Friday, May 29, 2015

Hacking the Nervous System - Vagal Nerve Stimulation to Control Inflammation (from Mosaic)

From Mosaic, this is an excellent article on the medical aspect of polyvagal theory. Those who work in the psychological trauma field already know a little or a lot about polyvagal theory from the work of Stephen Porges (as well as Bessel van der Kolk and Peter Levine, who have done a lot to get Porges' work better known) - see Porges' The Polyvagal Theory: Neurophysiological Foundations of Emotions, Attachment, Communication, and Self-regulation.

In this piece by Gaia Vince, the role of the vagus nerve in physical issues, such as autoimmune disorders is examined. Controlling inflammation through vagal stimulation could be a HUGE breakthrough in treating nearly all forms of disease (which are inflammatory illnesses at the molecular level).

© Job Boot

Hacking the nervous system

One nerve connects your vital organs, sensing and shaping your health. If we learn to control it, the future of medicine will be electric. 

By Gaia Vince.

When Maria Vrind, a former gymnast from Volendam in the Netherlands, found that the only way she could put her socks on in the morning was to lie on her back with her feet in the air, she had to accept that things had reached a crisis point. “I had become so stiff I couldn’t stand up,” she says. “It was a great shock because I’m such an active person.”

It was 1993. Vrind was in her late 40s and working two jobs, athletics coach and a carer for disabled people, but her condition now began taking over her life. “I had to stop my jobs and look for another one as I became increasingly disabled myself.” By the time she was diagnosed, seven years later, she was in severe pain and couldn’t walk any more. Her knees, ankles, wrists, elbows and shoulder joints were hot and inflamed. It was rheumatoid arthritis, a common but incurable autoimmune disorder in which the body attacks its own cells, in this case the lining of the joints, producing chronic inflammation and bone deformity.

Waiting rooms outside rheumatoid arthritis clinics used to be full of people in wheelchairs. That doesn’t happen as much now because of a new wave of drugs called biopharmaceuticals – such as highly targeted, genetically engineered proteins – which can really help. Not everyone feels better, however: even in countries with the best healthcare, at least 50 per cent of patients continue to suffer symptoms.

Like many patients, Vrind was given several different medications, including painkillers, a cancer drug called methotrexate to dampen her entire immune system, and biopharmaceuticals to block the production of specific inflammatory proteins. The drugs did their job well enough – at least, they did until one day in 2011, when they stopped working.

“I was on holiday with my family and my arthritis suddenly became terrible and I couldn’t walk – my daughter-in-law had to wash me.” Vrind was rushed to hospital, where she was hooked up to an intravenous drip and given another cancer drug, one that targeted her white blood cells. “It helped,” she admits, but she was nervous about relying on such a drug long-term.

Luckily, she would not have to. As she was resigning herself to a life of disability and monthly chemotherapy, a new treatment was being developed that would profoundly challenge our understanding of how the brain and body interact to control the immune system. It would open up a whole new approach to treating rheumatoid arthritis and other autoimmune diseases, using the nervous system to modify inflammation. It would even lead to research into how we might use our minds to stave off disease.

And, like many good ideas, it came from an unexpected source.

© Job Boot

The nerve hunter

Kevin Tracey, a neurosurgeon based in New York, is a man haunted by personal events – a man with a mission. “My mother died from a brain tumour when I was five years old. It was very sudden and unexpected,” he says. “And I learned from that experience that the brain – nerves – are responsible for health.” This drove his decision to become a brain surgeon. Then, during his hospital training, he was looking after a patient with serious burns who suddenly suffered severe inflammation. “She was an 11-month-old baby girl called Janice who died in my arms.”

These traumatic moments made him a neurosurgeon who thinks a lot about inflammation. He believes it was this perspective that enabled him to interpret the results of an accidental experiment in a new way.
In the late 1990s, Tracey was experimenting with a rat’s brain. “We’d injected an anti-inflammatory drug into the brain because we were studying the beneficial effect of blocking inflammation during a stroke,” he recalls. “We were surprised to find that when the drug was present in the brain, it also blocked inflammation in the spleen and in other organs in the rest of the body. Yet the amount of drug we’d injected was far too small to have got into the bloodstream and travelled to the rest of the body.” 

After months puzzling over this, he finally hit upon the idea that the brain might be using the nervous system – specifically the vagus nerve – to tell the spleen to switch off inflammation everywhere.
It was an extraordinary idea – if Tracey was right, inflammation in body tissues was being directly regulated by the brain. Communication between the immune system’s specialist cells in our organs and bloodstream and the electrical connections of the nervous system had been considered impossible. Now Tracey was apparently discovering that the two systems were intricately linked.

The first critical test of this exciting hypothesis was to cut the vagus nerve. When Tracey and his team did, injecting the anti-inflammatory drug into the brain no longer had an effect on the rest of the body. The second test was to stimulate the nerve without any drug in the system. “Because the vagus nerve, like all nerves, communicates information through electrical signals, it meant that we should be able to replicate the experiment by putting a nerve stimulator on the vagus nerve in the brainstem to block inflammation in the spleen,” he explains. “That’s what we did and that was the breakthrough experiment.”

© Job Boot

The wandering nerve

The vagus nerve starts in the brainstem, just behind the ears. It travels down each side of the neck, across the chest and down through the abdomen. ‘Vagus’ is Latin for ‘wandering’ and indeed this bundle of nerve fibres roves through the body, networking the brain with the stomach and digestive tract, the lungs, heart, spleen, intestines, liver and kidneys, not to mention a range of other nerves that are involved in speech, eye contact, facial expressions and even your ability to tune in to other people’s voices. It is made of thousands and thousands of fibres and 80 per cent of them are sensory, meaning that the vagus nerve reports back to your brain what is going on in your organs.

Operating far below the level of our conscious minds, the vagus nerve is vital for keeping our bodies healthy. It is an essential part of the parasympathetic nervous system, which is responsible for calming organs after the stressed ‘fight-or-flight’ adrenaline response to danger. Not all vagus nerves are the same, however: some people have stronger vagus activity, which means their bodies can relax faster after a stress. 
The strength of your vagus response is known as your vagal tone and it can be determined by using an electrocardiogram to measure heart rate. Every time you breathe in, your heart beats faster in order to speed the flow of oxygenated blood around your body. Breathe out and your heart rate slows. This variability is one of many things regulated by the vagus nerve, which is active when you breathe out but suppressed when you breathe in, so the bigger your difference in heart rate when breathing in and out, the higher your vagal tone.

Research shows that a high vagal tone makes your body better at regulating blood glucose levels, reducing the likelihood of diabetes, stroke and cardiovascular disease. Low vagal tone, however, has been associated with chronic inflammation. As part of the immune system, inflammation has a useful role helping the body to heal after an injury, for example, but it can damage organs and blood vessels if it persists when it is not needed. One of the vagus nerve’s jobs is to reset the immune system and switch off production of proteins that fuel inflammation. Low vagal tone means this regulation is less effective and inflammation can become excessive, such as in Maria Vrind’s rheumatoid arthritis or in toxic shock syndrome, which Kevin Tracey believes killed little Janice.

