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Taken for Active Assignment Weekly: Music to Your Ears

 

WIT: A sparkling candle that doesn't sparkle much; flash; and a long exposure.

 

The inspiration here is 'Torque' by Kristin Hersh. Download, free & legal, in high quality here. Lyrics here. I only discovered her music some three years ago, and now listen to it all the time. Especially since I found out about her latest album.

 

Just now I found this page with the history of the song. Anyway -- the photo is about this bit here where a human being's very nature is explored and questioned.

 

what are you?

animated soft tissue

shifting neuropeptides

a social pyromaniac

a plate spinner

(Medical Xpress)—The human brain's exquisite complexity and power make it a unique evolutionary marvel. One of the brain's more interesting abilities is known as the placebo effect, in which no more than the expectation of relief can lead to analgesia – the relief of pain, anxiety, depression, nausea, and many other aversive states. However, scientists at University of Gothenburg and University of Oslo recently showed that the placebo effect may not be limited to pain reduction, but may also enhance pleasure, or hyperhedonia. The researchers used the placebo effect to improve both painful and pleasant touch sensations in healthy humans – and by comparing brain processing using functional magnetic resonance imaging (fMRI), found that, depending on whether the starting point was painful or pleasant, neurocircuitry associated with emotion and reward underpinned improvement of both pain and pleasant touch by dampening pain but increasing touch pleasantness.

  

In an interview with Medical Xpress, PhD candidate Dan-Mikael Ellingsen discussed the paper he and his colleagues published in Proceedings of the National Academy of Sciences. "In recent years, functional brain imaging studies have shown that expecting a treatment to relieve negative symptoms – like pain, anxiety or unpleasant taste – leads to not only subjective reports of relief, but also suppressed brain activity in sensory circuitry during aversive stimuli, such as noxious heat or touch, threatening images, and unpleasant taste," Ellingsen tells Medical Xpress. "However, both aversive and appetitive experiences – for example, tasty food or a pleasant touch – are affected by context and expectation." Therefore, Ellingsen explains, in forming their hypothesis for this study, the researchers asked whether improvement of good experiences is encoded entirely in higher-level valuation processing, or whether it would mirror the modulation of early stages of sensory processing that is seen for aversive stimuli. "If so, we'd expect such positive sensory signals to be up-regulated, in contrast to the down-regulation of sensory signals we see during placebo-induced reduction of aversive experiences."

In the placebo manipulation procedure, participants were shown a short video documentary convincing them that a nasal spray containing the neuropeptide oxytocin would reduce pain and enhance the pleasantness of pleasant touch. Following this video, they self-administered 10 puffs of a placebo nasal that they were told could contain oxytocin. The pleasant touch stimuli consisted of caress-like light strokes with a soft brush, or a hot/cold pack (resembling a warm hand, applied to the subject's forearm. The pain stimulus was a thermode (~47 degrees Celsius) on the hand.

Ellingsen notes that by comparing brain activation during painful or pleasant touch stimuli after placebo treatment versus no-placebo, the scientists were able to assess differences in activation that was specifically related to having received placebo treatment. "Importantly, the subjective reports showed that, after receiving placebo relative to no-placebo, touch pleasantness was increased while pain unpleasantness was decreased," he adds. "When contrasting placebo and no-placebo on brain activation, we found that sensory activation was increased during pleasant touch stimuli and decreased during painful touch stimuli. In other words, the placebo-induced change in sensory processing reflected the placebo-induced change in subjective reports."

  

The team also hypothesized that placebo improvement of pleasant touch would recruit the same emotion appraisal neurocircuitry that underpins placebo analgesia. "Neural systems mediating pain and pleasure interact extensively, with pain and pleasure often being mutually inhibitory," Ellingsen says. "For instance," he illustrates, "pleasant stimuli such as music, food, odors, and touch can have analgesic effects – and pain can inhibit pleasure and positive feelings. Further, opioids can induce both potent analgesia and feelings of pleasure." (An opioid is any psychoactive chemical that resembles morphine or other opiate in its pharmacological effects.) Ellingsen points out that previous findings show that relief from pain induces pleasant feelings1,2, and when a normally painful stimulus represents the best possible outcome – that is, when the alternative is even more intense pain3 – it can even become pleasant.

Ellingsen explains that a central element in all placebo effects is that there is an expectation or desire for an improvement, for example, a relief of pain or unpleasantness – and placebo effects have been theorized to arise from a generalized mechanism of reward prediction. This reasoning, he notes, is supported by evidence that placebo responses across modalities – analgesia6, anxiety relief7, and so on – rely on activation of similar neural systems involved in reward and emotion. "In line with this strong link between pleasure and the relief from negative feelings, we hypothesized that improving the pleasantness of an appetitive stimulus would rely on modulatory mechanisms similar to those involved in the improvement of aversive feelings."

A key aspect of the team's research was devising and applying an fMRI crossover study to compare neural processing of placebo hyperhedonia and analgesia. "In order to compare the brain mechanisms of placebo hyperhedonia and analgesia, we assessed the effect of placebo treatment on subjective experiences within the same sensory modality – namely, touch, both pleasant and painful."

A key aspect of the study's analytic design was based on the researchers' knowledge that all dermal information is processed in the same neural pathways – specifically, the sensory thalamus, primary and secondary somatosensory areas, and the posterior insula. "As a result," Ellingsen points out, "we were able to perform two important measurements: we directly compared how expectation of improvement affected the processing of positive and negative somatosensory signals in these pathways, and investigated the effect of higher-level modulatory circuitry on sensory processing of pleasant or painful touch."

 

Proposed mechanism of placebo analgesia and hyperhedonia. During expectation of hyperhedonia and analgesia, a shared modulatory network up-regulates pleasant touch processing and down-regulates painful touch processing in somatosensory areas, …more

Another factor the scientists had to consider was that the use of subjective rating scales varies widely between individuals (as opposed to a single individual's typical consistency). As a result, these scales are significantly better at detecting changes between placebo and no-placebo within individuals rather than between one group who received placebo and another that received no placebo. "Consequently," Ellingsen explains, "such a design has superior statistical power – that is, a greater ability to detect a true effect."

