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* dedicated to our dearest Li, who is an expert professional on the treatment of addictions 🙂
I prepared this summary to introduce you to the topic:
Addiction, or substance use disorder, is a primary and chronic disease of the brain reward, motivation, memory and related circuitry. This is characterized by compulsive drug craving, seeking and use that persist even in the face of extremely negative consequences.
The term reward system describes a group of structures that are activated by rewarding or reinforcing stimuli, such as addictive drugs or alcohol. When the brain is exposed to a rewarding stimulus, it reacts by increasing levels of the neurotransmitter dopamine.
Instead of a simple, pleasurable surge of dopamine, many drugs of abuse—such as opioids, cocaine, or nicotine—cause dopamine to flood the reward pathway, 10 times more than a natural reward. The brain remembers this surge and associates it with the addictive substance.
When rewarding stimuli are experienced, the dopaminergic mesolimbic system is activated which causes the release of dopamine to the targeted nuclei (Small et al. 2003; Cameron et al. 2014). The ventral striatum, including the nucleus accumbens (NAcc), is a major substrate involved in reward.
Dopamine (DA)is the neurotransmitter that has been classically associated with the reinforcing effects of drugs of abuse and may have a key role in triggering the neurobiological changes associated with addiction.
Research has shown that the drugs most commonly abused by humans (including opiates, alcohol, nicotine, amphetamines, and cocaine) create a neurochemical reaction that significantly increases the amount of dopamine that is released by neurons in the brain’s reward centre.
Midbrain dopamine neurons are well known for their strong responses to rewards and their critical role in positive motivation. It has become increasingly clear, however, that dopamine neurons also transmit signals related to salient but non-rewarding experiences such as aversive and alerting events.
Addiction is now understood to be a brain disease. Whether it’s alcohol, prescription pain pills, nicotine, gambling, or something else, overcoming an addiction isn’t as simple as just stopping or exercising greater control over impulses. That’s because addiction develops when the pleasure circuits in the brain get overwhelmed, in a way that can become chronic and sometimes even permanent. This is what’s at play when you hear about reward “systems” or “pathways” and the role of dopamine when it comes to addiction.
But what does any of that really mean?
One of the most primitive parts of the brain, the reward system, developed as a way to reinforce behaviours we need to survive—such as eating. When we eat foods, the reward pathways activate a chemical called dopamine, which, in turn, releases a jolt of satisfaction. This encourages you to eat again in the future. When a person develops an addiction to a substance, it’s because the brain has started to change. This happens because addictive substances trigger an outsized response when they reach the brain. Instead of a simple, pleasurable surge of dopamine, many drugs of abuse—such as opioids, cocaine, or nicotine—cause dopamine to flood the reward pathway, 10 times more than a natural reward.
The brain remembers this surge and associates it with the addictive substance. However, with chronic use of the substance, over time the brain’s circuits adapt and become less sensitive to dopamine. Achieving that pleasurable sensation becomes increasingly important, but at the same time, you build tolerance and need more and more of that substance to generate the level of high you crave.
Addiction can also cause problems with focus, memory, and learning, not to mention decision-making and judgement. Seeking drugs, therefore, is driven by habit—and not conscious, rational decisions. Unfortunately, the belief that people with addictions are simply making bad choices pervades. Furthermore, the use of stigmatizing language, such as “junkie” and “addict” and getting “clean,” often creates barriers when it comes to accessing treatment. There’s also stigma that surrounds treatment methods, creating additional challenges.
Though treatment modalities differ based on an individual’s history and the particular addiction he or she has developed, medications can make all the difference. “A lot of people think that the goal of treatment for opioid use disorder, for example, is not taking any medication at all,” says David A. Fiellin, MD, a Yale Medicine primary care and addiction medicine specialist.
“Research shows that medication-based treatments are the most effective treatment. Opioid use disorder is a medical condition just like depression, diabetes or hypertension, and as with those conditions, it is most effectively treated with a combination of medication and counselling.”
