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How to control a robotic arm with your mind — no implanted electrodes required

Research subjects at the University of Minnesota fitted with a specialized noninvasive EEG brain cap were able to move a robotic arm in three dimensions just by imagining moving their own arms (credit: University of Minnesota College of Science and Engineering)

Researchers at the University of Minnesota have achieved a “major breakthrough” that allows people to control a robotic arm in three dimensions, using only their minds. The research has the potential to help millions of people who are paralyzed or have neurodegenerative diseases.

The open-access study is published online today in Scientific Reports, a Nature research journal.


College of Science and Engineering, UMN | Noninvasive EEG-based control of a robotic arm for reach and grasp tasks

“This is the first time in the world that people can operate a robotic arm to reach and grasp objects in a complex 3D environment, using only their thoughts without a brain implant,” said Bin He, a University of Minnesota biomedical engineering professor and lead researcher on the study. “Just by imagining moving their arms, they were able to move the robotic arm.”

The noninvasive technique, based on a brain-computer interface (BCI) using electroencephalography (EEG), records weak electrical activity of the subjects’ brain through a specialized, high-tech EEG cap fitted with 64 electrodes. A computer then converts the “thoughts” into actions by advanced signal processing and machine learning.

An example of an implanted electrode array, allowing for a patient to control a robot arm with her thoughts (credit: UPMC)

The system solves problems with previous BCI systems. Early efforts used invasive electrode arrays implanted in the cortex to control robotic arms, or the patient’s own arm using neuromuscular electrical stimulation. These early systems face the risk of post-surgery complications and infections and are difficult to keep working over time. They also limit broad use.

An EEG-based device that allows an amputee to grasp with a bionic hand, powered only by his thoughts (credit: University of Houston)

More recently, noninvasive EEG has been used. It doesn’t require risky, expensive surgery and it’s easy and fast to attach scalp electrodes. For example, in 2015, University of Houston researchers developed an EEG-based system that allows users to successfully grasp objects, including a water bottle and a credit card. The subject grasped the selected objects 80 percent of the time using a high-tech bionic hand fitted to the amputee’s stump.

Other EEG-based systems for patients have included ones capable of controlling a lower-limb exoskelton and a thought-controlled robotic exoskeleton for the hand. However, these systems have not been suitable for  multi-dimensional control of a robotic arm, allowing the patient to reach, grasp, and move an object in three-dimensional (3D) space.

Full 3D control or a robotic arm by just thinking — no implants

The new University of Minnesota EEG BCI system was developed to enable such natural, unimpeded movements of a robotic arm in 3D space, such as picking up a cup, moving it around on a table, and drinking from it — similar to the robot arm controlled by implanted-electrodes shown in the photo above of a patient served a chocolate bar.*

The new  technology basically works in the same way as the robot system using implanted electrodes. It’s based on the motor cortex, the area of the brain that governs movement. When humans move, or think about a movement, neurons in the motor cortex produce tiny electric currents. Thinking about a different movement activates a new assortment of neurons, a phenomenon confirmed by cross-validation using functional MRI in He’s previous study. In the new study, the researchers sorted out the possible movements, using advanced signal processing.

User controls flight of a 3D virtual helicopter using brain waves

User controls flight of a 3D virtual helicopter using brain waves (credit: Bin He/University of Minnesota)

This robotic-arm research builds upon He’s research published in 2011, in which subjects were able to fly a virtual quadcopter using noninvasive EEG technology, and later research allowing for flying a physical quadcopter.

The next step of He’s research will be to further develop this BCI technology, using a brain-controlled robotic prosthetic limb attached to a person’s body for patients who have had a stroke or are paralyzed.

The University of Minnesota study was funded by the National Science Foundation (NSF), the National Center for Complementary and Integrative Health, National Institute of Biomedical Imaging and Bioengineering, and National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NIH), and the University of Minnesota’s MnDRIVE (Minnesota’s Discovery, Research and InnoVation Economy) Initiative funded by the Minnesota Legislature.

* Eight healthy human subjects completed the experimental sessions of the study wearing the EEG cap. Subjects gradually learned to imagine moving their own arms without actually moving them to control a robotic arm in 3D space. They started from learning to control a virtual cursor on computer screen and then learned to control a robotic arm to reach and grasp objects in fixed locations on a table. Eventually, they were able to move the robotic arm to reach and grasp objects in random locations on a table and move objects from the table to a three-layer shelf by only thinking about these movements.

All eight subjects could control a robotic arm to pick up objects in fixed locations with an average success rate above 80 percent and move objects from the table onto the shelf with an average success rate above 70 percent.