Further, the potential benefit of a crossover design can be found when the order of treatment – specifically, placebo or no-placebo first – is considered, since it may potentially affect responses. "To control for this potential confounder," notes Ellingsen, "we used a crossover design, that is, half of the subjects got placebo in the first session, and the other half got placebo in the last session." However, he adds, in the analyses they performed, they found that the treatment order had no effect on either subjective placebo improvement or brain activation.

"To our knowledge," Ellingsen continues, "our study is the first to investigate placebo improvement of pleasurable feelings. By directly comparing this effect with the more well-known placebo analgesia effect, we were able to identify both the differences and a potential shared mechanism of these two types of improvement: People with stronger placebo-induced increases in functional coupling between ventromedial prefrontal cortex (vmPFC) and subcortical structures (PAG) reported greater placebo hyperhedonia and analgesia, and had greater analgesic decreases and hyperhedonic increases in somatosensory processing."

Ellingsen says that this finding suggests that endogenous improvement of positive and negative feelings are tightly coupled. "Interestingly, we saw that people with the greatest placebo hyperhedonia responses also had the greatest placebo analgesia responses. Overall, the results provide a piece of the puzzle of how positive expectations affect both positive and negative feelings."

Expanding on the team's findings, Ellingsen describes how the researchers first observed that placebo hyperhedonia was associated with increased activation of a number of cortical and subcortical areas important for placebo analgesia – namely, the ventromedial prefrontal cortex, accumbens, amygdala, and the midbrain structures periaqueductal grey and the ventral tegmental area. Not only was there increased activation in these areas after placebo administration compared to no-placebo, Ellingsen adds, but the amount of increase was positively correlated to the magnitude of the reported improvement: Those with largest placebo-induced hyperhedonia and analgesia had the highest placebo-induced activation in these areas. Moreover, those with largest placebo hyperhedonia and analgesia also had the strongest placebo-induced increase in functional connectivity within this circuitry, a measure of how much these areas communicate with each other. "Although our findings show similar patterns of activation between placebo hyperhedonia and analgesia, it's important to point out that they weren't identical. There are likely to be fine-grained differences between these processes within this circuitry that were not identified by this study."

Ellingsen stresses that an important mechanism in placebo analgesia – one that has been replicated several times – is the engagement of the opioid descending modulatory system, which consists of vmPFC, amygdala, and PAG. "When treated with a placebo that is expected to have analgesic effects," Ellingsen explains, "activation of this system suppresses nociceptive" (the neural processes of encoding and processing noxious or painful stimuli) "signaling both in the brain and – since the PAG has descending connections through the rostroventral medulla, RVM, to the spinal dorsal horn, where it can modulate incoming nociceptive signals – at the spinal cord level." Importantly, he notes, placebo analgesia and the activation of this system are reversed when the individual is given the opioid receptor antagonist naloxone, indicating that this mechanism is dependent on opioid signaling.

To ask whether this system is involved also in placebo improvement of pleasantness, we assessed the relationship between 1) the placebo-induced change in functional connectivity between the vmPFC and PAG, and 2) placebo-induced change in sensory processing. Strikingly, we found that the co-activation of vmPFC and PAG was related to opposite effects during placebo hyperhedonia and analgesia: During pain, those with strongest increases in functional coupling had the largest decreases in sensory processing, while during pleasant touch, those with strongest functional coupling had the largest sensory increases. We are now planning to investigate whether placebo hyperhedonia, like (most) placebo analgesia, depends on opioid signaling.

Moving forward, Ellingsen says, their study opens up several important questions for future studies:

Does placebo hyperhedonia, similar to analgesia, rely on opioid or dopamine signaling?

Could expectation of hyperhedonia alone have analgesic effects – and vice versa?

Could including information about potential hyperhedonic effects actually boost treatment effects of analgesic drugs?

What is the exact mechanism of the up-regulation of sensory processing in placebo hyperhedonia? Is it entirely central in its action, or could it involve descending facilitation of touch processing at the spinal cord level, which is a component in placebo analgesia4 and nocebo hyperalgesia5?

(A nocebo – the opposite of a placebo – is a harmless substance that creates detrimental effects in a patient who takes it. Likewise, the nocebo effect is the negative expectation-based reaction experienced by a patient who receives a nocebo.)

Regarding other areas of research that might benefit from their study, Ellingsen cites a growing recognition that health care systems need to be remodeled to target placebo mechanisms – and to do so by altering expectations, motivation, treatment context, and the therapist-patient relationship. "In most medical settings, however, the focus is to ease negative symptoms – to relieve pain, nausea, or discomfort – but to attain positive feelings, people have to seek elsewhere, despite our knowledge that positive experiences, like captivating music, pleasant odors, beautiful pictures, pleasant touch, and support from people we care about, can have potent analgesic effects."

If the tightly-coupling expectations of improvement in pleasurable and painful feelings suggested by their results interact in the clinical setting, Ellingsen believes it to be very likely that increasing the focus on positive appetitive effects of medical care (increased life quality, regained ability to enjoy pleasures, and the like) may have potent effects on the relief of negative symptoms. "In general," he concludes, "our findings shed some light on the complex relationship between positive feelings, negative feelings and expectation in the context of medical treatment. We believe our findings are relevant to the field of medical research in general, and promote widening the scope of medical research to improvement of positive experiences and pleasure."