Having found evidence of a role for the vagus in a range of chronic inflammatory diseases, including rheumatoid arthritis, Tracey and his colleagues wanted to see if it could become a possible route for treatment. The vagus nerve works as a two-way messenger, passing electrochemical signals between the organs and the brain. In chronic inflammatory disease, Tracey figured, messages from the brain telling the spleen to switch off production of a particular inflammatory protein, tumour necrosis factor (TNF), weren’t being sent. Perhaps the signals could be boosted?

He spent the next decade meticulously mapping all the neural pathways involved in regulating TNF, from the brainstem to the mitochondria inside all our cells. Eventually, with a robust understanding of how the vagus nerve controlled inflammation, Tracey was ready to test whether it was possible to intervene in human disease.

© Job Boot

Stimulating trial

In the summer of 2011, Maria Vrind saw a newspaper advertisement calling for people with severe rheumatoid arthritis to volunteer for a clinical trial. Taking part would involve being fitted with an electrical implant directly connected to the vagus nerve. “I called them immediately,” she says. “I didn’t want to be on anticancer drugs my whole life; it’s bad for your organs and not good long-term.”

Tracey had designed the trial with his collaborator, Paul-Peter Tak, professor of rheumatology at the University of Amsterdam. Tak had long been searching for an alternative to strong drugs that suppress the immune system to treat rheumatoid arthritis. “The body’s immune response only becomes a problem when it attacks your own body rather than alien cells, or when it is chronic,” he reasoned. “So the question becomes: how can we enhance the body’s switch-off mechanism? How can we drive resolution?”

When Tracey called him to suggest stimulating the vagus nerve might be the answer by switching off production of TNF, Tak quickly saw the potential and was enthusiastic to see if it would work. Vagal nerve stimulation had already been approved in humans for epilepsy, so getting approval for an arthritis trial would be relatively straightforward. A more serious potential hurdle was whether people used to taking drugs for their condition would be willing to undergo an operation to implant a device inside their body: “There was a big question mark about whether patients would accept a neuroelectric device like a pacemaker,” Tak says.

He needn’t have worried. More than a thousand people expressed interest in the procedure, far more than were needed for the trial. In November 2011, Vrind was the first of 20 Dutch patients to be operated on.

“They put the pacemaker on the left-hand side of my chest, with wires that go up and attach to the vagus nerve in my throat,” she says. “I waited two weeks while the area healed, and then the doctors switched it on and adjusted the settings for me.”

She was given a magnet to swipe across her throat six times a day, activating the implant and stimulating her vagus nerve for 30 seconds at a time. The hope was that this would reduce the inflammatory response in her spleen. As Vrind and the other trial participants were sent home, it became a waiting game for Tracey, Tak and the team to see if the theory, lab studies and animal trials would bear fruit in real patients. “We hoped that for some, there would be an easing of their symptoms – perhaps their joints would become a little less painful,” Tak says.

At first, Vrind was a bit too eager for a miracle cure. She immediately stopped taking her pills, but her symptoms came back so badly that she was bedridden and in terrible pain. She went back on the drugs and they were gradually reduced over a week instead.

And then the extraordinary happened: Vrind experienced a recovery more remarkable than she or the scientists had dared hope for.

“Within a few weeks, I was in a great condition,” she says. “I could walk again and cycle, I started ice-skating again and got back to my gymnastics. I feel so much better.” She is still taking methotrexate, which she will need at a low dose for the rest of her life, but at 68, semi-retired Vrind now plays and teaches seniors’ volleyball a couple of hours a week, cycles for at least an hour every day, does gymnastics, and plays with her eight grandchildren.

Other patients on the trial had similar transformative experiences. The results are still being prepared for publication but Tak says more than half of the patients showed significant improvement and around one-third are in remission – in effect cured of their rheumatoid arthritis. Sixteen of the 20 patients on the trial not only felt better, but measures of inflammation in their blood also went down. Some are now entirely drug-free. Even those who have not experienced clinically significant improvements with the implant insist it helps them; nobody wants it removed.

“We have shown very clear trends with stimulation of three minutes a day,” Tak says. “When we discontinued stimulation, you could see disease came back again and levels of TNF in the blood went up. We restarted stimulation, and it normalised again.”

Tak suspects that patients will continue to need vagal nerve stimulation for life. But unlike the drugs, which work by preventing production of immune cells and proteins such as TNF, vagal nerve stimulation seems to restore the body’s natural balance. It reduces the over-production of TNF that causes chronic inflammation but does not affect healthy immune function, so the body can respond normally to infection.

“I’m really glad I got into the trial,” says Vrind. “It’s been more than three years now since the implant and my symptoms haven’t returned. At first I felt a pain in my head and throat when I used it, but within a couple of days, it stopped. Now I don’t feel anything except a tightness in my throat and my voice trembles while it’s working.

“I have occasional stiffness or a little pain in my knee sometimes but it’s gone in a couple of hours. I don’t have any side-effects from the implant, like I had with the drugs, and the effect is not wearing off, like it did with the drugs.”

© Job Boot

Raising the tone

Having an electrical device surgically implanted into your neck for the rest of your life is a serious procedure. But the technique has proved so successful – and so appealing to patients – that other researchers are now looking into using vagal nerve stimulation for a range of other chronic debilitating conditions, including inflammatory bowel disease, asthma, diabetes, chronic fatigue syndrome and obesity.

But what about people who just have low vagal tone, whose physical and mental health could benefit from giving it a boost? Low vagal tone is associated with a range of health risks, whereas people with high vagal tone are not just healthier, they’re also socially and psychologically stronger – better able to concentrate and remember things, happier and less likely to be depressed, more empathetic and more likely to have close friendships. 
Twin studies show that to a certain extent, vagal tone is genetically predetermined – some people are born luckier than others. But low vagal tone is more prevalent in those with certain lifestyles – people who do little exercise, for example. This led psychologists at the University of North Carolina at Chapel Hill to wonder if the relationship between vagal tone and wellbeing could be harnessed without the need for implants.

In 2010, Barbara Fredrickson and Bethany Kok recruited around 70 university staff members for an experiment. Each volunteer was asked to record the strength of emotions they felt every day. Vagal tone was measured at the beginning of the experiment and at the end, nine weeks later. As part of the experiment, half of the participants were taught a meditation technique to promote feelings of goodwill towards themselves and others.

Those who meditated showed a significant rise in vagal tone, which was associated with reported increases in positive emotions. “That was the first experimental evidence that if you increased positive emotions and that led to increased social closeness, then vagal tone changed,” Kok says.

Now at the Max Planck Institute in Germany, Kok is conducting a much larger trial to see if the results they found can be replicated. If so, vagal tone could one day be used as a diagnostic tool. In a way, it already is. “Hospitals already track heart-rate variability – vagal tone – in patients that have had a heart attack,” she says, “because it is known that having low variability is a risk factor.”

The implications of being able to simply and cheaply improve vagal tone, and so relieve major public health burdens such as cardiovascular conditions and diabetes, are enormous. It has the potential to completely change how we view disease. If visiting your GP involved a check on your vagal tone as easily as we test blood pressure, for example, you could be prescribed therapies to improve it. But this is still a long way off: “We don’t even know yet what a healthy vagal tone looks like,” cautions Kok. “We’re just looking at ranges, we don’t have precise measurements like we do for blood pressure.”