Scientists have restored cellular function in 32 pig brains that had been dead for hours, opening up a new avenue in treating brain disease—and shaking our definition of brain death to its core. Announced on Wednesday in the journal Nature, researchers at the Yale University School of Medicine devised a system roughly analogous to a dialysis machine, called BrainEx, that restores circulation and oxygen flow to a dead brain.
The researchers did not kill any animals for the purposes of the experiment; they acquired pig heads from a food processing plant near New Haven, Connecticut, after the pigs had already been killed for their meat. And technically, the pig brains remained dead—by design, the treated brains did not show any signs of the organized electrical neural activity required for awareness or consciousness.
“Clinically defined, this is not a living brain,” says study coauthor Nenad Sestan, a neuroscientist at the Yale University School of Medicine.
The new system instead kept the brains in far better shape than brains left to decompose on their own, restoring functions such as the ability to take in glucose and oxygen for up to six hours at a time. Researchers say that the technique could give a major boost to studies of human health by providing a rich testbed for studying brain disorders and diseases.
“We’re really excited about this as a platform that could help us better understand how to treat people who have had heart attacks and have lost normal blood flow to the brain,” adds Khara Ramos, a senior policy analyst at the U.S. National Institutes of Health. “It really enhances our ability to study cells as they exist in connection with each other, in that three-dimensional, large, complicated way.”
Even so, the finding opens up considerable ethical questions, a conversation that the researchers themselves welcome.
“This is an extraordinary and very promising breakthrough for neuroscience. It immediately offers a much better model for studying the human brain, which is extraordinarily important, given the vast amount of human suffering from diseases of the mind [and] brain,” says Nita Farahany, a bioethicist at the Duke University School of Law who wrote a commentary about the study for Nature.
“It [also] challenges a lot of the fundamental assumptions that we had in neuroscience, like that once there is a loss of oxygen to the brain, it’s an irreversible march toward organismal death,” she adds. “That turns out not to be true—and because that’s not true, there’s some pretty profound ethical and legal issues that are raised as a result.”
Defining death
Death is final, but the number of truly irreversible medical outcomes has shrunk over time. For millennia, people were considered dead when they stopped breathing and their hearts ceased to beat. But then modern medicine intervened. The invention of mechanical ventilators allowed failing bodies to be kept alive for longer, and decades of improvements to heart surgery and transplants mean that even a stopped heart might not necessarily be the end.
But the brain remains a finicky patient. Mammal brains such as ours are high-performance machines; they demand a constant stream of oxygen-rich blood to work to their fullest. If blood flow is cut off, we lose consciousness after just a few seconds. Within five minutes, the brain’s stores of vital molecules such as glucose and ATP—the body’s universal currency for chemical energy—run out.
The brain then enters a death spiral that, up to now, scientists considered irreversible: Nerve cells’ delicate chemistries get thrown out of whack, a buildup of carbon dioxide makes the brain’s blood more acidic, and leaks of a powerful neurotransmitter called glutamate quickly become toxic. Soon, enzymes that break down nerve tissue come online, and the brain’s smaller structures and blood vessels rupture and break.
The more researchers understood this process, the more they incorporated it into the definition of death itself. In 1968, a committee of doctors assembled by Harvard University put forth a landmark definition of “irreversible coma,” what we now call “brain death”: a total lack of responsiveness, the inability to breathe on one’s own, a total lack of reflexes, and no signs of large-scale electrical activity in the brain. Now, the American Academy of Neurology maintains a checklist that clinicians use to judge brain death in patients.
But there have been hints of greater brain resilience. Some parts of brain cells, such as the mitochondria that process chemical energy, still work up to 10 hours after death. In cats and macaques, researchers have successfully made brains recover after a full hour cut off from blood by carefully restoring circulation. And in humans, some medical case studies point to a brain that can bounce back. In 2007, researchers reported that a woman suffering from acute hypothermia—with a body temperature less than 65 degrees Fahrenheit—made a full neurological recovery.