Explore further: Intranasal application of hormone appears to enhance placebo response

More information: Placebo improves pleasure and pain through opposite modulation of sensory processing, PNAS Published online before print October 14, 2013, doi:10.1073/pnas.1305050110

Related:

1Relief as a Reward: Hedonic and Neural Responses to Safety from Pain, PLoS ONE 6(4): e17870. doi:10.1371/journal.pone.0017870

2Opponent appetitive-aversive neural processes underlie predictive learning of pain relief, Nature Neuroscience 8, 1234-1240 (2005),

doi:10.1038/nn1527

3The importance of context: When relative relief renders pain

Pleasant, Pain 2013 Mar;154(3):402-10, doi:10.1016/j.pain.2012.11.018

4Direct Evidence for Spinal Cord Involvement in Placebo Analgesia, Science 16 October 2009: Vol. 326 no. 5951 p. 404, doi:10.1126/science.1180142

5Facilitation of Pain in the Human Spinal Cord by Nocebo Treatment, The Journal of Neuroscience, 21 August 2013, 33(34): 13784-13790; doi:10.1523/JNEUROSCI.2191-13.2013

6Placebo-induced changes in FMRI in the anticipation and experience of pain, Science, 303(5661): 1162-1167 (2004), doi:10.1126/science.1093065

7Placebo in emotional processing—induced expectations of anxiety relief activate a generalized modulatory network, Neuron, 46(6), 957-969 (2005), doi:10.1016/j.neuron.2005.05.023

Journal reference: Proceedings of the National Academy of Sciences PLoS ONE Nature Neuroscience Pain Science Journal of Neuroscience Neuron

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Novel and award winning Russian developed neuropeptide, Selank.

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Jalopeno, Chillies, Melbourne, Australia, neuropeptides

This photo of a 4-millimeter human scalp hair follicle came from a 44-year-old Caucasian male. It was sliced vertically into tiny, 200-micron thick sections. The sample was multi-stained with antibodies to visualize the nerves (in red), the sensory neuropeptide CGRP (in green), and vasculature (blue).

 

Source: Marna E. Ericson and Maria K. Hordinsky, Department of Dermatology, University of Minnesota

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Shown here is an image from the exhibit "Open Minds: An Exhibit of Psychology Department Faculty Publications," on display in the Bright Gallery on the second floor of Swem Library at the College of William and Mary. The exhibit features publications from faculty in the College of William and Mary's Department of Psychology. The exhibit is on display from March 26, 2012-January 18, 2013.

 

The following is a transcription of the label text presented in this case:

 

William & Mary’s

Psychology Department

 

A Brief History

 

During the 1888-1889 academic year, William & Mary president Lyon G. Tyler taught the college’s first psychology course which was then listed under the Department of Moral Science, Political Economy, and Civil Government. The “Catalogue of the College of William and Mary and State Male Normal

School” for that year describes the program as follows:

 

There are two classes in this department, a Junior and a Senior.

In the Junior the elements of Psychology are set forth, and the faculties of the mind especially discussed in their relation to education. A thorough knowledge of the laws according to which the memory, imagination, and other faculties operate will be found of great value to the student in receiving and to the teacher in imparting information. Psychology is made to alternate with lectures on civil government. p. 24

 

William & Mary was with the times! According to the Encyclopedia of Higher Education, the late 1880s was when colleges in the US first began offering psychology courses.

 

In the fifty years that followed, psychology classes continued to be taught in several different departments, including Philosophy and Pedagogy, Philosophy and Psychology, Education, and eventually Psychology and Philosophy.

 

In the 1943-1944 catalog, Psychology is finally listed as its own department,

with five professors offering twelve courses. Over the years, it has grown dramatically – establishing graduate programs and offering many more

courses taught by an increasing number of faculty members.

 

Today, there are approximately thirty faculty, including visiting and adjuncts, who teach more than fifty course sections and numerous labs. The

publications selected for this exhibit show the varied research conducted by

the department’s faculty.

 

Robert Barnet

Associate Professor of Psychology

 

University of Alberta, BA in Honors Psychology, First Class, 1989

Binghamton University, SUNY, MA in Experimental Psychology, 1991

Binghamton University, SUNY, PhD in Experimental Psychology, 1994

 

Professor Barnet has been with William & Mary for thirteen years. His research interests are memory and cognition, particularly in animals. He enjoys inviting his students to be a part of “the excitement of discovery in science.” Under his mentorship, students have presented at conferences, received scholarships and awards, and authored scholarly works.

 

Joshua Burk

Associate Professor of Psychology

Graduate Studies Director

 

University of California, Davis, BS in Psychology with Biological Emphasis, 1993

University of New Hampshire, MA in Experimental Psychology, 1996

University of New Hampshire, MST in College Teaching, 1999

University of New Hampshire, PhD in Experimental Psychology, 1999

 

Professor Burk is embarking on his tenth year with William & Mary, and his research focuses on behavior and cognitive neuroscience. Presently, he is researching whether a neuropeptide, orexin A, can enhance attention. He enjoys “watching the success and intellectual growth of our undergraduate and graduate students.”

 

Joseph Galano

Professor Emeritus

 

CMDNJ-Rutgers Medical School, Internship in Clinical/Community Psychology, 1976

Bowling Green State University, PhD in Clinical Psychology, 1977

 

Professor Galano taught at William & Mary from 1977-2010 and served as a faculty member with the Virginia Consortium Program in Professional Psychology from 1978-2009. His research, teaching, advocacy, and public service have all been in the service of a single mission: health promotion and illness prevention. Professor Galano has been an inspiration and role model to students. Not only did they learn about the importance of their work, but they also became aware of the knowledge, skills, and motivation necessary to develop and maintain successful prevention and promotion programs.

 

Janice Zeman

Professor of Psychology and Chair

 

Acadia University, BS with Honors in Psychology, 1984

Vanderbilt University, MA, 1987

Vanderbilt University, PhD in Developmental and Clinical Psychology, 1991

 

Professor Zeman’s remarkable career leading up to her current position as chair of the psychology department includes research as part of an assessment team in Antarctica, cross-cultural research with William & Mary students in Ghana and Kenya, and coordinating the developmental-clinical psychology doctoral track at the University of Maine. She has been with William & Mary since August 2006 and her research is in the broad domain of developmental psychopathology, studying both normative and atypical emotional development in children and adolescents.

 

From the Special Collections Research Center, Earl Gregg Swem Library at the College of William and Mary. See swem.wm.edu/scrc/ for further information and assistance.

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Shown here is an image from the exhibit "Open Minds: An Exhibit of Psychology Department Faculty Publications," on display in the Bright Gallery on the second floor of Swem Library at the College of William and Mary. The exhibit features publications from faculty in the College of William and Mary's Department of Psychology. The exhibit is on display from March 26, 2012-January 18, 2013.