What seems more likely in the shorter term is that devices will be implanted for many diseases that today are treated by drugs: “As the technology improves and these devices get smaller and more precise,” says Kevin Tracey, “I envisage a time where devices to control neural circuits for bioelectronic medicine will be injected – they will be placed either under local anaesthesia or under mild sedation.”

However the technology develops, our understanding of how the body manages disease has changed for ever. “It’s become increasingly clear that we can’t see organ systems in isolation, like we did in the past,” says Paul-Peter Tak. “We just looked at the immune system and therefore we have medicines that target the immune system. 
“But it’s very clear that the human is one entity: mind and body are one. It sounds logical but it’s not how we looked at it before. We didn’t have the science to agree with what may seem intuitive. Now we have new data and new insights.”

And Maria Vrind, who despite severe rheumatoid arthritis can now cycle pain-free around Volendam, has a new lease of life: “It’s not a miracle – they told me how it works through electrical impulses – but it feels magical. I don’t want them to remove it ever. I have my life back!”

Thursday, May 28, 2015

How Perpetrators Make Themselves the Vicitms: "Deny, Attack, and Reverse Victim and Offender" (DARVO)

It's a well-known feature of perpetrators that they generally deny what they have done, attack the accusers (often attempting to destroy their character), and then reverse the situation so that they claim to be the victims.

If you have any doubt about this, look closely at EVERY situation in which Marc Gafni has been accused of sexually inappropriate relationships with his students (often two or more at a time), which includes forcing them to lie about the relationships and controlling their contact with others outside his circle of trust.

Psychologist Jennifer J. Freyd, at the University of Oregon, has detailed this behavior in a model she calls DARVO = Deny, Attack, and Reverse Victim and Offender. What follows comes from her web page on this topic. Freyd is one of the world's experts on betrayal trauma.

Her books include:
Freyd, J.J. (2014). What is DARVO? Retrieved 5.28.2015 from

What is DARVO?

Jennifer J. Freyd, University of Oregon

Short Definition

DARVO refers to a reaction perpetrators of wrong doing, particularly sexual offenders, may display in response to being held accountable for their behavior. DARVO stands for "Deny, Attack, and Reverse Victim and Offender." The perpetrator or offender may Deny the behavior, Attack the individual doing the confronting, and Reverse the roles of Victim and Offender such that the perpetrator assumes the victim role and turns the true victim -- or the whistle blower -- into an alleged offender. This occurs, for instance, when an actually guilty perpetrator assumes the role of "falsely accused" and attacks the accuser's credibility or even blames the accuser of being the perpetrator of a false accusation. 
  • DARVO as a concept is based on observation and analysis. The author has not completed systematic empirical research testing the coherence or frequency of DARVO. However, research is currently in progress in the author's laboratory at the University of Oregon.
  • Other observers have likely noted the same phenomena and related phenomena using different terms; the author has been informed that some people have found the term DARVO a helpful mnemonic and organizing concept.
  • Also the presence of DARVO is not necessarily evidence in support of the accusation of guilt; a truly innocent person may deny an accusation, attack the person making the accusation, or claim the victim role. Future research may be able to determine the probability of a DARVO response as a function of guilt or innocence. The author hypothesized that some sorts of denials and reactions such as DARVO are more likely when the perpetrator is guilty than innocent (Freyd, 1997); however this hypothesis has not yet been tested. Furthermore, even if research indicates that a DARVO reaction is more likely when there is actual guilt, it would be an error to use a DARVO reaction as proof of guilt.
  • For now the concept of DARVO is offered as potentially memorable and useful term for anticipating the behavior of perpetrators when held accountable, and for making sense of responses that may otherwise be confusing (particularly when victim and offender get reversed). Research is needed.
History of Terminology & Writings about DARVO

Jennifer Freyd introduced the term "DARVO" near the end of a 1997 publication about her primary research focus, "betrayal trauma theory." (For more on betrayal trauma theory, see

The reference for the 1997 article introducing the term is:

Freyd, J.J. (1997) Violations of power, adaptive blindness, and betrayal trauma theory. Feminism & Psychology, 7, 22-32.
In that paper Freyd explained that DARVO responses may be effective for perpetrators. "...I have observed that actual abusers threaten, bully and make a nightmare for anyone who holds them accountable or asks them to change their abusive behavior. This attack, intended to chill and terrify, typically includes threats of law suits, overt and covert attacks on the whistle-blower's credicility, and so on..... [T]he offender rapidly creates the impression that the abuser is the wronged one, while the victim or concerned observer is the offender. Figure and ground are completely reversed... The offender is on the offense and the person attempting to hold the offender accountable is put on the defense." (Freyd, 1997, p 29-30)

These ideas were further developed in an article by Veldhuis and Freyd (1999):

Veldhuis, C. B., & Freyd, J. J. (1999). Groomed for silence, groomed for betrayal. In M. Rivera (Ed.), Fragment by Fragment: Feminist Perspectives on Memory and Child Sexual Abuse (pp. 253-282). Charlottetown, PEI Canada: Gynergy Books.
In the 1999 article Veldhuis and Freyd explore the separate components of DARVO, and they also note a connection between DARVO and "betrayal blindness," a concept from betrayal trauma theory (Freyd, 1996).
"By denying, attacking and reversing perpetrators into victims, reality gets even more confusing and unspeakable for the real victim. .... These perpetrator reactions increase the need for betrayal blindness. If the victim does speak out and gets this level of attack, she quickly gets the idea that silence is safer." (Veldhuis & Freyd, 1999. p 274).
Since then the concept of DARVO has appeared in various writings, the most significant of which is our new book Blind to Betrayal (Freyd & Birrell, 2013).

Blind to Betrayal: Why We Fool Ourselves We Aren't Being Fooled

In Blind to Betrayal we urge institutions to cherish the whistle blower (see p. 173) and we offer suggestions for specific steps institutions can take to prevent and repair institutional betrayal. In Blind to Betrayal we also talk about institutional denial which plays such a crucial role in instutional betrayal. DARVO is a particularly pernicious form of denial (see p 119 of Blind to Betrayal).
Two Common Types of Denial

Two common forms of perpetrator (or bystander) denial are:

  1. It didn't happen (an instance) or It rarely happens (a type of event)
  2. It wasn't harmful
Put together they can take the form: "It didn't happen, but if it did, it wasn't that bad" or "It rarely happens, but when it does it isn't harmful." The two claims both serve to deny, but they depend upon different sorts of evidence. They may both be true, but they are sometimes somewhat suspicious when claimed simultaneously (or by the same person at different times), as for instance can occur in response to allegations of rape or child sexual abuse.

Wednesday, May 20, 2015

Arthur Gillard Interviews the Creators of the SF / Lucid Dreaming Web Series "Anamnesis"

The following is a guest post from my friend Arthur Gillard. He recently interviewed the creators of the science fiction/lucid dreaming web series, Anamnesis. Here is a brief synopsis of the series, from the website:
When a woman dreams of her boyfriend’s death on the same night he’s murdered, she and a group of strangers begin to unravel a greater mystery by journeying into their subconscious.
An abbreviated version of this interview will appear soon in Lucid Dreaming Experience, a free online journal.