Abstract of Noninvasive Electroencephalogram Based Control of a Robotic Arm for Reach and Grasp Tasks

Brain-computer interface (BCI) technologies aim to provide a bridge between the human brain and external devices. Prior research using non-invasive BCI to control virtual objects, such as computer cursors and virtual helicopters, and real-world objects, such as wheelchairs and quadcopters, has demonstrated the promise of BCI technologies. However, controlling a robotic arm to complete reach-and-grasp tasks efficiently using non-invasive BCI has yet to be shown. In this study, we found that a group of 13 human subjects could willingly modulate brain activity to control a robotic arm with high accuracy for performing tasks requiring multiple degrees of freedom by combination of two sequential low dimensional controls. Subjects were able to effectively control reaching of the robotic arm through modulation of their brain rhythms within the span of only a few training sessions and maintained the ability to control the robotic arm over multiple months. Our results demonstrate the viability of human operation of prosthetic limbs using non-invasive BCI technology.

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Macaque monkeys have the anatomy for human speech, so why can’t they speak?

Researchers used X-ray videos (right) to capture and trace the movements of the different parts of a macaque’s vocal anatomy — such as the tongue, lips, and larynx — during a number of orofacial behaviors. (credit: Illustration by Tecumseh Fitch, University of Austria, and image courtesy of Asif Ghazanfar, Princeton Neuroscience Institute)

While they have a speech-ready vocal tract, primates can’t speak because they lack a speech-ready brain, contrary to widespread opinion that they are limited by anatomy, researchers at Princeton University and associates have reported Dec. 9 in the open-access journal Science Advances.

The researchers reached this conclusion by first recording X-ray videos showing the movements of the different parts of a macaque’s vocal anatomy — such as the tongue, lips and larynx. They then converted that data into a computer model that could predict and simulate a macaque’s vocal range.


Audio file of researchers’ macaque vocal model uttering the same phrase “Will you marry me?,” synthesized with the same noisy source (credit: W. Tecumseh Fitch et al./Science Advances)


Audio file of an adult human female saying “Will you marry me?,” resynthesized with a noisy source (credit: W. Tecumseh Fitch et al./Science Advances)

The model was used to create computer-generated audio clips (above — may not work with older browsers) that simulate what a macaque (top) might sound like if it could speak, compared to a human female (bottom). The clearly audible phrase: “Will you marry me?”

The researchers found that a macaque would be able to produce comprehensible vowel sounds — and even full sentences — with its vocal tract if it had the neural ability to speak, according to co-corresponding author Asif Ghazanfar, a Princeton University professor of psychology and the Princeton Neuroscience Institute.

“The key conclusion from our study is that the basic primate vocal production apparatus is easily capable of producing five clearly distinguishable vowels … the worldwide norm for human languages, and many of the world’s languages make do with only three vowels,” the researchers note in their paper. “The common stop consonants (/p/, /b/, /k/, and /g/) along with a variety of other consonantal sounds (for example, /h/, /m/, and /w/) would be easily attainable by a macaque monkey.”

The work was supported by the National Institutes of Health and European Research Council advanced and starting grants.

Abstract of Monkey vocal tracts are speech-ready

For four decades, the inability of nonhuman primates to produce human speech sounds has been claimed to stem from limitations in their vocal tract anatomy, a conclusion based on plaster casts made from the vocal tract of a monkey cadaver. We used x-ray videos to quantify vocal tract dynamics in living macaques during vocalization, facial displays, and feeding. We demonstrate that the macaque vocal tract could easily produce an adequate range of speech sounds to support spoken language, showing that previous techniques based on postmortem samples drastically underestimated primate vocal capabilities. Our findings imply that the evolution of human speech capabilities required neural changes rather than modifications of vocal anatomy. Macaques have a speech-ready vocal tract but lack a speech-ready brain to control it.

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Scientists track amazing restoration of communication in ‘minimally conscious’ patient

Nancy Smith Worthen doing art therapy with her daughter, Maggie, who was initially minimally conscious. (credit: Nancy Worthen)

In a three-year study of a severely brain-injured woman’s remarkable recovery, doctors measured aspects of brain structure and function before and after recovering communication, a first — raising the question: could other minimally responsive or unresponsive chronic-care patients also regain organized, higher-level brain function?

Challenging what neurologists thought was possible, the pioneering study by Weill Cornell Medicine scientists was published Dec. 7 in Science Translational Medicine.

It began 21 months after Margaret Worthen suffered massive strokes. Most doctors diagnosed her as being in a vegetative state, unable to speak and unaware of herself and her environment.

Then, during her first visit with a new team led by senior study author Nicholas D. Schiff, M.D.,* doctors detected an unexpected ability to respond to their command to look down with her left eye.

Her ability was initially intermittent, but over the course of a year she developed a viable one-way communication system. She was able to respond to yes and no questions, such as “Is your name Margaret?” or “Is your father’s name Michael?” by moving her left eye down or up, but still lacked a method to ask questions or use a brain-computer interface.

But over the next nearly two years, the connections and function of the areas of her brain responsible for producing expressive language and responding to human speech were also gradually restored.

To measure the changes in Margaret’s brain as she recovered the ability to communicate, the researchers used a number of state-of-the-art imaging tools. The main technique, called diffusion tensor imaging, uses the diffusion of water molecules to generate contrast in magnetic resonance (MRI) images, enabling scientists to infer the degree of white-matter connection between specific areas.

