Posts Tagged ‘PTSD’

The 60 souls that signed on for Dr. Alain Brunet’s memory manipulation study were united by something they would rather not remember. The trauma of betrayal.

For some, it was infidelity and for others, a brutal, unanticipated abandonment. “It was like, ‘I’m leaving you. Goodbye,” the McGill University associate professor of psychiatry says.

In cold, clinical terms, his patients were suffering from an “adjustment disorder” due to the termination (not of their choosing) of a romantic relationship. The goal of Brunet and other researchers is to help people like this — the scorned, the betrayed, the traumatized — lose their total recall. To deliberately forget.

Over four to six sessions, volunteers read aloud from a typed script they had composed themselves — a first-person account of their breakup, with as many emotional details as possible — while under the influence of propranolol, a common and inexpensive blood pressure pill. The idea was to purposely reactivate the memory and bring the experience and the stinging emotions it aroused to life again. “How did you feel about that?” they were asked. How do you feel right now? And, most importantly: Has your memory changed since last week?

The investigators had hypothesized that four to six sessions of memory reactivation under propranolol would be sufficient to dramatically blunt the memories associated with their “attachment injury.” Decrease the strength of the memory, Brunet says, and you decrease the strength of the pain.

The study is now complete, and Brunet is hesitant to discuss the results, which have been submitted to a journal for peer review and publication. However, the participants “just couldn’t believe that we could do so much in such a small amount of time,” he confides.

“They were able to turn the page. That’s what they would tell us — ‘I feel like I’ve turned the page. I’m no longer obsessed by this person, or this relationship.’”

Brunet insists he isn’t interested in deleting or scrubbing painful memories out entirely. The idea of memory erasure, of finding the cellular imprint of a specific, discreet memory in the brain, of isolating and inactivating the brain cells behind that memory, unnerves him. ‘It’s not going to come from my lab,” he says, although others are certainly working on it. Memories are part of who we are, what forms our identity, what makes us authentic, “and as long as only one choice exists right now, and it’s toning down a memory, we feel on very solid and comfortable ground,” ethically speaking, Brunet says.

“However, if one day you had two options — I can tone down your memory, or I can remove it altogether, from your head, from your mind — what would you choose?”

The choice might soon be yours.

“If you could erase the memory of the worst day of your life, would you,” Elizabeth Phelps and Stefan Hofmann write in the journal, Nature. “How about your memory of a person who has caused you pain?”

What was once purely science fiction is moving ever closer to clinical reality. Researchers are working on techniques and drugs that might enable us to edit our memories or at least seriously dull their impact — to make the intolerable bearable — by, say, swallowing a pill to block the synaptic changes needed for a memory to solidify. A pill that could be taken hours, even months or years after the event.

Much of the work is based on the theory of memory reconsolidation – the belief that the mere conscious act of recalling or conjuring a memory makes it vulnerable to tinkering or meddling. When a memory is evoked, a reconsolidation window opens for a brief period of time (two to five hours, according to Brunet), during which time the memory returns to a state of “lability.” It becomes pliable, like Play-Doh. It also becomes susceptible to modification, before “reconsolidating” or re-storage. The thought is that propranolol interferes with proteins in the brain needed to lock down the memory again.

A similar line of thinking holds that a memory isn’t an exact impression of the original event, an Iphone video of the past, says Boston University neuroscientist Steve Ramirez. Rather it’s more like Plato’s wax tablet. Press a signet ring into the wax and it leaves an imprint, but the wax can melt when we recall the memory, form again and then melt all over again. “Memory is dynamic,” Ramirez says. It isn’t static. Memories can also be updated with new information when they’re recalled, like hitting “save as” every time you go into a Word file.

But the idea that memories can be edited, softened or dialled down, is more than a little discomfiting to some, and not just for what it means for eyewitness testimony. “We’re not reliable narrators when it comes to some details, and sometimes even entire scenarios,” Ramirez says. More profoundly, without good and bad memories it’s hard to imagine how we would know how to behave, says Dr. Judy Illes, professor of neurology and Canada Research Chair in neuroethics at the University of British Columbia.

Learning doesn’t occur without memory. How do we learn from a bad relationship, if we can’t remember it? “And so now, if we pre-select what memories stick and don’t stick, it almost starts to be like the eugenics of memory,” Illes says. “We ought to think carefully about that.”

She has absolutely no qualms about using memory manipulation for people suffering desperately from post-traumatic stress disorder, people whose burden of suffering from horrifying experiences exceeds any moral argument against using it.