Working, but not aware
Sestan and his colleagues, led by Zvonimir Vrselja and Stefano Daniele, resolved to test a complex mammal brain’s ability to recover, so they devised what they call the BrainEx system.
BrainEx consists of computer-controlled pumps and filters that send a nourishing solution through a dead, surgically exposed brain, with an ebb and flow that mimics the body’s natural circulation. The proprietary solution is based on hemoglobin, the oxygen-ferrying protein in red blood cells, and is made to show up in ultrasound scans, so researchers can track its flow through the brain. Yale University has filed a patent for the system on behalf of its creators, but all of BrainEx’s parts and procedures will be freely available to non-profit and academic researchers.
The team took steps to ensure that the brains would not “wake up” in any way, let alone have awareness of the procedure’s trauma. Though none of the brains in the experiment showed any sign of awareness, researchers stood at the ready to administer anesthesia and lower the brains’ temperatures, just in case. What’s more, the team added compounds in the solution to block neural activity, which served the extra goal of resting the brains’ cells to give them better odds of healing.
“It was in fact never a goal—and even sort of the opposite of a goal—of the research to have consciousness restored,” says study coauthor Stephen Latham, director of the Yale Interdisciplinary Center for Bioethics.
First, the team checked to see whether BrainEx could restore circulation in the brain, even in its tiniest blood vessels. It does. Researchers also confirmed that the brain’s blood vessels were in good enough shape that they could dilate in response to medications. Next, the researchers checked how well BrainEx preserved the overall structure of brain tissue. For the most part, BrainEx-treated brains looked comparable to brains in living animals or untreated brains an hour after death, and they were far more intact than untreated brains examined 10 hours after death.
Brain areas that are especially sensitive to oxygen loss, such as the hippocampus, also preserved well under BrainEx, as did the structures of individual neurons. And as they monitored the chemical differences in the solution flowing into and out of the brain, researchers found that the brain was making CO2 and using up glucose and oxygen—signs of brain-wide metabolism restarting.
Though researchers ensured that the experimental brains wouldn’t have large-scale activity, they took small slices of brain tissue to test whether individual hippocampus neurons could still fire after treatment. They could.
“[That result was] the most surprising aspect to me as a working neuroscientist,” says Allen Institute for Brain Science director Christof Koch, who wasn’t involved with the study. “They were still capable of generating the spikes that are the universal idiom of fast electrical communication. It means that in principle, those neurons seem capable of neural activity.”
Ethics of animal research
The BrainEx team is acutely aware of the ethical implications of its work, which is why they have consulted with leading neuroscientists and ethicists for years. The Neuroethics Working Group, a consortium convened by the U.S. National Institutes of Health’s BRAIN Initiative, which funded the research, has been consulting with Sestan since 2016. The researchers also presented their work at a 2017 bioethics conference at Duke University and at a 2018 NIH workshop.
“Cutting-edge science needs cutting-edge ethics,” says Ramos, who serves as the Neuroethics Working Group’s executive secretary. “There is an existing, robust framework of laws and policies that our funded researchers are expected to follow, but the development and application of new neuro-technologies may require us to examine those ethical standards, and for those standards to evolve.”
For one, the technique opens up questions about the ethical use of non-human animals in experiments. As it stands, two sets of rules apply, one for live animals and another for dead animal tissues, since live animals can experience pain or distress. But which rules apply to BrainEx-treated brains from dead animals, especially if there is a chance they could be partially reawakened?
“There’s this kind of gaping hole in our protections of animal research subjects, [since] we now have this part-revived, slightly-alive category with the potential—and, as of yet, not fully understood potential—for recovery of function,” says Farahany, who is also a member of the Neuroethics Working Group. “If you’re seeking to revive pig brains, or other animal brains, does that mean that that becomes an animal research subject, rather than dead tissue?”