 

The following is a transcription of the label text presented in this case:

 

William & Mary’s

Psychology Department

 

A Brief History

 

During the 1888-1889 academic year, William & Mary president Lyon G. Tyler taught the college’s first psychology course which was then listed under the Department of Moral Science, Political Economy, and Civil Government. The “Catalogue of the College of William and Mary and State Male Normal

School” for that year describes the program as follows:

 

There are two classes in this department, a Junior and a Senior.

In the Junior the elements of Psychology are set forth, and the faculties of the mind especially discussed in their relation to education. A thorough knowledge of the laws according to which the memory, imagination, and other faculties operate will be found of great value to the student in receiving and to the teacher in imparting information. Psychology is made to alternate with lectures on civil government. p. 24

 

William & Mary was with the times! According to the Encyclopedia of Higher Education, the late 1880s was when colleges in the US first began offering psychology courses.

 

In the fifty years that followed, psychology classes continued to be taught in several different departments, including Philosophy and Pedagogy, Philosophy and Psychology, Education, and eventually Psychology and Philosophy.

 

In the 1943-1944 catalog, Psychology is finally listed as its own department,

with five professors offering twelve courses. Over the years, it has grown dramatically – establishing graduate programs and offering many more

courses taught by an increasing number of faculty members.

 

Today, there are approximately thirty faculty, including visiting and adjuncts, who teach more than fifty course sections and numerous labs. The

publications selected for this exhibit show the varied research conducted by

the department’s faculty.

 

Robert Barnet

Associate Professor of Psychology

 

University of Alberta, BA in Honors Psychology, First Class, 1989

Binghamton University, SUNY, MA in Experimental Psychology, 1991

Binghamton University, SUNY, PhD in Experimental Psychology, 1994

 

Professor Barnet has been with William & Mary for thirteen years. His research interests are memory and cognition, particularly in animals. He enjoys inviting his students to be a part of “the excitement of discovery in science.” Under his mentorship, students have presented at conferences, received scholarships and awards, and authored scholarly works.

 

Joshua Burk

Associate Professor of Psychology

Graduate Studies Director

 

University of California, Davis, BS in Psychology with Biological Emphasis, 1993

University of New Hampshire, MA in Experimental Psychology, 1996

University of New Hampshire, MST in College Teaching, 1999

University of New Hampshire, PhD in Experimental Psychology, 1999

 

Professor Burk is embarking on his tenth year with William & Mary, and his research focuses on behavior and cognitive neuroscience. Presently, he is researching whether a neuropeptide, orexin A, can enhance attention. He enjoys “watching the success and intellectual growth of our undergraduate and graduate students.”

 

Joseph Galano

Professor Emeritus

 

CMDNJ-Rutgers Medical School, Internship in Clinical/Community Psychology, 1976

Bowling Green State University, PhD in Clinical Psychology, 1977

 

Professor Galano taught at William & Mary from 1977-2010 and served as a faculty member with the Virginia Consortium Program in Professional Psychology from 1978-2009. His research, teaching, advocacy, and public service have all been in the service of a single mission: health promotion and illness prevention. Professor Galano has been an inspiration and role model to students. Not only did they learn about the importance of their work, but they also became aware of the knowledge, skills, and motivation necessary to develop and maintain successful prevention and promotion programs.

 

Janice Zeman

Professor of Psychology and Chair

 

Acadia University, BS with Honors in Psychology, 1984

Vanderbilt University, MA, 1987

Vanderbilt University, PhD in Developmental and Clinical Psychology, 1991

 

Professor Zeman’s remarkable career leading up to her current position as chair of the psychology department includes research as part of an assessment team in Antarctica, cross-cultural research with William & Mary students in Ghana and Kenya, and coordinating the developmental-clinical psychology doctoral track at the University of Maine. She has been with William & Mary since August 2006 and her research is in the broad domain of developmental psychopathology, studying both normative and atypical emotional development in children and adolescents.

 

From the Special Collections Research Center, Earl Gregg Swem Library at the College of William and Mary. See swem.wm.edu/scrc/ for further information and assistance.

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Exert from: ‘The Absurdity of Pigeon Feed’ by Tom Tomlinson

‘Yet another act of God, Pt. 2.’

 

Context: The international space station undergoes a catastrophic accident. Shit is launched into deep space and spawns life on two distant planets. Billions of years later the two planets tune into slightly different radio broadcasts from planet Earth (broadcasts of religious wars and children’s programs).

Result: they are infected by different belief memes and decide to go to war against each other. A space ship from another civilization is about to enter their solar system…..

 

‘Sir, we’ll be entering the constellation in less time than it takes for a Greater Naked Mole Rat to engage in a quick Jiffy.’

‘Is that your best effort at humour Mr Speck? Pathetic. Besides, don’t mention greater naked mole rats when Piranha’s about, she suffers from arachnophobia; human beings have feelings, don’t you know?’

‘I think you mean zemmiphobia. The psychological condition is totally illogical, there is no evidence that the greater naked mole rat ever existed, and hence zemmiphobia is doubly irration….’

‘Shut the fuck up you insignificant…. Take her out of hyperinflation drive and engage subprime engines, mark 3, plot a course intersecting the two planets and bring us to rest between them.’

‘Aye, aye, Captain Buckfirst.’

 

‘Captain Sir, sensors are picking up hundreds of craft around that very location. Captain, they appear to be engaged in warfare?’

‘What? Warfare. Thank you Mr Stalin. Science officer Speck, what do you make of it?’

‘Antiquated weapon systems, no problem for our shields. However, the two class P planets do seem to be engaged in an unauthorised war of attrition and yet both planets appear to have abundant resources Sir. Laser weaponry isn’t up to much, they’d be better off throwing soggy turds at each other. However, I recommend engaging the shields.’

‘Mr Speck I’m going to need two science crews, one to beam down to each planet. I want to find out why these beings are engaged in ignorant economically crippling activities without any sign of profitable outside subversion. We’ve no records of selling arms to either side.’

‘Yes Captain, in their case warfare does seem totally irrational.’

The ship came to rest, the science teams got on their way. The Captain had nothing to do so he and the other members of the bridge crew returned to their game of ‘Risk,’ its objective the economic dominance of the entire Universe. The Captain kept his eye on Communications Officer Piranha. Sassy bitch always cheated.