“To me, a PTSD that is profound and debilitating is like a disease of any other and, to the extent that we can have an intervention that treats it, we should vigorously pursue it.”

Even the heartbroken recruited for Brunet’s study were experiencing symptoms congruent with PTSD. We’re geared to form attachments, he says, and not so much to detach.

But memory manipulation has a slippery slope. Would it bleed into not-so-disabling disorders? If someone misbehaves at a cocktail party and would really sooner forget what happened, is that an appropriate use? Isn’t it good to be embarrassed by your past behaviour, to keep you from doing it again? What about war fighters, asks Illes. “If we had a drug that can mitigate a bad memory, could we possibly use it in advance of an act to actually prevent a memory from forming, and therefore enable people to fight less fearfully, and more fiercely, because there’s no consolidation of the acts of crime, or acts of war?”

The pull of moral responsibility — “one’s future ‘oughtness’” — is grounded in our life story, writes bioethicist Dr. Peter DePergola in the Journal of Cognition and Neuroethics. Using blood pressure pills or some other intervention like, say, transcranial direct current stimulation, to deaden or blast away memories of trauma “ultimately undermines one’s ability to seek, identify and act on the good,” DePergola argues.

And how do you manipulate a bad memory, without risking happy, shiny, positive ones? What does a memory even look like in the brain? Can we visualize it? Can we see what happens when positive and negative memories form? And where would all the bad memories go? Saved in glass bottles in the Ministry of Magic?

We can’t go into the brain and erase memories in an Eternal-Sunshine-of-the-Spotless-Mind kind of way, Ramirez says, at least not yet. We can’t touch or poke a memory. However, scientists are starting to get unprecedented glimpses into the physical structure of memory in the brain. The goal is to identify the brain cells a particular memory gloms onto, and artificially manipulate those cells.

The challenge is that human memories aren’t localized to one specific location in the brain. There’s no spot X you can point to, and say, Aha! There it is. Rather, they’re scattered throughout the organ. The sights and sounds and smells and emotions of a memory are going to recruit different corners of the brain that are involved in processing the sights and sounds and smells and emotions, Ramirez says.

“Right now, there are a lot of memories that are asleep in your brain. If I asked you, ‘what did you do last night?’, that memory just woke up. How did that happen? You just did that effortlessly in, like, 500 milliseconds. And yet we don’t know how that process works.”

However, we know that it does happen, and scientists have some pretty good indications of what happens physiologically when we recall a memory, and what it means for that memory to become awake again.

American-Canadian neurosurgeon Wilder Penfield was one of the first to hint at where to look. When Penfield stimulated cells in the hippocampus of people who were undergoing surgery for epilepsy in the 1940s with mild jolts of electricity, specific episodic memories — memories of actual experiences — suddenly popped into their minds. “It was like, ‘I have no idea why, but I’m randomly remembering my 16th birthday and I was walking my cat,’’” Ramirez said on a National Geographic podcast earlier this year.

In experiments that helped open the floodgates, Ramirez and other scientists at MIT reported that they could identify — in mice — the cells that make up part of an engram, the coding for a specific memory, and reactive those same cells using a technology called optogenetics.

Briefly, here’s what they did: Viruses were inserted into the brain cells of genetically modified mice that made the cells glow green in response to light. Next, the researchers isolated cells in the hippocampus of a mouse as the rodents were forming a specific memory — in this case, the memory of receiving a mild electric foot shock while exploring a box.

A day later, the mouse was placed in a different box — different smells, different floor, meaning there should be no reason for them to be fearful. But when those memory cells were activated with a laser, the mouse froze in fear.

More recently, in a paper published earlier this year, Ramirez and co-author Briana Chen mapped out which cells in the hippocampus were being activated when male mice made new memories of positive (meeting a female mouse) and negative (those mild electric foot zaps again) experiences. They were able to trigger the memories again later, using laser light to activate the memory cells. When memory cells in the bottom part of the hippocampus were stimulated, it seemed to dial up the negative memories. But stimulating memory cells in the top part of the hippocampus seemed to dial them down.

The goal, says Ramirez, is to artificially activate positive memories to overwrite the bad ones — in a sense, using the brain as a drug. “In depression, there is a bias toward negative thinking,” Ramirez says. We’ve been using drugs like Xanax and Prozac for decades, but we haven’t really advanced all that much since the 1970s, Ramirez says. “Maybe we need to tackle these kinds of disorders from all angles.”