Enjoy the FULL interview!

Photo original

* * * * *

Interview with the Creators of the SF/ Lucid Dreaming Web Series Anamnesis by Arthur Gillard

Anamnesis is a science fiction web series about lucid dreaming based on an original short film of the same name. It has been getting a great deal of positive attention in the lucid dreaming community based on its accurate and realistic portrayal of lucid dreaming, as well as its compelling storyline, good acting, professional production values, and gorgeous cinematography. I had a chance recently to interview Alex Calleros, writer and director of the original short, and Michael Tucker, who co-wrote and co-directed the web series with Alex. 

The following interview may contain some spoilers, so I recommend watching the original short and the five episode web series before reading the interview. You can see the original short here, and the web series here. Altogether it takes a little over an hour to watch. 

You can find out more about the series by following them on Google Plus, Twitter [@AnamnesisSeries], or Facebook, or via email at

(Disclosure: I've agreed to manage the Anamnesis Google Plus page on a volunteer basis, without compensation.)

Arthur Gillard: Why did you decide to make a film/web series about lucid dreaming? Was it inspired by your own experiences with lucidity, or did you simply find the subject intriguing?

Alex Calleros: I’ve always been intrigued by the relationship between cinema and dreams. The experience of watching a film is often thought of as entering a sort of dream-state, and many of my favorite films play with questions of reality, consciousness, etc. The Matrix, Inception, Eternal Sunshine of the Spotless Mind—these films were huge influences for me as a filmmaker and I had always wanted to play in the world of dreams using cinema. So, when I had the opportunity to write and direct the short film in 2012, it was a chance to finally make a film that essentially takes place entirely in the dream world. One of my favorite films is The Fountain, which explores the theme of death in an incredibly profound way, and that was also a huge influence on the short film.

Michael Tucker: When we began thinking of how to continue the short film (which has a pretty definite conclusion), we played around with a lot of ideas. Alex’s close friend Gary Ruiz was very into lucid dreaming and had talked to Alex about it. The idea of becoming lucid within a dream world and being able to manipulate your surroundings fascinated us and seemed like a great concept to play with cinematically, as well as an idea we hadn’t seen done before. So we spent time researching lucid dreaming techniques and experiences, and grew attached to the idea of trying to portray the sensation of dreaming as accurately as possible. We didn’t want it to be blurry and fuzzy like how dreaming is often shown in TV shows, but we also didn’t want it to be as rigid and straight-forward as Inception. So finding that balance was our guiding light, and hopefully we achieved that to some degree.

Arthur: Could you explain the meaning of the word “anamnesis,” and how that relates to the themes explored in the series and the original short film?

Alex: The Google definition of anamnesis is:
1) recollection, in particular
2) the remembering of things from a supposed previous existence

I first discovered the word being used in a philosophical / spiritual context—anamnesis was used to describe the process of “awakening to” or “remembering” one’s true nature or identity. The original short film explores the theme of identity—who are you, really? That’s the question being asked of the main character, Adam, throughout the short. His process of remembering what he had forgotten forms the arc of the story, and I thought the word “anamnesis” represented that arc perfectly.

Arthur: How does the web series relate to the original short? Is it a straightforward continuation, or is it more like a reboot, a variation on a theme?

Michael: We wanted the web series to stand on its own for anyone who hadn’t seen the original short, but we also wanted people that had seen the short to be able to watch it as a continuation. So even though stylistically-speaking there are differences between them, story-wise we tried to make it as directly connected as we could.

Arthur: I understand that lucid dreaming expert and author Daniel Love consulted on the show. How did he get involved, and how closely did he work with you? Did he review scenes in the script and suggest changes? Did he suggest any details or scenes to include?

Michael: Daniel Love contacted us after he stumbled upon our Kickstarter campaign. He had just finished his book on lucid dreaming, “Are You Dreaming?” and sent us free copies to check out. We also took him up on his offer to look over the scripts as we were finalizing them, and he made several suggestions of how to tweak things so that they would be more accurate. He explained some reality tests that we hadn’t heard of, and helped us pinpoint exactly where and when the characters might use them. And since the series has released, he’s connected us with a lot of the lucid dreaming community, which has been amazing. So overall Daniel Love was a really big help.

Arthur: Who among the cast and crew of Anamnesis is a lucid dreamer? Could you share some of your own lucid dreams? Please go into as much detail as you are willing. To what extent did lucid dreams of the cast and crew influence how dreams are portrayed? Did working on Anamnesis influence your dreams?

Alex: Brad C. Wilcox, who plays Noah, had frequent lucid dreams for a period of his life. In fact, they had gotten so constant that he had to “cut back,” as he wasn’t feeling properly rested in the morning.

Michael: Zach Brown plays Sean, the show’s expert lucid dreamer. To prepare for the role, Zach researched lucid dreaming and practiced it in his daily life. He would actually draw the letter “A” on his hand, as Sean does in the show, as a reminder to ask himself, “Am I awake?” He told us about a lucid dream he had in which Whoopi Goldberg was his dream guide. It sounded pretty awesome.

Alex: I had a really striking wake-induced lucid dream during the production of Anamnesis. I had woken up extra-early one morning, and as I was falling back asleep I managed to maintain awareness. I’ll never forget the moment I passed into the dream state: all at once, I felt my body launch off the bed and hover for a moment near the ceiling of my bedroom. I passed through some sort of portal and found myself floating above the swimming pool in my childhood backyard in Arizona. I didn’t really have any control over what was happening; I was just along for the ride. My dream body plunged into the pool, where I was delighted to find I could breathe underwater. I looked up and watched in awe as raindrops created thousands of intricate ripples on the surface of the water. A red Arizona dust storm colored the sunlight filtering into the water. It was one of the most vibrant, beautiful visions I’ve ever beautiful that I got excited and promptly woke up. But that one really stuck with me.

Michael: The only lucid dream that I can for sure say was me becoming lucid happened during the midst of shooting the series. Between researching lucid dreaming, and writing the scripts, and then filming all the scenes, all of that information was swirling around in my head all the time. In my dream, I was in my high school cafeteria, looking around, when suddenly I remembered one of the reality tests that the character Hannah does in the show. She pinches her nose with her fingers in such a way that she shouldn’t be able to breathe in—but she can. So I thought, “eh, may as well give it a try and see what happens.” So I pinched my nose and then breathed in—and it worked! I suddenly realized I was dreaming, and immediately did a slow-motion backflip into the air and started to fly. I remember I knew exactly how to control my body in flight, how to turn, spin, everything. Unfortunately I became really overwhelmed by the excitement of it all. I tried to calm myself down so I wouldn’t wake up, but it was all too much and I woke up almost immediately after I started flying. It was a pretty awesome experience.

Arthur: I found the original short film particularly moving. The repeated inquiries into Adam's true identity and the suggestion that he was now “who he had always been” were suggestive and yet open to interpretation by the viewer—almost like a Zen koan, inviting a deeper look at one's own ultimate identity. Did any particular spiritual tradition or school of thought inform the original short film?

