes closed, with non-invasive sensors attached to your scalp that are picking up signals from various areas of your brain. The signals are converted by a computer to audio tones that you can hear on earbuds. Over several sessions, the different frequencies (pitches) of the tones associated with the two hemispheres of the brain create a mirror for your brainwave activity, helping your brain reset itself to reduce traumatic stress.
In a study conducted at Wake Forest School of Medicine, 20 sessions of noninvasive brainwave “mirroring” neurotechnology called HIRREM* (high-resolution, relational, resonance-based electroencephalic mirroring) significantly reduced symptoms of post-traumatic stress resulting from service as a military member or vet.
“We observed reductions in post-traumatic symptoms**, including insomnia, depressive mood, and anxiety, that were durable through six months after the use of HIRREM, but additional research is needed to confirm these initial findings,” said the study’s principal investigator, Charles H. Tegeler, M.D., professor of neurology at Wake Forest School of Medicine, a part of Wake Forest Baptist.
About 500 patients have participated in HIRREM clinical trials at Wake Forest School of Medicine and other locations, according to Brain State Technologies Founder and CEO Lee Gerdes.
Brain State Technologies | HIRREM process, showing a technologist applying Brain State Technologies’ proprietary HIRREM process with a military veteran client.
HIRREM is intended for medical research. A consumer version of the core underlying brainwave mirroring process is available as “Brainwave Optimization” from Brain State Technologies in Scottsdale, Arizona. The company also offers a wearable device for ongoing brain support, BRAINtellect B2v2.
How HIRREM neurotechnology works
(credit: Brain State Technologies)
HIRREM is a neurotechnology that dynamically measures brain electrical activity. It uses two or more EEG (electroencephalogram, or brain-wave detection) scalp sensors to pick up signals from both sides of the brain. Computer software algorithms then convert dominant brain frequencies in real time into audible tones with varying pitch and timing, which can be heard on earbuds.
In effect, the brain is listening to itself. It the process, it makes self-adjustments towards improved balance (between brain temporal lobe activity in the two hemispheres — sympathetic (right) and parasympathetic (left) — of the brain), resulting in reduced hyper-arousal. No conscious cognitive activity is required. Signals from other areas of the brain can also be studied.
The net effect is to reset stress response patterns that have been wired by repetitive traumatic events (physical or non-physical).***
“Thus, if the stimulus is acoustic response to brain function (often called neurofeedback (NFB), then the response is made based on a threshold of the NFB provider. Since the brain moves three to five times faster than the thoughtful response of the client, the brain’s activity is way beyond any kind of activity which the client can mitigate. The NFB hypothesis is that the operant conditioning can be learned by the brain so it changes itself.
“In a HIRREM placebo-controlled insomnia study, HIRREM showed statistically significant improvement in sleep function over the placebo. Additionally, HIRREM demonstrated that biomarkers for the test were also statistically significant over the placebo. Posters for this study were presented at the International Sleep Conference and at the Dept of Defense Research meeting on sleep. A full length manuscript of the study is in process with hopes to be published Q1 2018).”
The study was published (open access) in the Dec. 22 online edition of the journal Military Medical Research with co-authors at Brain State Technologies. It was supported through the Joint Capability Technology Demonstration Program within the Office of the Under Secretary of Defense and by a grant from The Susanne Marcus Collins Foundation, Inc. to the Department of Neurology at Wake Forest Baptist.
The researchers acknowledge limitations of the study, including the small number of participants and the absence of a control group. It was also an open-label project, meaning that both researchers and participants knew what treatment was being administered.
* HIRREM is a registered trademark of Brain State Technologies based in Scottsdale, Arizona, and has been licensed to Wake Forest University for collaborative research since 2011. In this single-site study, 18 service members or recent veterans, who experienced symptoms over one to 25 years, received an average of 19½ HIRREM sessions over 12 days. Symptom data were collected before and after the study sessions, and follow-up online interviews were conducted at one-, three- and six-month intervals. In addition, heart rate and blood pressure readings were recorded after the first and second visits to analyze downstream autonomic balance with heart rate variability and baroreflex sensitivity. HIRREMhas been used experimentally with more than 500 patients at Wake Forest School of Medicine.
** According to the U.S. Department of Veterans Affairs, approximately 31 percent of Vietnam veterans, 10 percent of Gulf War (Desert Storm) veterans and 11 percent of veterans of the war in Afghanistan experience PTSD. Symptoms can include insomnia, poor concentration, sadness, re-experiencing traumatic events, irritability or hyper-alertness, and diminished autonomic cardiovascular regulation.