Ten years ago, Sheena Josselyn’s lab was the first to offer fairly convincing evidence that we can erase a specific fear memory in mice, without erasing every one of the rodent’s fears. The University of Toronto neuroscientist used a toxin to destroy a handful of neurons housing the memory “It wasn’t like a huge legion. If you take out the entire brain, the mouse doesn’t remember a darn thing.”

That’s obviously not technically, or ethically ideal in humans. No one is talking about ablating neurons in people, or injecting viruses into human brain cells to make them glow green. “But it does tell us that in order to manipulate a memory in people we don’t have to give an entire, systemic thing,” Josselyn says. Rather, we could go in and just hit the target neurons using some kind of smart bomb.

Mice aren’t humans, and efforts to translate the results from animal experiments to healthy humans have been mixed, Phelps and Hoffman note in their Nature article. Still, whether it’s beta-blockers like propranolol, or ecstasy or ketamine or other drugs being tested that might block the synthesis of proteins required to lock down a memory after it’s been retrieved, Ramirez and others believe we could tackle the emotional “oomph,” the psychological sting, of a traumatic memory, while leaving the autobiographic experience — the actual, conscious recollection of the event — intact. No, you may not be able to erase the memory of the “venomous, evil snake that is my ex,” as one Redditor asked Ramirez. There isn’t a memory anti-venom. With memory manipulation, people would still remember the breakup, and the person, but the toxic, gut-twisting emotions associated with it would melt, like ice cream in the sun. And, just as doctors shouldn’t hand out anti-depressants to the entire population of Boston, Ramirez says memory manipulation should be reserved for those suffering crippling anxiety, depression or other symptoms.

Betrayal and abandonment themselves are “no small stuff,” adds Brunet. “This is the material Greek tragedies are made of.” People can become hyper vigilant, he says. They have intrusive thoughts. Everything around them reminds them of the former relationship. “It affects negatively your world views, your self esteem and the trust you can place in other people,” Brunet says.

However, a memory buster is challenging, Illes, of UBC says, because it interferes with our experience as humans.

Our brains are hardwired to remember emotionally charged events. “Do you remember where you were on 9/11? Do you remember five supermarkets ago?” Illes asks.

Our memories are so closely interrelated and interconnected, she adds, that you can’t just pull one brick out without the integrity of the entire wall being affected.

“Go back to your dating question,” Illes says as a thought experiment. “We have a bad relationship. Unless two people are on an isolated island and don’t interact with other humans, your bad relationship has other people in there. And, so, how do you remove all the memories associated with all the complexities that we have on a daily basis?”

Memories give us a sense of consciousness, she says, of who we are and what we know to be right and wrong and moral and immoral.

A prescient 2003 report from the U.S. President’s Council on Bioethics asked whether the then-emerging field of memory-alteration would mean abandoning our own truthful identities.

“Armed with new powers to ease the suffering of bad memories, we might come to see all psychic pain as unnecessary and in the process come to pursue a happiness that is less than human,” the authors wrote, “an unmindful happiness, unchanged by time and events, unmoved by life’s vicissitudes.”

Steve Ramirez was running in the Boston marathon in 2013 when two crude pressure cooker bombs detonated 12 seconds apart near the finish line, killing three and injuring several hundred more. The sights, the sounds, the smells — “they helped carve a very deep corner into my personality,” he says.

“It exposed a darker aspect of humanity, but I wouldn’t really find any personal gain in not knowing that corner, either.”

If you could erase the worst memory of your life, would you? Scientists are working on a pill for that

Thanks to Kebmodee for bringing this to the It’s Interesting community.

Within four hours of a traumatic experience, certain physiological markers—namely, sweating—are higher in people who go on to develop posttraumatic stress disorder (PTSD), according to a new study by a researcher at Case Western Reserve University and other institutions.

Around 90% of people who experience a traumatic event do not develop PTSD, according to existing data and research, making the medical community eager for better insights into the 10% who do—and for how to best treat these patients.

The study, conducted at Atlanta’s Grady Memorial Hospital, found that micro perspirations—detected non-invasively by a mobile device in an emergency department—can be plugged into a new mathematical model developed by the researchers to help predict who may be more at risk for developing PTSD.

The findings are especially important for targeting early treatment efforts and prevention of the disorder, said Alex Rothbaum, a pre-doctoral researcher in the Department of Psychological Sciences in the College of Arts and Sciences at Case Western Reserve.

“With PTSD, there is a need for more reliable and immediate patient information, especially in situations where research suggests people may underreport their own symptoms, such as with men, and those who live in violent neighborhoods or are on active duty,” said Rothbaum, a co-author of the study, which was published in the journal Chronic Stress.