Alex: We made the short film as part of this year-long project where we asked our audience to send us 1-sentence constraints that we’d have to follow in our next film. One of the constraints for Anamnesis was: “The dialogue from one scene must be exactly the same in one scene as it is in another,” which fortuitously led to the idea of posing this question “Who are you?” to Adam throughout the movie. I definitely wanted to tap into a “Zen koan” feel with those repeated inquiries. Only at the end does he understand the at-first puzzling answer, “You’re who you’ve always been.”

Over the past several years, I’ve been really interested in Western-born philosophers who take the deep wisdom embedded in Eastern religions (Buddhism in particular) and translate/update them for the modern age. Alan Watts was one of the first to do this in the 50’s and 60’s, and hundreds of audio recordings of his wonderful lectures are widely available online today. Listening to him speak is both enlightening and incredibly fun (he’s got a delightful British accent and a sharp sense of humor). I’m also very interested in the work of American philosopher Ken Wilber, who has pioneered a movement to see the world “integrally,” integrating the truths of science, psychology, art, spirituality, etc. I believe I actually discovered the word “anamnesis” while reading an article by Wilber.

Arthur: In the original short, Hannah is seemingly portrayed as a powerful lucid dreamer, for example creating portals from one dream scene to another. “I know my way around in here,” she remarks to Adam at one point. In the series, it's less clear that she's lucid dreaming. Based on the short film I see her in the series as dreaming lucidly, probably assuming that Sean is a character in her dreams. Is that an accurate interpretation? Will we see Hannah coming forth again as a powerful lucid dreamer in her own right in future episodes?

Alex: I’ll be honest, when we made the short film, we weren’t even sure Hannah was a “real” character or simply a figment of Adam’s imagination fashioned after his memory of Hannah. Once we had the opportunity to create a web series based on the short, we came up with the premise that it was actually the real Hannah, and that she was somehow sharing a dream with Adam.

All that said, I’d argue that Hannah wasn’t particularly lucid in the short film. She “knew her way around” and kind of went with the flow, but really it was Adam’s subconscious driving the whole dream forward, she was just along for the ride. When she wakes up in Episode 01 of the web series, Hannah has a very foggy memory of the dream, and only remembers it in flashes when she comes across dream signs in her waking life (the water glass spilling, the copy shop, etc.), which further suggests she wasn’t fully lucid.

The first time I think Hannah actually becomes lucid in the series is Episode 04, when Sean calls to her attention that they’re in a dream and teaches her about reality tests. In a lot of ways, the long-term trajectory we see for the characters in Anamnesis is a journey from being “asleep” to becoming “lucid” or “awake”—in more ways than one.

Arthur: I've recently finished re-reading Patricia Garfield's excellent book The Dream Messenger: How Dreams of the Departed Bring Healing Gifts, which explores the various kinds of dreams people have after a loved one has died, and the role such dreams play in the healing process. This seems like a rich potential territory to explore in Anamnesis. Might Adam start showing up in Hannah's or Vera's dreams in future episodes?

Alex: We’ve definitely talked about this as a possibility. We’d love to bring Adam back in some fashion. If Hannah continues to become more lucid in the dream world, it’s kind of inevitable that he’ll show up in some form or another.

Arthur: Is there any significance to the names of the characters? “Vera,” for example, reminded me of veritas, truth, the idea that “the truth shall set you free.” She certainly seems happy to break rules in an attempt to uncover the truth.

Michael: In general we didn’t choose the character names specifically because of their meanings. For the most part, we based it on which names sounded good and felt like they matched the characters. Vera is a name I’ve always liked, both because of how it sounds and because of its meaning, and I think it fits Vera’s character really well for exactly the reason you mentioned. Noah’s name is also an obvious reference, but that wasn’t the only reason we chose it for him. We love it when elements of a story can have deeper meanings, but I also think you can go overboard with that to the point that it’s hitting the audience over the head with it. Inception, for instance, is not subtle at all when it comes to character names having deeper meanings—which while cool, I found more distracting than anything else.

Arthur: Whereas the original short is completely self-contained, the series continues to get more complex and mysterious episode-by-episode, leaving the viewer hungry for more. Are you planning to make more episodes? If so, do you have an overall story arc in mind for the show? Can you say anything about specific ideas or themes you'd like to explore in future episodes?

Alex: When we were brainstorming what we wanted to do with the web series, one of our main inspirations was Lost, which unraveled an incredibly intricate mystery over several seasons. We wanted to see if we could pull off the same kind of science-fiction mystery in the world of lucid dreaming—but actually know where it was all going, from the very first episode. So yes, we definitely have an overall story arc in mind for the show. It will probably change and evolve if we get to make more episodes, but there are clues hidden as early as Episode 01 as to what’s coming next.

Arthur: You explore a number of dream themes in the series—lucid dreaming, of course, but also night terrors and out-of-body experiences. In future episodes, do you plan to explore a greater variety of dream and dreamlike states, such as false awakenings, sleep paralysis, hypnagogia?

Michael: If we get to make more episodes we would absolutely want to explore more of these dream / dreamlike states. I get excited about there being so many interesting experiences to be played with, that they all lend themselves so well to film. The medium of film can convey the dream experience better than any other, in my opinion, and we have a lot of fun as filmmakers coming up with ways to translate these dream experiences to the screen. In particular, I find the idea of sleep paralysis it’d be fun to play with that on screen.

Arthur: The first season of Anamnesis was made possible through a highly successful Kickstarter campaign, in which you raised 151% of the money you were asking for. If you make more episodes, how do you plan to finance them? How can fans of the series support you in making more episodes?

Michael: Figuring out how to finance more episodes is the main challenge we’re facing right now. It blew us away that we surpassed our funding goal on Kickstarter, and we combined that with funding from, whose founder, Jeremy Norris, reached out to us and essentially convinced us to make the web series in the first place. But even with these combined funds, Anamnesis was primarily a labor of love. We didn’t have enough to pay most of the cast and crew, and almost all of the money went to locations, food, and equipment rentals.

If we were to make more, we would have to be able to pay all the cast and crew for the excellent work that they do. And considering the first five episodes are about 70 minutes long, each season is essentially a feature film. So we would need the budget of an indie feature film. Crowdfunding a next season would definitely be an option, but we’re also trying to reach out to websites like Vimeo, for example, who are getting into the original content market. Having a distributor for the series that could also help fund another season would be absolutely great. So the best thing fans can do to help us make more episodes is share the series with anyone and everyone. The more we can show that we have a large group of dedicated fans, the more likely we can raise money via crowdfunding and the easier it would be to convince a potential distribution partner.

Arthur: What do you think of YouTube's plan to start offering an ad-free subscription service? How might that affect Finite Films?

Michael: I understand that YouTube has been trying to figure out how to make a profit since they first began, but this feels somewhat like a betrayal of what has made YouTube so popular in the first place. There is a freedom and accessibility that YouTube has (which admittedly comes with some chaos and a lot of junk) that I think may be tainted by a subscription fee. Especially if they keep forcing unskippable ads onto every video to make the viewing experience more unpleasant in order to convince people to pay the subscription fee.

On the other hand, if it means that they’re helping content creators like ourselves get something more out of it (financially speaking), then perhaps they’re incentivizing and enabling people to make more quality content. Ultimately I think it will depend largely on how much the subscription fee is, and how optional they make it feel. If it’s $2.99 a month, maybe that’s an okay deal that feels worthwhile; if it’s $19.99 a month and every YouTube video has a 2-minute unskippable ad—then I think that will be bad for views, for content creators, and for YouTube. I guess we’ll just have to wait and see.