Experts add that the ethical tradeoff here hinges on BrainEx’s ability to further research into human disease—or even save people from brain death.
“We cannot willy-nilly impose, just for our curiosity, pain or agony on another creature unless there’s a very good motive and the appropriate experiments,” Koch says. “Can this be used to rescue brains? Not just gee-whiz, let’s see what happens here.”
Experts also say that BrainEx’s ethical implications extend to the next logical question: Would it work on humans? On a technical level, Koch says that would not be a major leap, since both pigs and humans have large, complexly folded brains. But Koch and every other outside expert contacted by National Geographic urged caution in moving toward human trials.
On even broader horizons, future versions of BrainEx could complicate the process of organ donation by blurring the lines of brain death, note Case Western Reserve University bioethicists Stuart Youngner and Insoo Hyun in an accompanying commentary published in Nature. But Kevin Cmunt, CEO of Gift of Hope, one of the United States’s largest organ donation networks, doesn’t see BrainEx as a major disruption. He says that in many cases, organ donors who are declared brain-dead have suffered oxygen loss well beyond the study’s time window, or substantial physical trauma. (Other researchers are creating human-pig chimeras to advance organ transplant options.)
“I think that in the vast majority of brain-dead donors, this intervention would not be material,” he says. “There may be a small subset of cases where [BrainEx] could impact the opportunity for donation, but I think it’s relatively small.”
And if BrainEx does appear in clinics, Cmunt adds that it would be incorporated into the list of interventions before declaring someone brain-dead or deciding to end life support. The promise of brain recovery could even improve organ donations by giving medical professionals an even greater imperative to maintain circulation. Then, if the patient is declared brain-dead even after treatment with BrainEx, their organs could be more viable for donation than they would be otherwise.
“I don’t necessarily see this as a conflict,” Cmunt says. “These treatments would certainly be a part of care, just like hypothermia protocols are a part of care, and other things that we try to do to stop damage to organs and brains.”
Only the beginning
At its most profound, the discussion around BrainEx shows how gains in knowledge and improvements in treatments have shifted the definition of death itself.
“Imagine you’re standing in the clinic, your dad is declared brain-dead, and you’ve just read this paper. You ask the surgeon, Well, what does brain-dead mean? He says it’s irreversible loss of brain function, and you say, Well, wait a minute, there was this paper—doesn’t that mean that ‘irreversible’ today may not be ‘irreversible’ tomorrow?” Koch says.
BrainEx’s space on the border of life and death echoes science fiction—and at its most lurid, people may well think of Frankenstein and the prospect of resurrecting the dead. But Farahany cautions that we are still many miles away from that feat.
“It is definitely has a good science-fiction element to it, and it is restoring cellular function where we previously thought impossible. But to have Frankenstein, you need some degree of consciousness, some ‘there’ there,” she says. “They did not recover any form of consciousness in this study, and it is still unclear if we ever could. But we are one step closer to that possibility.”
Voynich Code – The Worlds Most Mysterious Manuscript – The Secrets of Nature
It is the world’s most mysterious manuscript. A book, written by an unknown author, illustrated with pictures that are as bizarre as they are puzzling — and written in a language that even the best cryptographers have been unable to decode. No wonder that this script even has a part in Dan Brown’s latest bestseller “The Lost Symbol”.
10 Words in Mysterious Voynich Manuscript Decoded By Megan Gannon, News Editor | February 20, 2014
The Voynich manuscript’s unintelligible writings and strange illustrations have defied every attempt at understanding their meaning.
The Voynich manuscript’s unintelligible writings and strange illustrations have defied every attempt at understanding their meaning. Credit: Beinecke Rare Book and Manuscript Library, Yale University
A researcher claims he’s decoded 10 possible words in the famously unreadable Voynich manuscript, which has eluded interpretation for a century.