“While skin is always secreting sweat, our method can discern meaningful, actionable information from perspirations too small for the naked eye to see,” he added.

The measurement differs from traditional practices to diagnose PTSD, which look for psychological differences in patients based on self-reported data and clusters of symptoms defined by the Diagnostic and Statistical Manual of Mental Disorders (often referred to as the DSM) published by the American Psychiatric Association.

“Eventually, this finding may help contribute to changes in how we diagnose and treat PTSD, pointing us toward which patients would do better in therapy, with medication, or a combination of the two—or no treatment at all,” said Rothbaum.

New testing device: less expensive, more accessible
Researchers hope the PTSD test can become available and standard in emergency departments, aided by the recent development of a practical and inexpensive device that can plug into common tablets and can measure “skin conductance response”—a measure of sweating.

Before, such tests could only be conducted on a large stand-alone machine costing upwards of $10,000. While the new device lacks the sensitivity of its more expensive counterpart, the readings it provides can be used to determine who should continue with additional testing and who is not at risk for developing PTSD.

The study—which included nearly 100 patients—was prompted, in part, by recent research showing the ineffectiveness of current methods practiced with patients immediately after traumas, known as critical incident stress debriefing and psychological debriefing.

Both the new method and model created by researchers will need to be further validated by a larger study underway with a National Institutes of Health grant.

The research
The study was co-authored with researchers at Emory University School of Medicine: Rebecca Hinrichs, Sanne J. H. van Rooij, Jennifer Stevens, Jessica Maples-Keller and Barbara O. Rothbaum; Vasiliki Michopoulos of Emory and Yerkes National Primate Research Center; Katharina Schultebraucks and Isaac Galatzer-Levy of New York University School of Medicine; Sterling Winters of Wayne State University; Tanja Jovanovic of Emory and Wayne State; and Kerry J. Ressler of Emory and Harvard/ McLean Hospital.

The research was supported by the National Institute of Mental Health and a Brain and Behavior Research Foundation NARSAD Independent Investigator Award.

Sweating is a clue into who develops PTSD—and who doesn’t


Brains of individuals with PTSD and suicidal thoughts (top) show higher levels of mGluR5 compared to healthy controls (bottom).

By Bill Hathawaymay

The risk of suicide among individuals with post-traumatic stress disorder (PTSD) is much higher than the general population, but identifying those individuals at greatest risk has been difficult. However, a team at Yale has discovered a biological marker linked to individuals with PTSD who are most likely to think about suicide, the researchers report May 13 in the journal Proceedings of the National Academy of Sciences.

Researchers used PET imaging to measure levels of metabotropic glutamatergic receptor 5 (mGluR5) — which has been implicated in anxiety and mood disorders — in individuals with PTSD and major depressive disorder. They found high levels of mGluR5 in the PTSD group with current suicidal thoughts. They found no such elevated levels in the PTSD group with no suicidal thoughts or in those with depression, with or without current suicidal thoughts.

There are two FDA approved treatments for PTSD, both of which are anti-depressants. It can take weeks or months to determine whether they are effective. That can be too late for those who are suicidal, note the researchers.

“If you have people who suffer from high blood pressure, you want to reduce those levels right away,” said Irina Esterlis, associate professor of psychiatry at Yale and senior author of the study. “We don’t have that option with PTSD.”

Esterlis said testing for levels of mGluR5 in people who have experienced severe trauma might help identify those at greatest risk of harming themselves and prompt psychiatric interventions. Also, researchers might investigate ways to regulate levels mGluR5 with hopes of minimizing suicide risk in PTSD patients, she said.

https://news.yale.edu/2019/05/13/biomarker-reveals-ptsd-sufferers-risk-suicide

Summary: Newly identified ‘extinction neurons’ in the hippocampus suppress fearful memories when activated, and allow the memories to return when deactivated. The findings may provide new treatment avenues for PTSD, phobias, and anxiety.

Neuroscientists at The University of Texas at Austin have discovered a group of cells in the brain that are responsible when a frightening memory re-emerges unexpectedly, like Michael Myers in every “Halloween” movie. The finding could lead to new recommendations about when and how often certain therapies are deployed for the treatment of anxiety, phobias and post-traumatic stress disorder (PTSD).

In the new paper, out today in the journal Nature Neuroscience, researchers describe identifying “extinction neurons,” which suppress fearful memories when they are activated or allow fearful memories to return when they are not.