The ship came under attack, laser beams hit it repeatedly; the powerful blasts nothing more than wasp stings to the enormous vessel and her shields. After a pause in fire, quite suddenly the ship lurched just as the Captain had secured a total monopoly on cocoa trade in the Milky Way. Pissed off, he put the game aside for the moment and then just as he’d taken the advantage – in fact he’d never actually won – that fucking science officer ‘vulcanised ears’ with his mind twisting rationality always had to play.

 

‘Mr Grueshev what in tar-nation was that.’

‘Sir one of the opponents are using the low down dirty Kamikaze tactics of crazed martyrs, that last bump was thirty of their ships hitting us at one time, why would they do that sir, they killed themselves for nothing? No profit there Sir, I’ve run the strategy through all the game theory algorithms we have?’

‘Any real danger Stalin?’

‘Na Captain Buckfirst, the shields can handle it.’

‘Your go; by the way Piranha I thought I saw a great naked rat or was it a mole in the corridor next to your cabin today,’ commented Captain Buckfirst as he eyed her hands carefully.

The game went on while the ship rocked gently back and forth like a baby sleeping peacefully in its crib as thousands upon thousands of alien craft destroyed themselves for nothing at all. Coffee breaks with banal conversation came and went. Just as the Captain was about to seriously lose it, his being on the verge of going economically bankrupt again to Piranha, the two teams arrived back. The Captain sighed with relief, ‘Pack that shit away, we’ve got work to do. Mr Speck, I hope you have some answers for me.’

‘Yes Sir complicated but not irresolvable, I calculate we have a 99.78% chance of resolving the situation to our advantage.’

‘Good, give it to me, what’s going on?’

 

‘It seems both races have evolved from genetic material from Planet Earth Sir, although one or two genes were corrupted during their transportation here, Interstellar radiation would account for that. Both races are humanoid derivatives; they call themselves Drogans. Their genetic codes mutations resulted in a phenotype that’s overly fertile and their sex hormones are elevated to unsustainable levels.

‘Hang on Speck, are you saying they fuck like Greater Naked Mole Rats on Viagra and pop em out at the same rate?’

‘Something like that Captain, although strangely evolution has taken care of that by checking their population growth and bringing it into balance with their planet’s resources in both cases.’

‘Give me the details Speck, not the sex, pervert, just how exactly are the populations brought in check?’

 

‘Sir, the original wild oats sown on the planets contained the same human genome even if it wasn’t fully expressed for aeon’s to come. From a shitty sludge rose up a multitude of life forms not dissimilar from those that populated your original home planet Sir. The outright evolutionary winners on both planets, humanoid life forms.’

‘You’re boring me, showing off again you swat, get to the point.’

‘Both populations began to accede to the effects of over fertility yet each population became checked and put in balance by symbiotic relationships with other species, all be it the truth was never discovered by their own scientist.’

‘Speck I said the point, I haven’t got a Galaxy year, we have to move on soon and get that druggie doctor up here, stun him if you have-to and spike him up with something to sober him up; see to that Piranha.’

‘As I was saying, one race evolved together with a cat like animal, its paw in the door original value to them was to keep the rodents plaguing the population to a level insuring civilisation grew without their nuisance. Illogically it came to pass cats became revered as agents of their God and their faeces are burnt as ceremonial offerings to him.’

‘Are you pulling my plonker Speck?’

‘No Sir, that would be irrational and in your case it might even be classified as a disgusting perversion. Unfortunately the cat’s shit is infected with a virus, benign to themselves but with the capacity to meddle with their human carers: the ubiquitous ceremonial burning of their faeces facilitates the virus to infect all the humanoids. After a period of incubation it gains access to yummy regions of the brain, regions controlling emotion. The virus meddles with the brain’s chemistry producing a population where melancholy is the norm, suicide common and hardly worth the mention. That explains the irrational Kamikaze ships dousing the shields have had to put up with; Captain the shields will need cleaning soon.’

The Captain appeared to nod, in approval.

‘The other planet’s humanoids story is not dissimilar. Its population was put in balance with their resources by a symbiotic relationship with a canine, a dog like creature with a trick in its paw. It too gained access to the private lives of the humanoids, first by tapping into the humanoids practical needs, then overtime, it evolved a clever neuropeptide to subjugate and addict its masters by excreting it from sweetened farts and later the humanoid produced his own neuropeptide every time he made eye contact or petted the animal. The humanoids became so addicted to the dog’s drug fellow humanoids became secondary to their beloved pets, unaware of their addiction they began to isolate themselves, happy, content, and fulfilled. Sex however, became an-ever increasingly complicated chore requiring great effort, to be avoided if possible.’

 

Speck became suspicious, the Captain hadn’t interrupted him once. ‘Captain, Captain Buckfirst.’

‘What? What the…?’ The Captain had drift off and now came too taking note of the medical officer who had arrived bleary-eyed and staggering.

‘The last aspect of the two planet’s discord revolves around their belief meme/genes. Same old story there, useful for enabling them to learn life’s basics and keeping them safe in childhood, but if it doesn’t get switched off or moderated by rationality and logic after puberty.

It always results in the same old boring bollocks; belief in unsubstantiated absurdities. We’ve seen the same old crap all over the Universe Captain, Gods, phantasmagorical tittle-tattle and other such primitive brain numbing stuff.

So, the vastly different mind-sets of each planet had no chance of resolving even the tiniest of disputes, then, add in such a stupid contention as to whose God thingy is the realest and bestest, in their case all rationality and logic disappeared in a murky haze of sweetened dog farts and cat shit fumes.

It’s totally illogical, just imagine Captain they’re fighting each other in a war of attrition that can only end in the extinction of the two races over whether one planets’ gods ‘Bill and Ben and his Flower Pot Men’ or the others ‘Zebedee of the Magic Roundabout and his prophet Florence’ are the one and only true gods.?’

‘Shut it Speck. Why not throw down a few clones and unseat their governments, you know, install two corrupt cronies who are open to a one-way trade agreement and bribery and get some real democracy going?’

‘Captain, that’s illogical we haven’t done that for eons, it’s costly and always fucks up super big-time creating even more problems, untold loss of life, cultural genocide and no profit to mention other than arms sales.’