*** The effect is based on the “bihemispheric autonomic model” (BHAM ), “which proposes that trauma-related sympathetic hyperarousal may be an expression of maladaptive right temporal lobe activity, whereas the avoidant and dissociative features of the traumatic stress response may be indicators of a parasympathetic “freeze” response that is significantly driven by the left temporal lobe. An implication [is that brain-based] intervention may facilitate the reduction of symptom clusters associated with autonomic disturbances through the mitigation of maladaptive asymmetries.” — Catherine L. Tegeler et al./Military Medical Research.
Update Jan. 10, 2017: What about a control group?
“Our study had an open label design, without a control group,” Tegeler explained to KurzweilAI in an email, in response to reader questions.
“We agree that a randomized design is scientifically a more powerful approach, and one we would have preferred. The reality was that for this cohort of participants, mostly drawn from the special operations community, constraints due to limitation on allowable time away from duties, training cycle pressures, therapeutic expectations, and available funding, prevented consideration of a controlled design.
“Other studies have used a placebo-controlled design utilizing acoustic stimulation linked to brainwaves, as compared to acoustic stimulation not linked to brainwaves. Manuscripts are being prepared to report those results. Finally, our current studies are all focused on evaluation of the effects and benefits of HIRREM alone, for a variety of symptoms or conditions. That said, in the future there may be opportunities to seek funding for projects that might combine, or follow up after HIRREM, with other strategies such as meditation, improved nutrition, or exercise.”
“Biofeedback/neurofeedback is an open-loop system indicating that the feedback from the brain or other biological function is provided back to the client as the function being analyzed triggers a stimulus,” Gerdes added.
Abstract of Successful use of closed-loop allostatic neurotechnology for post-traumatic stress symptoms in military personnel: self-reported and autonomic improvements
Background: Military-related post-traumatic stress (PTS) is associated with numerous symptom clusters and diminished autonomic cardiovascular regulation. High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM®) is a noninvasive, closed-loop, allostatic, acoustic stimulation neurotechnology that produces real-time translation of dominant brain frequencies into audible tones of variable pitch and timing to support the auto-calibration of neural oscillations. We report clinical, autonomic, and functional effects after the use of HIRREM® for symptoms of military-related PTS.
Methods: Eighteen service members or recent veterans (15 active-duty, 3 veterans, most from special operations, 1 female), with a mean age of 40.9 (SD = 6.9) years and symptoms of PTS lasting from 1 to 25 years, undertook 19.5 (SD = 1.1) sessions over 12 days. Inventories for symptoms of PTS (Posttraumatic Stress Disorder Checklist – Military version, PCL-M), insomnia (Insomnia Severity Index, ISI), depression (Center for Epidemiologic Studies Depression Scale, CES-D), and anxiety (Generalized Anxiety Disorder 7-item scale, GAD-7) were collected before (Visit 1, V1), immediately after (Visit 2, V2), and at 1 month (Visit 3, V3), 3 (Visit 4, V4), and 6 (Visit 5, V5) months after intervention completion. Other measures only taken at V1 and V2 included blood pressure and heart rate recordings to analyze heart rate variability (HRV) and baroreflex sensitivity (BRS), functional performance (reaction and grip strength) testing, blood and saliva for biomarkers of stress and inflammation, and blood for epigenetic testing. Paired t-tests, Wilcoxon signed-rank tests, and a repeated-measures ANOVA were performed.
Results: Clinically relevant, significant reductions in all symptom scores were observed at V2, with durability through V5. There were significant improvements in multiple measures of HRV and BRS [Standard deviation of the normal beat to normal beat interval (SDNN), root mean square of the successive differences (rMSSD), high frequency (HF), low frequency (LF), and total power, HF alpha, sequence all, and systolic, diastolic and mean arterial pressure] as well as reaction testing. Trends were seen for improved grip strength and a reduction in C-Reactive Protein (CRP), Angiotensin II to Angiotensin 1–7 ratio and Interleukin-10, with no change in DNA n-methylation. There were no dropouts or adverse events reported.
Conclusions: Service members or veterans showed reductions in symptomatology of PTS, insomnia, depressive mood, and anxiety that were durable through 6 months after the use of a closed-loop allostatic neurotechnology for the auto-calibration of neural oscillations. This study is the first to report increased HRV or BRS after the use of an intervention for service members or veterans with PTS. Ongoing investigations are strongly warranted.