Longitudinal structural remodeling of the brain, as identified by diffusion tensor imaging. The “fractional anisotropy” (FA) between cortical regions, which indicates the concentration in specific white matter fibers — measured (from 0 to 1) at the first (A) and last (B) time point of evaluation — is shown as colored lines between the connected brain regions (black squares), exhibiting a notable increase of connections. The FA changes reflect fiber density, axonal diameter, and myelination (covering) in white matter. The inferior temporal gyrus, which is associated with visual object recognition, is denoted with a white square. (credit: Daniel J. Thengone et al./Science Translation Medicine)

The researchers also found a reconnection of Broca’s area — the region of the brain located in the frontal lobe of the dominant hemisphere that is associated with language and speech. In addition, the two hemispheres of the patient’s brain increased their connectivity. The findings suggest that reconnection began within the left hemisphere and extended to the right, corresponding to the restoration of Worthen’s ability to communicate.

Local and global changes in brain structure and function captured over time using multimodal imaging analyses. The time line shows the four time points of evaluation (T1 to T4) since the patient suffered a traumatic brain injury. From the first time point of evaluation (at 21 months after injury) to the last (at 54 months after injury), structural and functional brain imaging and electrophysiological studies revealed concordant findings in global remodeling and local changes, supporting the recovery of language abilities over the 2-year and 9-month period. Note the increase (more red) in white matter fiber density between 21 and 54 months. (credit: Daniel J. Thengone et al./Science Translation Medicine)

The researchers also used functional MRI (fMRI) to measure blood flow changes in response to brain activity while Ms. Worthen listened to a human voice speaking. They found that the functional recovery of Broca’s area over time corresponded with the change in structural connectivity. In addition, language-responsive brain regions showed increasing correlation across both hemispheres over time.

“She was being treated as if she was there, and she was present.”

What triggered the restoration of her brain’s expressive language system was her caregivers’ attempts to establish communication over the nearly three years of the study. Her recovered expressive language networks may also have triggered a restoration of her inner speech or inner dialogue, which could have reinforced those same networks, according to the study authors.

The findings raise important questions about how clinicians care for patients who are diagnosed as in vegetative or minimally conscious state, Schiff said. “We looked carefully at Margaret, made an observation that there was a way to try to connect with her, and the world changed for her. Her life changed because now she wasn’t being treated as if she may or may not be conscious. She was being treated as if she was there, and she was present.”

The discovery changed everything, according to her mother, Nancy Smith Worthen. For example, it opened the door to speech therapy, which enabled caregivers to assess whether or not she was experiencing pain, and for her mother to determine her daughter’s wants or needs. Margaret was able to produce paintings with her mother’s hand guiding her, which her mother credits with further stimulating her brain.

Margaret went on to develop enough facility with a computer interface that she was actually able to attend her five-year college reunion and hold conversations with classmates, assisted by a speech therapist. Her story is among those included in Rights Come to Mind: Brain Injury, Ethics, and the Struggle for Consciousness, by Joseph Fins, M.D., the E. William Davis Jr., MD, Professor of Medical Ethics and chief of the Division of Medical Ethics at Weill Cornell Medicine.

Regrettably, she died of complications from pneumonia in 2015.

“When I would ask Margaret if she wanted to do this work with Dr. Schiff, she would always say yes,” Nancy Smith Worthen said. “To have her brain be studied was the way she could do something in the world with her disability. And now, even after she’s gone, she’s still contributing. I’m just so proud of her.”

New hope for minimally conscious patients

Although the findings are from a single-subject study, scientists say they could apply to other patients, based on the proposed mechanism and previous research findings. Ten years ago, team members reported similar changes of increased connections between the two cerebral hemispheres in Terry Wallis, a minimally conscious patient who spontaneously recovered speech 19 years after a traumatic brain injury.

In addition, other studies have implicated injuries to the central thalamus such as those Margaret experienced in a general mechanism underlying impaired function in patients with disorders of consciousness.

This research was supported by the National Institutes of Health, the Charles A. Dana Foundation, the James S. McDonnell Foundation, the Jerold B. Katz Foundation and the Fred Plum Fellowship in Systems Neurology and Neurosciences.

* Schiff is the Jerold B. Katz Professor of Neurology and Neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine.

Abstract of Local changes in network structure contribute to late communication recovery after severe brain injury

Spontaneous recovery of brain function after severe brain injury may evolve over a long time period and is likely to involve both structural and functional reorganization of brain networks. We longitudinally tracked the recovery of communication in a patient with severe brain injury using multimodal brain imaging techniques and quantitative behavioral assessments measured at the bedside over a period of 2 years and 9 months (21 months after initial injury). Structural diffusion tensor imaging revealed changes in brain structure across interhemispheric connections and in local brain regions that support language and visuomotor function. These findings correlated with functional brain imaging using functional magnetic resonance imaging and positron emission tomography, which demonstrated increased language network recruitment in response to natural speech stimuli, graded increases in interhemispheric interactions of language-related frontal cortices, and increased cerebral metabolic activity in the language-dominant hemisphere. In addition, electrophysiological studies showed recovery of synchronization of sleep spindling activity. The observed changes suggest a specific mechanism for late recovery of communication after severe brain injury and provide support for the potential of activity-dependent structural and functional remodeling over long time periods.