Since the time of Pavlov and his dogs, scientists have known that memories we thought we had put behind us can pop up at inconvenient times, triggering what is known as spontaneous recovery, a form of relapse. What they didn’t know was why it happened.

“There is frequently a relapse of the original fear, but we knew very little about the mechanisms,” said Michael Drew, associate professor of neuroscience and the senior author of the study. “These kinds of studies can help us understand the potential cause of disorders, like anxiety and PTSD, and they can also help us understand potential treatments.”

One of the surprises to Drew and his team was finding that brain cells that suppress fear memories hid in the hippocampus. Traditionally, scientists associate fear with another part of the brain, the amygdala. The hippocampus, responsible for many aspects of memory and spatial navigation, seems to play an important role in contextualizing fear, for example, by tying fearful memories to the place where they happened.

The discovery may help explain why one of the leading ways to treat fear-based disorders, exposure therapy, sometimes stops working. Exposure therapy promotes the formation of new memories of safety that can override an original fear memory. For example, if someone becomes afraid of spiders after being bitten by one, he might undertake exposure therapy by letting a harmless spider crawl on him. The safe memories are called “extinction memories.”

“Extinction does not erase the original fear memory but instead creates a new memory that inhibits or competes with the original fear,” Drew said. “Our paper demonstrates that the hippocampus generates memory traces of both fear and extinction, and competition between these hippocampal traces determines whether fear is expressed or suppressed.”

Given this, recommended practices around the frequency and timing of exposure therapy may need revisiting, and new pathways for drug development may be explored.

In experiments, Drew and his team placed mice in a distinctive box and induced fear with a harmless shock. After that, when one of the mice was in the box, it would display fear behavior until, with repeated exposure to the box without a shock, the extinction memories formed, and the mouse was not afraid.

Scientists were able to artificially activate the fear and suppress the extinction trace memories by using a tool called optogenetics to turn the extinction neurons on and off again.

“Artificially suppressing these so-called extinction neurons causes fear to relapse, whereas stimulating them prevents fear relapse,” Drew said. “These experiments reveal potential avenues for suppressing maladaptive fear and preventing relapse.”

The studies were led by graduate student Anthony Lacagnina of The University of Texas at Austin, with contributions from Emma Brockway, Chelsea Crovetti, Francis Shue, Meredith McCarty and Kevin Sattler of The University of Texas; and Sean Lim, Sofia Leal Santos and Christine Denny of Columbia University.

https://neurosciencenews.com/ptsd-hippocampus-fear-10966/

by PETER DOCKRILL

When bad things happen, we don’t want to remember. We try to block, resist, ignore – but we should perhaps be doing the opposite, researchers say.

A new study led by scientists in Texas suggests the act of intentionally forgetting is linked to increased cerebral engagement with the unwanted information in question. In other words, to forget something, you actually need to focus on it.

“A moderate level of brain activity is critical to this forgetting mechanism,” explains psychologist Tracy Wang from the University of Texas at Austin.

“Too strong, and it will strengthen the memory; too weak, and you won’t modify it.”

Trying to actively forget unwanted memories doesn’t just help prevent your brain from getting overloaded.

It also lets people move on from painful experiences and emotions they’d rather not recall, which is part of the reason it’s an area of active interest to neuroscientists.

“We may want to discard memories that trigger maladaptive responses, such as traumatic memories, so that we can respond to new experiences in more adaptive ways,” says one of the researchers, Jarrod Lewis-Peacock.

“Decades of research has shown that we have the ability to voluntarily forget something, but how our brains do that is still being questioned.”

Much prior research on intentional forgetting has focussed on brain activity in the prefrontal cortex, and the brain’s memory centre, the hippocampus.

In the new study, the researchers monitored a different part of the brain called the ventral temporal cortex, which helps us process and categorise visual stimuli.

In an experiment with 24 healthy young adults, the participants were shown pictures of scenes and people’s faces, and were instructed to either remember or forget each image.

During the experiment, each of the participants had their brain activity monitored by functional magnetic resonance imaging (fMRI) machines.

When the researchers examined activity in the ventral temporal cortex, they found that the act of forgetting effectively uses more brain power than remembering.

“Pictures followed by a forget instruction elicited higher levels of processing in [the] ventral temporal cortex compared to those followed by a remember instruction,” the authors write in their paper.

“This boost in processing led to more forgetting, particularly for items that showed moderate (vs. weak or strong) activation.”