The book’s 250 vellum pages are filled with writings in an
unknown alphabet and elaborate drawings depicting a range of subjects from female nudes to medicinal herbs to Zodiac symbols. The medieval text was discovered by an antique book dealer in 1912, and it has been rather stingy in giving up its secrets ever since.
Now Stephen Bax, a professor of applied linguistics at the University of Bedfordshire in England, says he’s deciphered 14 characters of the script and can read a handful of items in the Voynich text, such as the words for coriander, hellebore and juniper next to drawings of the plants. He says he’s also picked out the word for Taurus written beside an illustration of the Pleiades, a star cluster in the constellation Taurus. [Voynich Manuscript: Images of the Unreadable Medieval Book]
“I hit on the idea of identifying proper names in the text, following historic approaches which successfully deciphered Egyptian hieroglyphs and other mystery scripts, and I then used those names to work out part of the script,” Bax said in a statement.
“The manuscript has a lot of illustrations of stars and plants,” Bax added. “I was able to identify some of these, with their names, by looking at mediaeval herbal manuscripts in Arabic and other languages, and I then made a start on a decoding, with some exciting results.”
The Voynich manuscipt now sits in a rare books library at Yale University. Carbon dating proved that it dates back to the 15th century, and researchers believe it was written in Central Europe. While some scholars have written it off as a Renaissance-era hoax full of nonsense text, others say the pattern of the letters and words suggest the book was written in a real language or at least an invented cipher. A recent statistical study published in the journal PLOS ONE found that “Voynichese” adheres to linguistic rules.
Bax notes that the manuscript is still a long way from being understood, and that he is coming forward with what he’s found thus far in the hopes that other linguists will work with him to crack the code. For now, he thinks the book is “probably a treatise on nature, perhaps in a Near Eastern or Asian language.”
*** A 600 YEAR OLD MYSTERY
Up until now the 15th century cryptic work has baffled scholars, cryptographers and codebreakers who have failed to read a single letter of the script or any word of the text.
Over time it has attained an infamous reputation, even featuring in the latest hit computer game Assassin’s Creed, as well as in the Indiana Jones novels, when Indiana decoded the Voynich and used it to find the ‘Philosopher’s Stone’.
However in reality no one has come close to revealing the Voynich’s true messages unitl now.
Many grand theories have been proposed. Some suggest it was the work of Leonardo da Vinci as a boy, or secret Cathars, or the lost tribe of Israel, or most recently Aztecs … some have even proclaimed it was done by aliens.
Has the Voynich manuscript been decoded? First words of mysterious 15th century text revealed
The Voynich manuscript was discovered in an Italian monastery in 1912
Due to its location, historians think the manuscript was written in Europe
It is full of illustrations, diagrams and a mysterious text written left to right
Cryptographers have been trying to decipher this text for decades
First nine words have now been decoded
By MARK PRIGG PUBLISHED: 23:00 GMT, 20 February 2014
For decades, researchers have been trying in vain to decipher ancient texts written on the Voynich manuscript – and a British researcher claims he has cracked it.
The world-renowned 600 year old manuscript is full of illustrations of exotic plants, stars, and mysterious human figures, as well as many pages written in an unknown text.
Now Stephen Bax, Professor of Applied Linguistics at the University of Bedfordshire, say he has decoded words in it for the first time.
Stephen Bax, Professor of Applied Linguistics at the University of Bedfordshire, say he has decoded words in it for the first time by identifying the plants
A 600 YEAR OLD MYSTERY
Up until now the 15th century cryptic work has baffled scholars, cryptographers and codebreakers who have failed to read a single letter of the script or any word of the text.
Over time it has attained an infamous reputation, even featuring in the latest hit computer game Assassin’s Creed, as well as in the Indiana Jones novels, when Indiana decoded the Voynich and used it to find the ‘Philosopher’s Stone’.
However in reality no one has come close to revealing the Voynich’s true messages unitl now.