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Trump considering libertarian reformer to head FDA

The Seasteading Institute wants to create new societies at sea, away from FDA (and other government) regulations. (credit: Seasteading Institute)

President-elect Donald Trump’s transition team is considering libertarian Silicon Valley investor Jim O’Neill, a Peter Thiel associate, to head the Food and Drug Administration, Bloomberg Politics has reported.

O’Neill, the Managing Director of Mithril Capital Management LLC, doesn’t have a medical background, but served in the George W. Bush administration as principal associate deputy secretary at the Department of Health and Human Services. He’s also a board member of the Seasteading Institute, a Thiel-backed venture to create new societies at sea, away from existing governments.

“We should reform FDA so there is approving drugs after their sponsors have demonstrated safety — and let people start using them, at their own risk, but not much risk of safety,” O’Neill said in a speech at the August 2014 Rejuvenation Biotechnology conference. “O’Neill also advocated anti-aging medicine in that speech, saying he believed it was scientifically possible to develop treatments that would reverse aging,” said Bloomberg.

O’Neill’s prospective nomination could also bring about “significant changes to medical cannabis policy and potentially address the regulations that have prevented medical cannabis research,” Mike Liszewski, the director of government affairs at Americans for Safe Access, told ATTN:.

Scott Gottlieb, M.D., a former FDA official and now at the American Enterprise Institute (AEI), is also reportedly under consideration, according to The Hill.

In a recent related announcement, Trump has selected Rep. Tom Price, M.D. (R., Ga.), a leader in the efforts to replace ObamaCare, to be his secretary of Health and Human Services. “His most frequent objection to [the Affordable Care Act] is that it interferes with the ability of patients and doctors to make medical decisions,” The New York Times notes. Price also proposes to deregulate the market for medical services, according to the AEI.

 

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Terasem Colloquium in Second Life

The 2016 Terasem Annual Colloquium on the Law of Futuristic Persons will take place in Second Life  in  ”Terasem sim” on Saturday, Dec. 10, 2016 at noon EDT. The main themes: “Legal Aspects of Futuristic Persons: Cyber-Humans” and “A Tribute to the ‘Father of Artificial Intelligence,’ Marvin Minsky, PhD.”

Each year on December 10th, International Human Rights Day, Terasem conducts a Colloquium on the Law of Futuristic Persons. The event seeks to provide the public with informed perspectives regarding the legal rights and obligations of “futuristic persons” via VR events with expert presentations and discussions. Terasem hopes to facilitate development of “a body of law covering the rights and obligations of entities that transcend, and yet encompass, conventional conceptions of humanness,” according to Terasem Movement, Inc.

12:10–12:30PM —How Marvin Minsky Inspired Me To Have a Mindclone Living on An O’Neill Space Habitat
Martine Rothblatt, JD, PhD
Co-Founder, Terasem Movement, Inc.
Space Coast, FL
Avatar name: Vitology Destiny

12:30–12:50PM — Formal Interaction

12:50–1:10PM — The Emerging Law of Cyborgs
Woodrow “Woody” Barfield, PhD, JD, LLM
Author: Cyber-Humans: Our Future with Machines
Chapel Hill, NC
Avatar name: WoodyBarfield

1:10–1:30PM — Formal Interaction

1:30–1:50PM — Cyborgs and Family Law Challenges
Rich Lee
Human Enhancement & Augmentation
St. George, UT
Avatar name: RichLee78

1:50–2:10PM — Formal Interaction

2:10–2:30PM — Synthetic Brain Simulations and Mens Rea*
Stephen Thaler, PhD.
President & CEO, Imagination-engines, Inc.
St. Charles, MO
Avatar name: SteveThaler

* Mens Rea refers to criminal intent. Moreover, it is the state of mind indicating culpability which is required by statute as an element of a crime. — Cornell University Legal Information Institute

 

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A machine-learning system that trains itself by surfing the web

MIT researchers have designed a new machine-learning system that can learn by itself to extract text information for statistical analysis when available data is scarce.

This new “information extraction” system turns machine learning on its head. It works like humans do. When we run out of data in a study (say, differentiating between fake and real news), we simply search the Internet for more data, and then we piece the new data together to make sense out of it all.

That differs from most machine-learning systems, which are fed as many training examples as possible to increase the chances that the system will be able to handle difficult problems by looking for patterns compared to training data.