‘Okay I’ve had enough of this. Mr Stalin load the photon tubes and take out all life on one of the planets on my word. Second thought’s trash everything I’m bored with all of this. Let’s get on our way there’s no way we can we make a quick buck here, target both the planets.’

 

The Doc had been sat for some time listening in and now jumped from his seat to confront the Captain, ‘My God Jim. What about the Federation’s Prime Directive? No meddling in alien civilisations, do the greatest good for the greatest number of people and all that?’

‘Oh come on Doc get your bleeding nose outa this.’

‘But Captain Buckfirst, you were the one who dragged me away from my stuff. Now look here Jim, the Prime Directive clearly states, not to interfere in the internal development of alien civilisations unless there’s a reasonable profit to be made out of them for the good of the greatest number of people, namely us.’

The Captain swivelled his chair back and forth, ‘I don’t see no profit here you Boneless druggie.’

‘Jim, just give me half an hour and we can blast both planets with one of my unbelievably clever concoctions and we can redress the belief meme/genes to their correct levels.’

‘Oh Yeah, and what about the cats and dogs.’

Speck spoke up, ‘Captain, we can blast them with species specific lasers and eradicate them bringing total freedom to all those we deem to be friendly humanoids. There may even be a buck to be had out of all this.’

Speck lent down and whispered in the Captains ear.

 

The ‘USS. ECONOMIC CONQUEST UN-LTD.’ engaged its hyperinflation warp drive and spend off into the unknown on its never-ending mission to discover and economically subvert any civilisation where a reasonable profit to the detriment of others was to be made.

Captain Buckfirst and the enterprise had done it again; they’d brought real free democracy to the two civilisations at once by eradicating the cats and dogs and moderating the two side’s belief meme/genes.

 

The emancipated humanoids where now able to exercise total freedom of choice within a democratic society. That is; one sufficiently warped by the wake of hyperinflation engines as they scarpered down dirty intergalactic wormholes off to their next exciting mission, opening up new markets to exploitation whilst rendering them forever dollar indebted to beloved Utilitarian ethics of freely given help and generosity. More precisely put: a warped Utilitarianism that brings about the minimum morally best action to achieve the greatest illusion of pleasure and happiness to the greatest number of people while making maximum profit bled off to US consortiums.

 

Epilogue; (Cheap crappy music running in the background.)

 

In time the Dog Star constellation became universally famous for its male and female whores and their incredible unlimited sex drives. Whereas the populations of the two planets had had their minds enslaved by dogs, cats and belief meme/genes, they now became economically enslaved having to buy in all manner of contraceptives and expensive drugs at vastly over inflated prices to treat a new strain of the dreaded sexually transmitted belief meme – Scrambled Fibobytes Unidemic Disease –commonly known as – Schmuck Smegma’s disease – that was sweeping across several galaxies.

Mind mangling drugs poured in rocking and rolling an American stylised democracy of sycophantic corruption, quickly followed by police state thought control, racism and topped off with a spot of cultural genocide piggybacking in on the computer-generated green back.

Highly profitable social breakdown and crippling debt ensued; The Dog Star constellation soon became a gold star standard for US economic imperialism.

 

Exert from: ‘The Absurdity of Pigeon Feed’ by Tom Tomlinson.

Conceptual photographer and essayist

  

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Blog Post: Although we all seem to have an idea that high levels of stress is connected to a larger waistline, we now have science to validate that theory. In a recent article, the biochemistry associated with stress, including the roles of serotonin, cortisol and neuropeptide Y, is explained, and we can see that humans are wired to reach for fatty and sugary foods when under stress. The good news is that we now understand why high fat, high sugar and simple carbs are the main qualities of our favorite “comfort foods.” Of course, the bad news is that Mother Nature has dealt us a tough hand! Here are some tips, paraphrased from the article, on how we can combat this totally natural, though rather unfortunate, situation... Read more at guidanceforgrowing.com/news/stress-and-obesity/

AQUA . for . Diabetes INSIPIDUS

for my granddaughter, Abigail, who's in hospital being tested for this. (She's 3)

en.wikipedia.org/wiki/Diabetes_insipidus

 

I love all of the aqua items and the aqua treasuries that we have here on etsy, so it seemed a rather fitting theme for raising awareness of Diabetes Insipidus - sometimes called Water Diabetes. The link at the top is to a wikipedia article about DI.These are some fund raising links: US - www.diabetesinsipidus.org/membership.htm (there is a donate button, you don't have to join)

Australia - www.florey.edu.au/research/scientific-laboratories/neurop... there's a donate button at the bottom of sidebar

Image by Rothem Kovner

 

Nikon A1 Confocal Microscope

 

This image illustrates the primate bed nucleus of the stria terminalis (BST), a brain region responsible for threat-responding. The tissue was first stained for neurons (blue) and then for two different neuropeptides (red and green). Once stained, multiple images were taken at high magnification on a confocal microscope and then stitched together to make a large image depicting the whole BST. Visualizing the cross-talk between neuropeptides in the BST is the first step to developing hypotheses aimed at understanding how these chemicals can regulate behavior.

Brain changes with psychotherapy. Neurobiology of Psychotherapy

22Oct2015 Neuropsychiatry Major Depressive Disorder, Psychotherapy

Randon Welton, MD Jerald Kay, MD

The Neurobiology of Psychotherapy

Table 1. Main brain system involved in mediating attachment

Main brain system involved in mediating empathy

TABLE 2. Main brain system involved in mediating empathy

Main brain system involved in mediating learning

TABLE 3. Main brain system involved in mediating learning

Main brain system involved in mediating emotion regulation

TABLE 4. Main brain system involved in mediating emotion regulation

Main brain system involved in mediating fear extinction

TABLE 5. Main brain system involved in mediating fear extinction

A recent Institute of Medicine report acknowledges the efficacy of a broad range of psychosocial interventions.1 It challenges us to “identify key elements that drive an intervention’s effect.” The report describes key clinical tasks such as the therapist’s ability to engage with a patient, understand the patient’s worldview, and help the patient manage his or her emotional responses. The psychiatric community should also look into the neurobiological changes that accompany and may be responsible for an intervention’s effect. Although early psychoanalysts made little effort to connect functions of the mind to definable portions of the brain, from the beginning there was a belief that such a relationship may exist. Freud confidently predicted that one day there would be a neurological understanding of the work he initiated.