Of course, forgetting specific images on demand in a contrived laboratory experiment is very different to moving on from painful or traumatic memories of events experienced in the real world.

But the mechanisms at work could be the same, researchers say, and figuring out how to activate them could be a huge benefit to people around the world who need to forget things, but don’t know how.

Especially since this finding in particular challenges our natural intuition to suppress things; instead, we should involve more rather than less attention to unwanted information, in order to forget it.

“Importantly, it’s the intention to forget that increases the activation of the memory,” Wang says.

“When this activation hits the ‘moderate level’ sweet spot, that’s when it leads to later forgetting of that experience.”

The findings are reported in JNeurosci.

https://www.sciencealert.com/to-forget-something-you-need-to-think-about-it-neuroscientists-reveal


Pinpoint stimulation of a cluster of nerve cells in the brains of mice encouraged timid responses to a perceived threat, whereas stimulation of an adjacent cluster induced boldness and courage.

Researchers at the Stanford University School of Medicine have identified two adjacent clusters of nerve cells in the brains of mice whose activity level upon sighting a visual threat spells the difference between a timid response and a bold or even fierce one.

Located smack-dab in the middle of the brain, these clusters, or nuclei, each send signals to a different area of the brain, igniting opposite behaviors in the face of a visual threat. By selectively altering the activation levels of the two nuclei, the investigators could dispose the mice to freeze or duck into a hiding space, or to aggressively stand their ground, when approached by a simulated predator.

People’s brains probably possess equivalent circuitry, said Andrew Huberman, PhD, associate professor of neurobiology and of ophthalmology. So, finding ways to noninvasively shift the balance between the signaling strengths of the two nuclei in advance of, or in the midst of, situations that people perceive as threatening may help people with excessive anxiety, phobias or post-traumatic stress disorder lead more normal lives.

“This opens the door to future work on how to shift us from paralysis and fear to being able to confront challenges in ways that make our lives better,” said Huberman, the senior author of a paper describing the experimental results. It was published online May 2 in Nature. Graduate student Lindsey Salay is the lead author.

Perilous life of a mouse
There are plenty of real threats in a mouse’s world, and the rodents have evolved to deal with those threats as best they can. For example, they’re innately afraid of aerial predators, such as a hawk or owl swooping down on them. When a mouse in an open field perceives a raptor overhead, it must make a split-second decision to either freeze, making it harder for the predator to detect; duck into a shelter, if one is available; or to run for its life.

To learn how brain activity changes in the face of such a visual threat, Salay simulated a looming predator’s approach using a scenario devised some years ago by neurobiologist Melis Yilmaz Balban, PhD, now a postdoctoral scholar in Huberman’s lab. It involves a chamber about the size of a 20-gallon fish tank, with a video screen covering most of its ceiling. This overhead screen can display an expanding black disc simulating a bird-of-prey’s aerial approach.

Looking for brain regions that were more active in mice exposed to this “looming predator” than in unexposed mice, Salay pinpointed a structure called the ventral midline thalamus, or vMT.

Salay mapped the inputs and outputs of the vMT and found that it receives sensory signals and inputs from regions of the brain that register internal brain states, such as arousal levels. But in contrast to the broad inputs the vMT receives, its output destination points were remarkably selective. The scientists traced these outputs to two main destinations: the basolateral amygdala and the medial prefrontal cortex. Previous work has tied the amygdala to the processing of threat detection and fear, and the medial prefrontal cortex is associated with high-level executive functions and anxiety.

Further inquiry revealed that the nerve tract leading to the basolateral amygdala emanates from a nerve-cell cluster in the vMT called the xiphoid nucleus. The tract that leads to the medial prefrontal cortex, the investigators learned, comes from a cluster called the nucleus reuniens, which snugly envelopes the xiphoid nucleus.

Next, the investigators selectively modified specific sets of nerve cells in mice’s brains so they could stimulate or inhibit signaling in these two nerve tracts. Exclusively stimulating xiphoid activity markedly increased mice’s propensity to freeze in place in the presence of a perceived aerial predator. Exclusively boosting activity in the tract running from the nucleus reuniens to the medial prefrontal cortex in mice exposed to the looming-predator stimulus radically increased a response seldom seen under similar conditions in the wild or in previous open-field experiments: The mice stood their ground, right out in the open, and rattled their tails, an action ordinarily associated with aggression in the species.