Andrew Ng, Associate Professor of Computer Science at Stanford, Chief Scientist of Baidu, and Chairman and Co-founder of Coursera, is writing an introductory book, Machine Learning Yearning, intended to help readers build highly effective AI and machine learning systems. If you want to download a free draft copy of each chapter as it is finished (and previous chapters), you can sign up here for his mailing list. Ng is currently up to chapter 14.

“In information extraction, traditionally, in natural-language processing, you are given an article and you need to do whatever it takes to extract correctly from this article,” says Regina Barzilay, the Delta Electronics Professor of Electrical Engineering and Computer Science and senior author of a new paper presented at the recent Association for Computational Linguistics’ Conference on Empirical Methods on Natural Language Processing.

“That’s very different from what you or I would do. When you’re reading an article that you can’t understand, you’re going to go on the web and find one that you can understand.”

Confidence boost from web data

Machine learning systems determine whether they have enough data by assigning each of its classifications a confidence score — a measure of the statistical likelihood that the classification is correct, given the patterns discerned in the training data. If not, additional training data is required.

Fig 1. Sample news article on a shooting case. Note how the article contains both the name of the shooter and the number of people killed, but both pieces of information require complex extraction schemes to make sense out of the information. (credit: Karthik Narasimhan et al.)

In the real world, that’s not always easy. For example, the researchers note in the paper that the example news article excerpt in Fig. 1, “does not explicitly mention the shooter (Scott Westerhuis), but instead refers to him as a suicide victim. Extraction of the number of fatally shot victims is similarly difficult as the system needs to infer that ‘A couple and four children’ means six people. Even a large annotated training set may not provide sufficient coverage to capture such challenging cases.”

Instead, with the researchers’ new information-extraction system, if the confidence score is too low, the system automatically generates a web search query designed to pull up texts likely to contain the data it’s trying to extract. It then attempts to extract the relevant data from one of the new texts and reconciles the results with those of its initial extraction. If the confidence score remains too low, it moves on to the next text pulled up by the search string, and so on.

The system learns how to generate search queries, gauge the likelihood that a new text is relevant to its extraction task, and determine the best strategy for fusing the results of multiple attempts at extraction.

Testing the new information-extraction system

The MIT researchers say they tested their system with two information-extraction tasks. In each case, the system was trained on about 300 documents. One task was focused on collecting and analyzing data on mass shootings in the U.S. (an essential resource for any epidemiological study of the effects of gun-control measures).

“We collected data from the Gun Violence archive, a website tracking shootings in the United States,” the authors note. “The data contains a news article on each shooting and annotations for (1) the name of the shooter, (2) the number of people killed, (3) the number of people wounded, and (4) the city where the incident took place.”

The other task was the collection of similar data on instances of food contamination. The researchers used the Foodshield EMA database, “documenting adulteration incidents since 1980.” The researchers extracted food type, type of contaminant, and location.

For the mass-shootings task, the researchers asked the system to extract from websites (such as news articles, as in Fig. 1) the name of the shooter, the location of the shooting, the number of people wounded, and the number of people killed.

The goal was to find other documents that contain the information sought, expressed in a form that a basic extractor can “understand.”

Fig. 2. Two other articles on the same shooting case. The first article clearly mentions that six people were killed. The second one portrays the shooter in an easily extractable form. (credit: Karthik Narasimhan et al.)

For instance, Figure 2 shows two other articles describing the same event in which the entities of interest — the number of people killed and the name of the shooter — are expressed explicitly. That simplifies things.

From those articles, the system learned clusters of search terms that tended to be associated with the data items it was trying to extract. For instance, the names of mass shooters were correlated with terms like “police,” “identified,” “arrested,” and “charged.” During training, for each article the system was asked to analyze, it pulled up, on average, another nine or 10 news articles from the web.

The researchers then compared their system’s performance to that of several extractors trained using more conventional machine-learning techniques. For every data item extracted in both tasks, the new system outperformed its predecessors, usually by about 10 percent.

“The challenges … lie in (1) performing event coreference (retrieving suitable articles describing the same incident) and (2) reconciling the entities extracted from these different documents,” the authors note in the paper. “We address these challenges using a Reinforcement Learning (RL) approach that combines query formulation, extraction from new sources, and value reconciliation.”

UPDATE Dec. 8, 2016 — Added sources for test data.

Abstract of Improving Information Extraction by Acquiring External Evidence with Reinforcement Learning

Most successful information extraction systems operate with access to a large collection of documents. In this work, we explore the task of acquiring and incorporating external evidence to improve extraction accuracy in domains where the amount of training data is scarce. This process entails issuing search queries, extraction from new sources and reconciliation of extracted values, which are repeated until sufficient evidence is collected. We approach the problem using a reinforcement learning framework where our model learns to select optimal actions based on contextual information. We employ a deep Qnetwork, trained to optimize a reward function that reflects extraction accuracy while penalizing extra effort. Our experiments on two databases – of shooting incidents, and food adulteration cases – demonstrate that our system significantly outperforms traditional extractors and a competitive meta-classifier baseline.