Arthur: What has been the reaction of the lucid dreaming community to Anamnesis? How do people without prior experience with lucid dreaming react to the show?

Alex: Honestly, we’ve been blown away by the reception we’ve had in the lucid dreaming community. We wanted Anamnesis to represent the experience of lucid dreaming in a more accurate way than we’d seen in other films and TV shows, and so to have such a positive response from the community has been incredible. Our fans in the lucid dreaming community really are the primary reason we want to find a way to finance and produce more episodes. We’ve also had great responses from our non-lucid-dreamer fans, and we’re now looking to try to expand our audience beyond the lucid dreaming niche into communities that value thoughtful science fiction / drama storytelling.

Arthur: Are there any particular resources—books, websites, etc.—that you would recommend to people wanting to more deeply explore lucid dreaming?

Alex: Are You Dreaming by Daniel Love provides a great introduction to the world of lucid dreaming. He developed the CAT (Cycle Adjustment Technique) for generating frequent lucid dreams, which he outlines in his book. Our friend Jay Mutzafi (aka Lucid Sage and host of The Lucid Dreaming Podcast) highly recommends Stephen LaBerge’s Lucid Dreaming: AConcise Guide to Awakening in Your Dreams and in Your Life as a great place to start one’s lucid dreaming practice. And finally, has a ton of resources for anyone looking to lucid dream.

Arthur: Thank you for producing such an excellent short film and web series, and in particular for the realistic portrayal of lucid dreaming. I wish you great success and will certainly be doing my part to help spread the word. Is there anything we haven't covered in the interview that you would like to add?

Alex: We’ve had a lot of people ask us if they can buy Season One of the series on DVD, and we’re currently putting together a DVD / Digital Download package that will include some exclusive special features. For updates on all things Anamnesis, people can follow us on Facebook, Twitter [@AnamnesisSeries], and Google Plus (and subscribe to our channel, Finite Films, on YouTube).

From the very beginning, Anamnesis has been a true labor of love and we’ve only made it this far because of the support of our fans. If anyone has any ideas or suggestions for how we can continue to reach out to the lucid dreaming community and rally support for future seasons, don’t hesitate to shoot us an email at

Saturday, April 11, 2015

George Lakoff: How Brains Think: The Embodiment Hypothesis

Published on Apr 7, 2015

Keynote address recorded March 14, 2015 at the inaugural International Convention of Psychological Science in Amsterdam.

Saturday, 14 March 2015

George Lakoff
Departments of Linguistics and Cognitive Science, University of California, Berkeley, USA
How do we answer the question, “How are thought and language constituted by the brain’s neural circuitry?” Neuroscience alone cannot answer this question. The field that studies the details of embodied conceptual systems and their expression in language is cognitive linguistics. In a book (in preparation with Srini Narayanan) we propose a neural computational “bridging model” as a way to answer the question. The talk gives illustrative details.

George Lakoff is a world-renowned cognitive linguist whose work reaches beyond the area of linguistics to provide groundbreaking insights into the realms of neuroscience and cognitive psychology as well. He is a pioneer in the multidisciplinary theory of the embodied mind, the idea that higher-order aspects of cognition are rooted in and constrained by bodily features such as the motor and perceptual systems. Additionally, his metaphor theory and insight into morally based framing, in which ideas are conveyed using very specific language that is tied to a larger conceptual framework such as freedom or equality, have made him a go-to strategist for politicians.
Read more about George Lakoff.

Books by George Lakoff that might be of interest.

Metaphors We Live By (2003, updated reissue)
Where Mathematics Comes From: How The Embodied Mind Brings Mathematics Into Being (2000)
Philosophy in the Flesh: the Embodied Mind & its Challenge to Western Thought (1999)

Friday, March 27, 2015

2014 Nobel Prize Winners Speak at the University of Arizona

Thursday afternoon, Edvard Moser, May-Britt Moser, and John O'Keefe, the three 2014 Nobel Prize winners for Physiology or Medicine, along with Eleanor Maguire, the winner of the 2003 Ig Nobel Prize for her "London taxi driver" study on hippocampal plasticity, spoke at a public forum at the University of Arizona.

Maquire's research on London taxi drivers, before and after going through two to three years of training required to learn and memorize 25,000 streets, revealed that their hippocampus grew as they memorized London's maze of streets. This was one of the first studies that demonstrated hippocampal neuroplasticity. She was awarded a 2003 Ig Nobel Prize for this study.

According to Improbable Research, the bestowers of the Ig Nobel Prize, "The Ig Nobel Prizes honor achievements that make people LAUGH, and then THINK. The prizes are intended to celebrate the unusual, honor the imaginative — and spur people's interest in science, medicine, and technology."

The Mosers and O'Keefe won their Nobel Prize in 2014 for their discoveries of specialized cells in the brain that together act as a navigation system. The Mosers discovered neurons that function as grid cells, found in the entorhinal cortex, while O'Keefe discovered neurons that function as place cells, found in the hippocampus.
"All memories are attached in some way to where you are, and in that way, the hippocampus acts as an anchor for remembering yourself within your experience," said Carol Barnes, Regents' Professor in the Departments of Psychology, Neurology and Neuroscience, the Evelyn F. McKnight Endowed Chair for Learning and Memory in Aging.
The hippocampus, according to Wikipedia, "belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation." If a person were to suffer severe damage to the hippocampus (both hippocampi, as one exists in each brain hemisphere), it's likely they may acquire anterograde amnesia, an inability to form and/or retain new memories (episodic or autobiographical memory, which are forms of declarative memory). In Alzheimer's Disease, the hippocampus is one of the first brain regions to experience damage, resulting in the disorientation and loss of recognition so common in the disease. However, damage to the hippocampus does not inhibit the ability to learn new skills, such as riding a bicycle (procedural memory).
 Spatial firing patterns of 8 place cells recorded from the CA1 layer of a rat. The rat ran back and forth along an elevated track, stopping at each end to eat a small food reward. Dots indicate positions where action potentials were recorded, with color indicating which neuron emitted that action potential. [via Wikipedia]
Below, I have included the honored guests as well as the first half of the press release about the public forum (which is heavy on the U of A is awesome rhetoric).

Edvard Moser
, Professor and Director, Kavli Institute of Systems Neuroscience; Co-Director, Centre of Neural Computation, Norwegian University of Science and Technology

May-Britt Moser, Professor and Director, Centre of Neural Computation; Co-Director, Kavli Institute of Systems Neuroscience, Norwegian University of Science and Technology

The Moser’s received the 2014 Nobel Prize in Medicine or Physiology (along with J. O’Keefe) for this discovery of grid cells.

John O’Keefe, Professor, Institute of Cognitive Neuroscience and Department of Anatomy, University College London. Dr. O’Keefe received the 2014 Nobel Prize in Medicine or Physiology (along with the Moser’s) for his discovery of place cells.