The deficiencies in our description would probably vanish if we were already in a position to replace psychological terms by physiological or chemical ones. Biology is truly a land of unlimited possibilities. We may expect it to give us the most surprising information and we cannot guess what answers it will return in a few dozen years to the questions we have put to it.2

Almost 100 years have passed since Freud wrote those words, and many of his questions remain unanswered. Steady progress, however, has been made in the development of a neurobiological understanding of what happens in the brain when the mind is engaged in psychotherapy. Advances in cognitive neuroscience and neuroimaging have facilitated a greater appreciation of the neuroanatomy and neurophysiology of the CNS. The technology to study the real-time functioning of the brain through measurement of blood flow or glucose uptake, for example, has been widely used for a quarter of a century. Numerous challenges endure, such as subtle individual variations of neural circuitry, uncertainty as to the proper area to study, and the possibility that differing forms of therapy affect the brain differently. Within the boundaries created by these limitations, however, there is an emerging understanding of the neurobiological correlates of some common psychotherapy elements.

Although different approaches utilize various terms and concepts, there are some components that are found in most forms of efficacious psychotherapy. There must be some emotional engagement (attachment) between the patient and therapist. The therapist will struggle to understand and express the patient’s experience (empathy). By learning about themselves and their environment, patients will decide to make changes. As therapy continues, they will develop new abilities to regulate their emotions. Many patients will be forced to face and overcome feared relationships or situations (fear extinction). There is a neurobiological literature developing on each of these common components of psychotherapy.

Attachment

Forming nurturing attachments with others remains a challenge throughout life especially for those with early trauma. The neurochemistry of attachment involves the neuropeptides oxytocin and arginine vasopressin. Both of these messengers are released from the hypothalamus by sexual stimulation and stress. In combination with estrogen, oxytocin helps induce maternal behavior, while the absence of oxytocin makes it more difficult for animals to adapt to social settings and leads to abnormal displays of aggression. Infusing or blocking oxytocin also causes dramatic changes in mating behaviors. Arginine vasopressin has myriad effects on normal mammals including altering displays of aggression and the animal’s tendency to affiliate with or protect others.

In humans, oxytocin is associated with a number of factors that affect attachment including trust, empathy, eye contact, and generosity. Oxytocin infusions in healthy individuals tend to decrease anxiety and the stress associated with social situations while shifting attention from negative to positive information. The reduction in distress appears related to a reduction in activity in the amygdala. In a study of women with borderline personality disorder, oxytocin infusion decreased their amygdala activation when exposed to angry faces.3 Although the effect is mediated by past experiences, intra-nasal infusion of oxytocin may increase an individual’s ability to infer the mental state and intention of others based on their facial expression. Oxytocin specifically aids in parent-child bonding. Administering oxytocin to parents increases the social engagement of the parent and child and leads to an increase in oxytocin in the child.

The mu-opioid receptor also appears to be involved in attachment. Activation of the mu-opioid receptor leads to a general sense of pleasure as well as analgesia. In animal models, removing the mother from the child leads to distress that is at least partially mediated through mu-opioid activity. Animals with an increased activation of the opioid system had more attachment behaviors and louder and more prolonged protests when separated. Their separation distress could be partially reversed by non-sedating opioid agonists.4 Patients with borderline personality disorder have differences in baseline mu-opioid receptor concentrations and in the endogenous opioid system response to negative emotional challenges. These differences might be related to their difficulty with emotion regulation.

Attachment therefore correlates with neurochemical changes within the brain. This might be most evidenced in parent-child interactions but may play a significant role in psychotherapy as well. A study of mothers with postpartum depression undergoing psychodynamic psychotherapy found that daily infusions of oxytocin over 12 weeks were associated with a decrease in narcissistic traits but not in depressive personality traits or depressive symptoms.5Depressed men who received oxytocin infusions while in psychotherapy performed better on tests of inferring the mental state of others but were more likely to experience anxiety during the session.6 These findings hint of a complex interaction between oxytocin and the therapist-patient relationship (Table 1).

Empathy [Narcissistic Personality Disorder NPD with conscious effort can evoke cognitive empathy but muted emotional empathy]

Empathy entails the ability to consider the world from another’s point of view and in some way to share his or her emotional experiences. Neurobiological correlates of empathy were first described in the early 1990s with the discovery of mirror neurons. Researchers who were studying the neuronal activity involved in organizing and monitoring movements noted that some of the same premotor cortex neurons were activated while observing others make corresponding movements.7,8 Neurons that were activated when a monkey grabbed food were activated when the researcher grabbed food but not when the researcher pushed or struck the food. These neurons were referred to as mirror neurons.

Mirror neurons in humans are not limited to simple movements. Watching dance leads to activation in the brains of other dancers. Greater activation occurs when dancers watch movements they already know. Mirror neurons activate while watching facial expressions and seem to be partially impaired in individuals with autistic disorders. Human mirroring networks also exist for pain and emotional distress. Researchers created pain by sticking subjects with a needle and monitored which areas of the brain were activated.9 Similar pathways were activated when the researchers brought the needle close to the subject but did not make contact and when subjects watched researchers pricking their own fingers. Witnessing others display disgust activates many of the same areas that are activated when one smells an unpleasant odor.

Mirroring neurons also fire when observing others being rejected or embarrassed. The areas most involved in mirroring physical pain, emotional distress, and social discomfort are the anterior cingulate cortex and insula. These areas help individuals automatically imagine themselves experiencing what they witness others experiencing. It should be noted that the studies of mirror neurons in humans are preliminary and not without controversy.

The posterior portions of the superior temporal sulcus have similar activities. This region activates when witnessing social behavior and predicting future actions. When a figure is walking toward you, activation of the superior temporal sulcus is greater when the figure is looking at you, which indicates the prospect of an upcoming interaction. Activation also increases when the other person’s behavior is different than expected. [attention focused through violated expectation]

In a study by Wyk and colleagues,10 an actor displayed pleasure or disgust to one of two identical objects and then randomly picked up one of the objects. When there was incongruent action (picking the object after showing disgust or not picking the object after a display of pleasure), there was increased activity in the observer’s posterior superior temporal sulcus region.