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Triggered by ultrasound, microbubbles open the blood-brain barrier to administer drugs without harming other areas of the body

Microbubbles containing a new fluorescent substance in their lipid coating, released in a designated point in the brain by ultrasound (credit: C. Sierra et al./Columbia University UEIL)

Using ultrasound to bypass the blood-brain barrier (BBB), Columbia University researchers have succeeded in releasing drugs only in the specific area of the brain where they are needed — not in the rest of the body. The goal is to help treat Parkinson’s, Alzheimer’s, and other neurodegenerative diseases without collateral damage.

The BBB is an impassable obstacle for 98% of drugs, which it treats as pathogens and blocks them from passing from patients’ bloodstream into the brain. Using ultrasound (sound whose frequency is higher than the range of human hearing), drugs can administered using an intravenous injection of innocuous lipid-coated gas microbubbles. That technique was perfected by Columbia University scientists, who reported their research in 2011 in PNAS and in 2014 in the Journal of Cerebral Blood Flow & Metabolism.

Microbubble (credit: C. Sierra et al./Journal of Cerebral Blood Flow & Metabolism)

With this method, ultrasound is focused on a specific region of the brain, causing the microbubbles to oscillate and increase in size and expand. When they reach the critical size of 8 microns, the blood–brain barrier near them opens, allowing the medicine circulating in the blood to pass through.

This technique has been used experimentally for over ten years, but has had a disadvantage: at excessive pressure, the microbubbles can suddenly collapse, so there is no lipid shell to retain the covering of  the microbubbles, allowing the contained drug to flow through the blood pool and causing microdamage to the cerebral vessels and elsewhere.

Now, scientists at the Ultrasound Elasticity Imaging Laboratory (UEIL) at Columbia University have taken a major step forward by incorporating a fluorescent molecule called 5-dodecanoylaminofluorescein into the lipid coating of the microbubbles.

This molecule allows the scientists to determine the optimal pressure to prevent bursting of the microbubbles*, according to UEIL physicist Carlos Sierra and lead author of a paper on this new finding published in the current issue of Journal of Cerebral Blood Flow & Metabolism.

Human trials planned

So far, the researchers have proven the efficacy of their technique on mice, confirming that this molecule was reaching the brain without affecting other parts of the animal. They also identified the acoustic pressure thresholds at which the substance is guaranteed to safely reach its target in vivo.

“Defining these parameters means we can think about how to transfer the technique to human patients, although it has to be tested on monkeys first,” Sierra explains. “It could be applied to diseases like Parkinson’s, Alzheimer’s, Huntington’s diseases, brain tumors, strokes, multiple sclerosis, and amyotrophic lateral sclerosis, where we expect to see a very significant rise in the efficacy of treatment and a considerable reduction in side effects.”

Sierra is funded by a grant from Berrié Foundation in Spain.

* By ex vivo fluorescence imaging and by in vivo transcranial passive cavitation detection.

Abstract of Lipid microbubbles as a vehicle for targeted drug delivery using focused ultrasound-induced blood–brain barrier opening

Focused ultrasound in conjunction with lipid microbubbles has fully demonstrated its ability to induce non-invasive, transient, and reversible blood–brain barrier opening. This study was aimed at testing the feasibility of our lipid-coated microbubbles as a vector for targeted drug delivery in the treatment of central nervous system diseases. These microbubbles were labeled with the fluorophore 5-dodecanoylaminfluorescein. Focused ultrasound targeted mouse brains in vivo in the presence of these microbubbles for trans-blood–brain barrier delivery of 5-dodecanoylaminfluorescein. This new approach, compared to previously studies of our group, where fluorescently labeled dextrans and microbubbles were co-administered, represents an appreciable improvement in safety outcome and targeted drug delivery. This novel technique allows the delivery of 5-dodecanoylaminfluorescein at the region of interest unlike the alternative of systemic exposure. 5-dodecanoylaminfluorescein delivery was assessed by ex vivo fluorescence imaging and by in vivo transcranial passive cavitation detection. Stable and inertial cavitation doses were quantified. The cavitation dose thresholds for estimating, a priori, successful targeted drug delivery were, for the first time, identified with inertial cavitation were concluded to be necessary for successful delivery. The findings presented herein indicate the feasibility and safety of the proposed microbubble-based targeted drug delivery and that, if successful, can be predicted by cavitation detection in vivo.

 

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Implantable device targets cancer, other illnesses with controlled long-term drug delivery

A drug-delivery capsule directly implanted into a cancerous tumor (credit: Lyle Hood/UTSA)

A new drug-delivery system based on an tiny implantable capsule could “revolutionize” the delivery of medicine to treat cancer and a host of other diseases and ailments, according to researchers at The University of Texas at San Antonio (UTSA).

“The problem with most drug-delivery systems is that you have a specific minimum dosage of medicine that you need to take for it to be effective,” said Lyle Hood, assistant professor of mechanical engineering. “There’s also a limit to how much of the drug can be present in your system so that it doesn’t make you sick.” So a person who needs frequent doses of a specific medicine is required to take a pill every day or visit a doctor for injections.