Many grand theories have been proposed. Some suggest it was the work of Leonardo da Vinci as a boy, or secret Cathars, or the lost tribe of Israel, or most recently Aztecs … some have even proclaimed it was done by aliens.
Professor Bax is using linguistic analysis to work on the script letter by letter.
‘I hit on the idea of identifying proper names in the text, following historic approaches which successfully deciphered Egyptian hieroglyphs and other mystery scripts, and I then used those names to work out part of the script,’ he said.
‘The manuscript has a lot of illustrations of stars and plants. I was able to identify some of these, with their names, by looking at medieval herbal manuscripts in Arabic and other languages, and I then made a start on a decoding, with some exciting results.’
Among the words he has identified is the term for Taurus, alongside a picture of seven stars which seem to be the Pleiades, and also the word KANTAIRON alongside a picture of the plant Centaury, a known mediaeval herb, as well as a number of other plants.
Altogether Bax says he has worked out: Juniper, Taurus, Coriander, Centaurea, Chiron, Hellebore Nigella Sativa, Kesar and Cotton.
Although Professor Bax admits his decoding is still only partial, it has generated a lot of excitement in the world of codebreaking and linguistics because it could prove a crucial breakthrough for an eventual full decipherment.
Due to its mysterious nature, the text and diagrams in the manuscript, pictured, have been studied by cryptographers around the world, yet no-one has succeeded in deciphering the reams of written passages. This has led to many people claim the book is hoax, or that the writing is nonsense
*** THE LOST LANGUAGE OF NAHUATL
Nahuatl originated in Central Mexico during the 7th century. It was the spoken predominantly by the Aztecs.
Following the Spanish conquest of Mexico in the 16th century, the alphabet was replaced with Latin.
Nahuatl became a literary language, used in poetry and passages, similar to the Voynich manuscript.
Varieties of Nahuatl are still spoken by approximately 1.5 million Nahua people in Central Mexico.
Recently a U.S. botanist studied illustrations of the plants throughout the 15th century book and pinpointed a number of them to the Central American region now known as Mexico.
Dr. Arthur Tucker claims at least 37 of the 303 plants would have grown in the region during the 15th and 16th century and believes the text is, therefore, written in the Aztec language of Nahuatl.
The writing is so bizarre, sceptics have stated the book is a hoax or that the writing is nonsense.
The Voynich manuscript was discovered in an Italian monastery in 1912 by book dealer Wilfred Voynich.
Carbon dating suggests the manuscript was created between approximately 1404 and 1438, during the Italian Renaissance.
The 240 pages of the book are made from a type of parchment produced using calf skin, known as vellum, and are decorated with illustrations, diagrams and a mysterious text written from left to right.
THE MYSTERY AND SCEPTICISM SURROUNDING THE VOYNICH MANUSCRIPT
The Voynich manuscript was discovered in an Italian monastery in 1912 by book dealer Wilfred Voynich.
Carbon dating suggests the manuscript was created in the early 15th century, between approximately 1404 and 1438, during the Italian Renaissance.
The 240 pages of the book are made from a type of parchment produced using calf skin, known as vellum.
Each page is decorated with illustrations, diagrams and a mysterious text written from left to right.
Due to its mysterious nature, the text has been studied by cryptographers around the world, yet no-one has succeeded in deciphering the reams of written passages.
This has led to many people claim the book is hoax, or that the writing is nonsense.
Due to the manuscript’s discovery in Italy, many researchers believe the book to have originated in Europe, however, the latest research from Dr. Tucker suggests it may have been written by the Aztecs in what is now modern-day Mexico.
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and it has been rather stingy in giving up its secrets ever since.
Up until now the 15th century cryptic work has baffled scholars, cryptographers and codebreakers who have failed to read a single letter of the script or any word of the text.
The Voynich manuscript was discovered in an Italian monastery in 1912 by book dealer Wilfred Voynich. 
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