Eileen O’Keefe
(John’s wife), Emeritus Professor, Public Health, London Metropolitan University

Eleanor Maguire, Professor of Cognitive Neuroscience, University College Dublin Dr. Maguire received the 2003 Ig Nobel Prize for Medicine for her ‘London taxi driver’ student on hippocampal plasticity.
And here is the beginning of the press release . . . 

Nobel Laureates Say UA Scientists Paved Way

By Daniel Stolte, University Relations - Communications | March 27, 2015
UA researcher Carol Barnes says the new Center for Innovation in Brain Science will serve as a hub of transdisciplinary research. (Photo: John de Dios/UANews)
UA researcher Carol Barnes says the new Center for Innovation in Brain Science will serve as a hub of transdisciplinary research. (Photo: John de Dios/UANews)

 Four internationally renowned brain scholars visit campus and describe the UA as "one of the centers of neuroscience." The new Center for Innovation in Brain Science will foster transdisciplinary research, with the goal of better diagnostics and treatments for disorders such as Alzheimer's disease.

Nobel Prize laureate John O'Keefe, with May-Britt Moser (left) and Eleanor Maguire, says the UA's Carol Barnes "has told us as much about how the brain ages as anyone else." (Photo: John de Dios/UANews)

Take it from several Nobel laureates: Brain researchers at the University of Arizona are poised to make important contributions to finding better diagnoses and possibly treatments for brain disorders such as Alzheimer's disease.

To help commemorate three milestones in brain science research at the UA, four internationally renowned brain scholars — including three who shared the latest Nobel Prize in Physiology or Medicine — visited the UA campus this week to speak about their scientific careers and reflect on the tight connections they have shared with UA colleagues over many years.

This year marks the 25th anniversary of the UA Arizona Research Laboratories Division of Neural Systems, Memory and Aging, or NSMA; the 10th anniversary of the Evelyn F. McKnight Brain Institute at the UA; and the fifth anniversary of the UA School of Mind, Brain and Behavior.

UA President Ann Weaver Hart has named neuroscience as a research priority under the UA's strategic Never Settle plan. The BIO5 Institute and the UA Health Sciences Center have goals of supporting transdisciplinary neuroscience research in partnership with institutions across the state — from the molecular underpinnings of brain-cell health to the translation of this biological knowledge into treatments for neurological disease. The College of Science and the Office for Research and Discovery also are involved in supporting these efforts through the School of Mind, Brain and Behavior; NSMA; and the Evelyn F. McKnight Brain Institute.

During a public forum on Thursday, the UA welcomed the four guests to share their stories of discoveries in neuroscience with UA students, members of the public and the media. The visitors were John O'Keefe and Edvard and May-Britt Moser, who shared the 2014 Nobel Prize in Physiology or Medicine, and Eleanor Maguire, who received the Ig Nobel Prize for Medicine in 2003.

O'Keefe and the Mosers received the prize for their discoveries of specialized cells in the brain that together act like a navigation system.

"All memories are attached in some way to where you are, and in that way, the hippocampus acts as an anchor for remembering yourself within your experience," said Carol Barnes, who organized the visit along with two other UA brain researchers: Lynn Nadel, a Regents' Professor of Psychology and Cognitive Science and chair of the UA faculty; and Mary Peterson, professor of psychology and chair of the School of Mind, Brain and Behavior executive committee; director of the Cognitive Science Program; and chair of the Cognitive Science Graduate Interdisciplinary Program.

Edvard Moser said that some important work leading up to the Nobel Prize was done at the UA — for example, developing the technology for recording the activity of many brain cells at the same time, and developing ideas of how memory is generated in the hippocampus.

"The UA is one of the centers of neuroscience," O'Keefe said. "As one of the world's experts on the aging brain, Carol has told us as much about how the brain ages by looking at the hippocampus as anyone else.
Read the whole report on the event.

Friday, March 06, 2015

SSRIs Add to the Existing Surplus of Serotonin in the Raphe Nucleus and Reduces Serotonin in Hippocampus, Where it Is Needed Most

This appears to be the first good research showing why SSRIs do not work for most people in treating depression and anxiety. It appears that early life stress increases serotonin levels in the brain to the point that a negative feedback loop develops, reducing the brain's sensitivity to the serotonin. The resulting depression and/or anxiety that develops is exacerbated by SSRIs, which just add to the existing surplus of serotonin in the raphe nucleus and reduces serotonin in hippocampus, where it is needed most.

Early life stress may cause excess serotonin release resulting in a serotonin deficit

Data suggest a reason why SSRI medications may fail in many patients
Studies indicate that the majority of people with mood and anxiety disorders who receive the most commonly prescribed class of antidepressant medications, Selective Serotonin Reuptake Inhibitors or SSRI's, are not helped by these medications. SSRIs are designed to increase serotonin, a neurotransmitter in the brain that is key to maintenance of mood. 

Researchers led by Jeremy D. Coplan, MD, professor of psychiatry at SUNY Downstate Medical Center, have published data suggesting an explanation for the longstanding puzzle as to why low serotonin could not be detected in depression without suicidal intent, even though many antidepressant treatments work by increasing serotonin in areas key for mood regulation, such as the hippocampus. The pre-clinical research was published in a recent edition of Frontiers in Behavioral Neuroscience.
Dr. Coplan explains, "We have shown that serotonin is too high near the serotonin brain cells, reducing firing of the serotonin nerve cells through a well-documented negative feedback mechanism in the raphe nucleus. The result is that the hippocampus and other critical brain structures needed for mood maintenance do not get enough serotonin. We can see this because the hippocampus is shrunken and the white matter loses integrity. By the time serotonin metabolites are measured in a lumbar spinal tap, the usual way serotonin levels have been measured, the high serotonin has mixed with the low serotonin and you have no difference from people who are healthy." 

He continues, "We have hypothesized in an earlier paper that this is a plausible reason why SSRIs may not work in a majority of people, because SSRIs will tend to make the high serotonin even higher in the raphe nucleus. The serotonin neuron may not be able to adapt and restore its firing, inducing a presumed serotonin deficit in terminal fields, evidenced by shrinkage of the hippocampus." 

He adds, "We cannot say categorically, in our pre-clinical model, that high serotonin in the raphe nucleus leads to low serotonin in the hippocampus, but studies by J. John Mann, MD, a co-author on the paper, and Victoria Arango, PhD, both of Columbia University Medical Center, have shown that people who committed suicide exhibited high serotonin in the raphe nucleus and low serotonin in another area of the brain critical for mood maintenance, the prefrontal cortex. Additional studies should be performed, especially since better understanding of the serotonin system will significantly improve future treatment options." 

In the earlier paper, also in Frontiers in Behavioral Neuroscience, Dr. Coplan proposed augmentation therapies in treatment-resistant patients, including stacking one medication upon another in the most difficult cases: "This is what physicians do for hypertension, diabetes, and congestive heart failure," said Dr. Coplan. "But in psychiatry, we sometimes act as if our medications are so effective that we are exempt from how the rest of medicine deals with difficult-to-treat cases." 

Other approaches to bypass the high midbrain serotonin impasse, according to Dr. Coplan, are shutting glutamate input into the raphe nucleus, a portion of the brain that controls the release of serotonin, and utilizing drugs that block noradrenergic input into the dorsal raphe. 