KurzweilAI has covered a number of drug-delivery systems targeting cancer this year, based on “Nanoparticle cluster bombs,” “magnetically guided bacteria,” and “DNA-based lock-and-key pores,” for example.

What makes the UTSA system different is that it’s an implantable capsule, filled with medicinal fluid that uses about 5000 nanochannels to regulate the rate of release of the medicine, Hood explained. “This way, we have the proper amount of drugs in a person’s system to be effective, but not so much that they’ll harm that person.”

The capsule can deliver medicinal doses for several days or a few weeks, says Hood, and can be used for any kind of ailment that needs a localized delivery over several days or a few weeks. He believes this makes it especially tailored for treating cancer.

A larger version of the device, originally created by Alessandro Grattoni, chair of the Department of Nanomedicine at Houston Methodist Research Institute, can treat diseases like HIV for up to a year. “In HIV treatment, you can bombard the virus with drugs to the point that that person is no longer infectious and shows no symptoms,” Hood said. “The danger is that if that person stops taking their drugs, the amount of medicine in his or her system drops below the effective dose and the virus is able to become resistant to the treatments.”

The new capsule could provide a constant delivery of the HIV-battling drugs to prevent such an outcome. Hood noted it can also be used to deliver cortisone to damaged joints to avoid painful, frequent injections, and possibly even to pursue immunotherapy treatments for cancer patients.

“The idea behind immunotherapy is to deliver a cocktail of immune drugs to call attention to the cancer in a person’s body, so the immune system will be inspired to get rid of the cancer itself,” he added.

The current prototype of the device is permanent and injected under the skin, but the researchers are working on 3-D printing technology to make a new, fully biodegradable version of the device that could potentially be swallowed.

Abstract of Nanochannel Implants for Minimally-Invasive Insertion and Intratumoral Delivery

Novel approaches to achieve local, intratumoral drug delivery have the dual benefit of reducing systemic toxicity while enhancing efficacy for malignant cells. We have developed a new implantable system combining a next-generation BioNEMS nanofluidic membrane with parallel nanochannels that offers controlled release of biomolecules. Based on concentration-driven diffusive transport, nanochannel membranes provide a “drug agnostic” delivery mechanism. Integrating this nanotechnology within a small implantable capsule permits multipurpose functionality and compatibility with different therapeutic approaches as well as diagnostic imaging capability. A minimally-invasive, percutaneous trocar delivery mechanism enables serial implantation throughout a target tissue volume. In this manuscript, we demonstrate that this platform is capable of sustained delivery for chemotherapy, radiosensitization, immunomodulation, and imaging contrast, among others. This platform’s utility was established through release of doxorubicin, OX86, FGK45, and Magnevist. Further proof-of-concept experiments demonstrated successful in vivo implantation and intratumoral release of antibodies and contrast agents, as well as the platform’s MR-compatibility and capability as a radiopaque fiducial. These results provide strong evidence for a flexible, multifunctional nanofluidic implant capable of broadening local delivery utility in the clinic.

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Disney Research wants to make VR haptics as immersive as visuals

The framework of  the VR360HD app. The game engine renders animated audiovisual and haptic media defined by triggers and user behaviors and associates them with a VR media stream. Haptics is played back on a passive user sitting on or wearing a haptic device. (credit: Disney Research)

Disney Research has developed a 360-degree virtual-reality app that enables users to enhance their experience by adding customized haptic (body sensations) effects that can be triggered by user movements, biofeedback, or timelines.

A team led by Ali Israr, senior research engineer at Disney Research, has demonstrated the haptic plugin using a unique chair to provide full body sensations and a library of “feel effects” that enabled users to select and customize sensations such as falling rain, a beating heart, or a cat walking.

Beyond buzz

“Our team is working to make VR haptic sensations just as rich as the 360-degree visual media now available,” said Israr.

“Current VR systems provide ‘buzz-like’ haptic sensations through hand controllers,” he said. “But technology exists for much richer sensations. We’ve created a framework that would enable users to select from a wide range of meaningful sensations that can be adjusted to complement the visual scene and to play them through a variety of haptic feedback devices.”

The haptic playback and authoring plugin developed by the researchers connects a VR game engine to a custom haptic device. It allows users to create, personalize and associate haptic feedback to the events triggered in the VR game engine.

Whole lotta shakin’ goin’ on

The haptic app, called VR360HD, was developed and tested using a consumer headset and Disney Research’s haptic chair. The chair features a grid of six vibrotactile actuators in its back and two subwoofers, or “shakers,” in the seat and back. The grid produces localized moving sensations in the back, while the subwoofers shake two different regions of the body and can create a sensation of motion.

Users were able to select from a library of feel effects, also assembled and tested by Disney Research. These feel effects are identified with common terms such as rain, pulsing, or rumbling, and can be adjusted so that people can distinguish, for instance, between a light sprinkle and a heavy downpour.