Thumping tails

This “courageous” behavior was unmistakable, and loud, Huberman said. “You could hear their tails thumping against the side of the chamber. It’s the mouse equivalent of slapping and beating your chest and saying, ‘OK, let’s fight!’” The mice in which the nucleus reuniens was stimulated also ran around more in the chamber’s open area, as opposed to simply running toward hiding places. But it wasn’t because nucleus reuniens stimulation put ants in their pants; in the absence of a simulated looming predator, the same mice just chilled out.

In another experiment, the researchers showed that stimulating mice’s nucleus reuniens for 30 seconds before displaying the “looming predator” induced the same increase in tail rattling and running around in the unprotected part of the chamber as did vMT stimulation executed concurrently with the display. This suggests, Huberman said, that stimulating nerve cells leading from the nucleus reunions to the prefrontal cortex induces a shift in the brain’s internal state, predisposing mice to act more boldly.

Another experiment pinpointed the likely nature of that internal-state shift: arousal of the autonomic nervous system, which kick-starts the fight, flight or freeze response. Stimulating either the vMT as a whole or just the nucleus reuniens increased the mice’s pupil diameter — a good proxy of autonomic arousal.

On repeated exposures to the looming-predator mockup, the mice became habituated. Their spontaneous vMT firing diminished, as did their behavioral responses. This correlates with lowered autonomic arousal levels.

Human brains harbor a structure equivalent to the vMT, Huberman said. He speculated that in people with phobias, constant anxiety or PTSD, malfunctioning circuitry or traumatic episodes may prevent vMT signaling from dropping off with repeated exposure to a stress-inducing situation. In other experiments, his group is now exploring the efficacy of techniques, such as deep breathing and relaxation of visual fixation, in adjusting the arousal states of people suffering from these problems. The thinking is that reducing vMT signaling in such individuals, or altering the balance of signaling strength from their human equivalents of the xiphoid nucleus and nucleus reuniens may increase their flexibility in coping with stress.

Reference:
Salay, L. D., Ishiko, N., & Huberman, A. D. (2018). A midline thalamic circuit determines reactions to visual threat. Nature. doi:10.1038/s41586-018-0078-2

http://med.stanford.edu/news/all-news/2018/05/scientists-find-fear-courage-switches-in-brain.html

mdma

By DAVE PHILIPPS

After three tours in Iraq and Afghanistan, C. J. Hardin wound up hiding from the world in a backwoods cabin in North Carolina. Divorced, alcoholic and at times suicidal, he had tried almost all the accepted treatments for post-traumatic stress disorder: psychotherapy, group therapy and nearly a dozen different medications.

“Nothing worked for me, so I put aside the idea that I could get better,” said Mr. Hardin, 37. “I just pretty much became a hermit in my cabin and never went out.”

Then, in 2013, he joined a small drug trial testing whether PTSD could be treated with MDMA, the illegal party drug better known as Ecstasy.

“It changed my life,” he said in a recent interview in the bright, airy living room of the suburban ranch house here, where he now lives while going to college and working as an airplane mechanic. “It allowed me to see my trauma without fear or hesitation and finally process things and move forward.”

Based on promising results like Mr. Hardin’s, the Food and Drug Administration gave permission Tuesday for large-scale, Phase 3 clinical trials of the drug — a final step before the possible approval of Ecstasy as a prescription drug.

If successful, the trials could turn an illicit street substance into a potent treatment for PTSD.

Through a spokeswoman, the F.D.A. declined to comment, citing regulations that prohibit disclosing information about drugs that are being developed.

“I’m cautious but hopeful,” said Dr. Charles R. Marmar, the head of psychiatry at New York University’s Langone School of Medicine, a leading PTSD researcher who was not involved in the study. “If they can keep getting good results, it will be of great use. PTSD can be very hard to treat. Our best therapies right now don’t help 30 to 40 percent of people. So we need more options.”

But he expressed concern about the potential for abuse. “It’s a feel-good drug, and we know people are prone to abuse it,” he said. “Prolonged use can lead to serious damage to the brain.”

The Multidisciplinary Association for Psychedelic Studies, a small nonprofit created in 1985 to advocate the legal medical use of MDMA, LSD, marijuana and other banned drugs, sponsored six Phase 2 studies treating a total of 130 PTSD patients with the stimulant. It will also fund the Phase 3 research, which will include at least 230 patients.

Two trials here in Charleston focused on treating combat veterans, sexual assault victims, and police and firefighters with PTSD who had not responded to traditional prescription drugs or psychotherapy. Patients had, on average, struggled with symptoms for 17 years.