Dr. Coplan notes that a recent large-scale study showed only a minority of patients do well on SSRIs, and of those, many lose response in a year or two. "There is an epidemic of inadequately treated depression and psychiatrists are not well trained to deal with this challenge," he observed. "What they often do is change from one antidepressant to another when there is a lack of response. Eventually the patient becomes non-compliant and the patient, rather than the treatment, is blamed for the non-efficacy." 

"These two papers provide possible insights as to why our treatments are ineffective and what we should be doing to treat patients effectively," Dr. Coplan said. "Many academic researchers currently do not practice clinically, so they are out of touch with real-life patients and their struggles. In the meantime, suicide rates have not budged in decades." 
Here are the abstracts from the original articles, both of which are open access.

Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid in macaques following early life stress and inverse association with hippocampal volume: preliminary implications for serotonin-related function in mood and anxiety disorders

Jeremy D. Coplan1*, Sasha L. Fulton2, Wade Reiner3, Andrea Jackowski4, Venkatesh Panthangi1, Tarique D. Perera2, Jack M. Gorman5, Yung-yu Huang6, Cheuk Y. Tang7, Patrick R. Hof8, Arie Kaffman9, Andrew J. Dwork6, Sanjay J. Mathew10,11, Joan Kaufman12 and J. John Mann6

  • 1Nonhuman Primate Laboratory, Department of Psychiatry and Behavioral Sciences, Downstate Medical Center, State University of New York, Brooklyn, NY, USA
  • 2Geriatric Psychiatry, New York State Psychiatric Institute, New York, NY, USA
  • 3College of Medicine, State University of New York Downstate Medical Center, Brooklyn, NY, USA
  • 4Departamento de Psiquiatria & Neuroradiologia, Universidade Federal de São Paulo, São Paulo, Brazil
  • 5Franklin Behavioral Health Consultants, Bronx, NY, USA
  • 6Department of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY, USA
  • 7Departments of Psychiatry, Neuroscience, and Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  • 8Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  • 9Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
  • 10Mental Health Care Line, Michael E. Debakey VA Medical Center, Houston, TX, USA
  • 11Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA
  • 12Child Study Center, Yale University School of Medicine, New Haven, CT, USA

Background: Early life stress (ELS) is cited as a risk for mood and anxiety disorders, potentially through altered serotonin neurotransmission. We examined the effects of ELS, utilizing the variable foraging demand (VFD) macaque model, on adolescent monoamine metabolites. We sought to replicate an increase in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) observed in two previous VFD cohorts. We hypothesized that elevated cisternal 5-HIAA was associated with reduced neurotrophic effects, conceivably due to excessive negative feedback at somatodendritic 5-HT1A autoreceptors. A putatively decreased serotonin neurotransmission would be reflected by reductions in hippocampal volume and white matter (WM) fractional anisotropy (FA).

Methods: When infants were 2–6 months of age, bonnet macaque mothers were exposed to VFD. We employed cisternal CSF taps to measure monoamine metabolites in VFD (N = 22) and non-VFD (N = 14) offspring (mean age = 2.61 years). Metabolites were correlated with hippocampal volume obtained by MRI and WM FA by diffusion tensor imaging in young adulthood in 17 males [10 VFD (mean age = 4.57 years)].

Results: VFD subjects exhibited increased CSF 5-HIAA compared to non-VFD controls. An inverse correlation between right hippocampal volume and 5-HIAA was noted in VFD- but not controls. CSF HVA and MHPG correlated inversely with hippocampal volume only in VFD. CSF 5-HIAA correlated inversely with FA of the WM tracts of the anterior limb of the internal capsule (ALIC) only in VFD.

Conclusions: Elevated cisternal 5-HIAA in VFD may reflect increased dorsal raphe serotonin, potentially inducing excessive autoreceptor activation, inducing a putative serotonin deficit in terminal fields. Resultant reductions in neurotrophic activity are reflected by smaller right hippocampal volume. Convergent evidence of reduced neurotrophic activity in association with high CSF 5-HIAA in VFD was reflected by reduced FA of the ALIC.

Full Citation: 
Coplan JD, Fulton SL, Reiner W, Jackowski A, Panthangi V, Perera TD, Gorman JM, Huang Y, Tang CY, Hof PR, Kaffman A, Dwork AJ, Mathew SJ, Kaufman J and Mann JJ (2014, Dec 24). Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid in macaques following early life stress and inverse association with hippocampal volume: preliminary implications for serotonin-related function in mood and anxiety disorders. Front. Behav. Neurosci. 8:440. doi: 10.3389/fnbeh.2014.00440

* * * * *

A neurobiological hypothesis of treatment-resistant depression – mechanisms for selective serotonin reuptake inhibitor non-efficacy

Jeremy D. Coplan1*, Srinath Gopinath1, Chadi G. Abdallah2,3 and Benjamin R. Berry4

  • 1Division of Neuropsychopharmacology, Department of Psychiatry and Behavioral Science, State University of New York Downstate Medical Center, Brooklyn, NY, USA
  • 2Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
  • 3Clinical Neuroscience Division, National Center for PTSD, West Haven, CT, USA
  • 4State University of New York Downstate College of Medicine, Brooklyn, NY, USA
First-line treatment of major depression includes administration of a selective serotonin reuptake inhibitor (SSRI), yet studies suggest that remission rates following two trials of an SSRI are <50%. The authors examine the putative biological substrates underlying “treatment resistant depression (TRD)” with the goal of elucidating novel rationales to treat TRD. We look at relevant articles from the preclinical and clinical literature combined with clinical exposure to TRD patients. A major focus was to outline pathophysiological mechanisms whereby the serotonin system becomes impervious to the desired enhancement of serotonin neurotransmission by SSRIs. A complementary focus was to dissect neurotransmitter systems, which serve to inhibit the dorsal raphe. We propose, based on a body of translational studies, TRD may not represent a simple serotonin deficit state but rather an excess of midbrain peri-raphe serotonin and subsequent deficit at key fronto-limbic projection sites, with ultimate compromise in serotonin-mediated neuroplasticity. Glutamate, serotonin, noradrenaline, and histamine are activated by stress and exert an inhibitory effect on serotonin outflow, in part by “flooding” 5-HT1A autoreceptors by serotonin itself. Certain factors putatively exacerbate this scenario – presence of the short arm of the serotonin transporter gene, early-life adversity and comorbid bipolar disorder – each of which has been associated with SSRI-treatment resistance. By utilizing an incremental approach, we provide a system for treating the TRD patient based on a strategy of rescuing serotonin neurotransmission from a state of SSRI-induced dorsal raphe stasis. This calls for “stacked” interventions, with an SSRI base, targeting, if necessary, the glutamatergic, serotonergic, noradrenergic, and histaminergic systems, thereby successively eliminating the inhibitory effects each are capable of exerting on serotonin neurons. Future studies are recommended to test this biologically based approach for treatment of TRD.

Full Citation: 
Coplan JD, Gopinath S, Abdallah CG and Berry BR. (2014, May 20). A neurobiological hypothesis of treatment-resistant depression – mechanisms for selective serotonin reuptake inhibitor non-efficacy. Front. Behav. Neurosci. 8:189. doi: 10.3389/fnbeh.2014.00189