“Combining creativity and innovation, this research continues Disney’s rich legacy of inventing new ways to tell great stories and leveraging technology required to build the future of entertainment,” the researchers note.

The researchers shook up the ACM Symposium on Virtual Reality Software and Technology with their VR360 player on Nov. 2–4 in Munich.

Abstract of VR360HD- A VR360° Player with Enhanced Haptic Feedback

We present a VR360° video player with haptic feedback playback. The VR360HD application enhances VR viewing experience by triggering customized haptic effects associated with user’s activities, biofeedback, network messages and customizable timeline triggers incorporated in the VR media. The app is developed in the Unity3D game engine and tested using a GearVR headset, therefore allowing users to add animations to VR gameplay and to the VR360° streams. A custom haptic plugin allows users to author and associate animated haptic effects to the triggers, and playback these effects on a custom haptic hardware, the Haptic Chair. We show that the VR360HD app creates rich tactile effects and can be easily adapted to other media types.

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Tracking large neural networks in the brain by making neurons glow

A neuron glows with bioluminescent light produced by a new genetically engineered sensor. (credit: Johnson Lab, Vanderbilt University)

A new kind of bioluminescent sensor developed by Vanderbilt scientists causes individual brain cells to glow in the dark, giving neuroscientists a new tool to track what’s happening in large neural networks in the brain.

The sensor is a genetically modified form of luciferase, the enzyme that fireflies and other species use to produce light.

Traditional electrical techniques for recording the activity of neurons are limited to small numbers of neurons at a time. Instead, the new sensors use a new combination of optical techniques to record the activity of hundreds of neurons at the same time, according to Carl Johnson, Stevenson Professor of Biological Sciences, who headed the effort.

The research is a spinoff of the team’s research in bioluminescence* in the green alga Chlamydomonas. Johnson and his colleagues realized that if they could combine luminescence with optogenetics (which uses light to control cells, particularly neurons), they could create a powerful new tool for studying brain activity.

To create the new sensor, Johnson and his collaborators first genetically modified a type of luciferase obtained from a luminescent species of shrimp so that it would light up when exposed to calcium ions (their level  pikes briefly when a neuron receives an impulse from one of its neighbors). Then they attached a virus that infects and genetically modifies neurons.

They tested their new calcium sensor with an optogenetic protein called channelrhodopsin that causes the calcium ion channels in the neuron’s outer membrane to open, flooding the cell with calcium. Using neurons grown in culture they found that the luminescent enzyme reacted visibly to the influx of calcium produced when the probe was stimulated by brief light flashes of visible light.


Vanderbilt University | Bioluminescent sensor causes brain cells to glow in the dark

To determine how well their sensor works with larger numbers of neurons, they inserted it into brain slices from mouse hippocampus containing thousands of neurons. In this case, they flooded the slices with an increased concentration of potassium ions, which causes the cell’s ion channels to open. Again, they found that the sensor responded to the variations in calcium concentrations by brightening and dimming.


Vanderbilt University | Optical sensor illuminates activity of neural network

“We’ve shown that the approach works,” Johnson said. “Now we have to determine how sensitive it is. We have some indications that it is sensitive enough to detect the firing of individual neurons, but we have to run more tests to determine if it actually has this capability.”

The research is described in a paper published in the open-access journal Nature Communications on Oct. 27 and was funded by the National Institutes of Health, the National Science Foundation, and a grant from the Vanderbilt Brain Institute.

* There have also been efforts in optical recording of neurons using fluorescence, but this requires a strong external light source which can cause the tissue to heat up and can interfere with some biological processes, particularly those that are light sensitive, Johnson explained. It would also interfere with the light used in optogenetics. In contrast, light in bioluminescence is produced by biochemical reactions (the light-emitting pigment luciferin and the enzyme luciferase).

Abstract of Coupling optogenetic stimulation with NanoLuc-based luminescence (BRET) Ca++ sensing

Optogenetic techniques allow intracellular manipulation of Ca++ by illumination of light-absorbing probe molecules such as channelrhodopsins and melanopsins. The consequences of optogenetic stimulation would optimally be recorded by non-invasive optical methods. However, most current optical methods for monitoring Ca++ levels are based on fluorescence excitation that can cause unwanted stimulation of the optogenetic probe and other undesirable effects such as tissue autofluorescence. Luminescence is an alternate optical technology that avoids the problems associated with fluorescence. Using a new bright luciferase, we here develop a genetically encoded Ca++ sensor that is ratiometric by virtue of bioluminescence resonance energy transfer (BRET). This sensor has a large dynamic range and partners optimally with optogenetic probes. Ca++ fluxes that are elicited by brief pulses of light to cultured cells expressing melanopsin and to neurons-expressing channelrhodopsin are quantified and imaged with the BRET Ca++ sensor in darkness, thereby avoiding undesirable consequences of fluorescence irradiation.