After three doses of MDMA administered under a psychiatrist’s guidance, the patients reported a 56 percent decrease of severity of symptoms on average, one study found. By the end of the study, two-thirds no longer met the criteria for having PTSD. Follow-up examinations found that improvements lasted more than a year after therapy.

“We can sometimes see this kind of remarkable improvement in traditional psychotherapy, but it can take years, if it happens at all,” said Dr. Michael C. Mithoefer, the psychiatrist who conducted the trials here. “We think it works as a catalyst that speeds the natural healing process.”

The researchers are so optimistic that they have applied for so-called breakthrough therapy status with the Food and Drug Administration, which would speed the approval process. If approved, the drug could be available by 2021.

Under the researchers’ proposal for approval, the drug would be used a limited number of times in the presence of trained psychotherapists as part of a broader course of therapy. But even in those controlled circumstances, some scientists worry that approval as a therapy could encourage more illegal recreational use.

“It sends the message that this drug will help you solve your problems, when often it just creates problems,” said Andrew Parrott, a psychologist at Swansea University in Wales who has studied the brains of chronic Ecstasy users. “This is a messy drug we know can do damage.”

Allowing doctors to administer the drug to treat a disorder, he warned, could inadvertently lead to a wave of abuse similar to the current opioid crisis.

During initial studies, patients went through 12 weeks of psychotherapy, including three eight-hour sessions in which they took MDMA. During the sessions, they lay on a futon amid candles and fresh flowers, listening to soothing music.

Dr. Mithoefer and his wife, Ann Mithoefer, and often their portly terrier mix, Flynn, sat with each patient, guiding them through traumatic memories.

“The medicine allows them to look at things from a different place and reclassify them,” said Ms. Mithoefer, a psychiatric nurse. “Honestly, we don’t have to do much. Each person has an innate ability to heal. We just create the right conditions.”

Research has shown that the drug causes the brain to release a flood of hormones and neurotransmitters that evoke feelings of trust, love and well-being, while also muting fear and negative emotional memories that can be overpowering in patients with post-traumatic stress disorder. Patients say the drug gave them heightened clarity and ability to address their problems.

For years after his combat deployments, Mr. Hardin said he was sleepless and on edge. His dreams were marked with explosions and death. The Army gave him sleeping pills and antidepressants. When they didn’t work, he turned to alcohol and began withdrawing from the world.

“I just felt hopeless and in the dark,” he said. “But the MDMA sessions showed me a light I could move toward. Now I’m out of the darkness and the world is all around me.”

Since the trial, he has gone back to school and remarried.

The chemist Alexander Shulgin first realized the euphoria-inducing traits of MDMA in the 1970s, and introduced it to psychologists he knew. Under the nickname Adam, thousands of psychologists began to use it as an aid for therapy sessions. Some researchers at the time thought the drug could be helpful for anxiety disorders, including PTSD, but before formal clinical trails could start, Adam spread to dance clubs and college campuses under the name Ecstasy, and in 1985, the Drug Enforcement Administration made it a Schedule 1 drug, barring all legal use.

Since then, the number of people seeking treatment for PTSD has exploded and psychiatry has struggled to keep pace. Two drugs approved for treating the disorder worked only mildly better than placebos in trials. Current psychotherapy approaches are often slow and many patients drop out when they don’t see results. Studies have shown combat veterans are particularly hard to treat.

In interviews, study participants said MDMA therapy had not only helped them with painful memories, but also had helped them stop abusing alcohol and other drugs and put their lives back together.

On a recent evening, Edward Thompson, a former firefighter, tucked his twin 4-year-old girls into bed, turned on their night light, then joined his wife at a backyard fire.

“If it weren’t for MDMA … ” he said.

“He’d be dead,” his wife, Laura, finished.

They both nodded.

Years of responding to gory accidents left Mr. Thompson, 30, in a near constant state of panic that he had tried to numb with alcohol and prescription opiates and benzodiazepines.

By 2015, efforts at therapy had failed, and so had several family interventions. His wife had left with their children, and he was considering jumping in front of a bus.

A member of a conservative Anglican church, Mr. Thompson had never used illegal drugs. But he was struggling with addiction from his prescription drugs, so he at first rejected a suggestion by his therapist that he enter the study. “In the end, I was out of choices,” he said.

Three sessions with the drug gave him the clarity, he said, to identify his problems and begin to work through them. He does not wish to take the drug again.

“It gave me my life back, but it wasn’t a party drug,” he said. “It was a lot of work.”

http://mobile.nytimes.com/2016/11/29/us/ptsd-mdma-ecstasy.html