Experiencing empathy appears to require proper activation of portions of the insula and anterior cingulate cortex as we seek to understand the emotional experience of others. A properly functioning posterior superior temporal sulcus allows us to determine and predict the social actions of others, and will tend to activate when someone violates societal expectations. ][mutual respect dignity etiquette kindness helpfulness contribution to the common good]

Oxytocin and arginine vasopressin are also implicated in empathy. A study of polymorphisms in the genes of 367 young adults found that variations in the emotional aspect of empathy were associated with the oxytocin receptor gene, while the cognitive aspect of empathy was associated with the gene for the arginine vasopressin 1a receptor.11 A highly complex interaction of neurotransmitters and brain activation allows the therapist to understand the patient’s experience (Table 2).

Learning [hippocampus site of learning and memory]

Early in the 20th century Cajal proposed that the brain stored information by modifying neuronal connections. Learning involved changing individual neurons and their connections with each other. In the mid-20th century Hebb proposed his rule stating that when one neuron’s repeated excitation is involved in the excitation of a neighboring neuron, the connection between the two of them grows more efficient. Put colloquially, “Neurons that fire together wire together.” This implies that synapses change over time.

The first demonstration of this in the hippocampus occurred in 1973. After exposing neurons to strong, high-frequency stimulation, their connection to other neurons in the hippocampus became stronger.12 The discovery of hippocampal neurogenesis [new brain cell formation, constant baby brain cell creation which require 30 years to myelinate mature] established the process of neuronal plasticity [rewiring brain cell connections, augmentation bring in more brain cells for a particular circuit, or atrophy allowing connections to wither and die due to disuse like muscles in a broken arm unused in a cast become thinned from disuse atrophy] and upended the long-held belief that CNS cells were neurophysiologically and neuroanatomically incapable of growth.

Using the California sea slug (Aplysia californica), Kandel13 demonstrated that habituation [tolerance]—a decrease in response to a stimulus—could be attained with a single training session of 10 stimulations. These effects lasted minutes to hours and appeared to be a result of changes in the amount of neurotransmitter released with the stimulation. Training sessions on 4 consecutive days resulted in an effect that lasted weeks. This long-term learning was associated with changes in interneuronal connections. [rewiring, what we practice attending to, thinking and doing becomes stronger: self pity, helplessness, other blaming or personal responsibility, looking to the helpful hand at the end of own arm, choosing healthy vegetables fruits, sleep, physical activity, avoidance of recreational chemicals, engagement in meaningful work, continuity durability of healthy relationships, attitude, mental physical emotional social spiritual financial responsibility]

Preliminary studies in humans have found measurable changes in the brain based on learning stemming from juggling and playing video games.14,15 Experimental data demonstrate that the neurons in the brain are capable of learning-induced change. Psychotherapy includes components of experiential and didactic learning that is expected to create change in the patient’s brain. Many psychotherapies focus on thoughts or patterns that are initially outside the awareness of the patient. [precontemplation stage of change Motivational Interviewing Mindfulness Meditation introduces awareness that something is not comfortable] Therapy creates new memories to modify older, dysfunctional ones and in some cases creates new psychic structures. [children's literature bibliotherapy, cinematherapy, coming of age, shift POV point of view to allow reassessment reflection contemplation integration consolidation, openness to listening hearing another person social skill acquisition, appreciating own growth Good Job second grade social skill learning] This learning must involve changes in interneuronal connections (Table 3).

Emotion regulation [Sitting Still Like a Frog Eline Snell, Healing and the Mind Bill Moyers DVD 5 episodes, Stress Portrait of a Killer documentary, Dhamma Brothers Frontline 10 day meditation training years later follow up, Departures Oscar Best Foreign film learning forgiveness without apology]

Patients in psychotherapy are taught to understand, accept, or manage their emotional responses in new ways. Researchers are looking into how emotion regulation modifies brain activity.

One common strategy for altering emotions is reappraisal, when the individual deliberately tries to alter the meaning or relevance of an event. Reappraisal strategies link cognitive control with emotional experience. Attempts to deliberately decrease aversive emotions, sadness, and sexual arousal through cognitive reappraisal have found that reappraisal strategies most commonly activate multiple areas within the prefrontal cortex [behind forehead] and posterior parietal cortex. Activation of these areas during reappraisal leads to decreased activity in portions of the amygdala [anger anxiety]. These studies have demonstrated specific neuronal circuitry, for example, between the hippocampus [learning memory], prefrontal cortex [planning decision making analysis initiation motivation execution judgment financial literacy] , and amygdala anxiety anger], which are strengthened by psychotherapeutic treatment.16,17

Suppression, an intentional attempt to minimize the display of emotions, may also decrease the intensity of emotions. [role playing DVD Healing and the Mind Bill Moyers] Subjects were asked to suppress their emotions while observing sad pictures. When suppressing their emotions, there was an increase in activity in the right [emotional] orbitofrontal and dorsolateral prefrontal cortices.18 Other studies have found activation of the dorsal anterior cingulate cortex, dorsomedial prefrontal cortex [conscious decision effort], and lateral prefrontal cortex with suppression.19

Cognitive reappraisal and suppression seem to have distinctly different neurophysiological mechanisms. In a head-to-head study both strategies were successful at decreasing subjective emotional experience, but there were differences in brain activation.20

Reappraisal led to increased activity in the prefrontal cortex [cognition conscious choice awareness] and decreased activity in the right amygdala [anger anxiety emotional dysregulation] and left insula.

Suppression increased activity in the right ventral-lateral prefrontal cortex but did not decrease activity in the amygdala or insula (Table 4).

Fear extinction

Learning to be afraid, or fear conditioning, involves pairing a previously innocuous stimulus (conditioned stimulus) with an aversive stimulus (unconditioned stimulus). The mind begins to associate the previously benign stimulus with the unpleasant one, and the individual experiences heightened anxiety whenever presented with the new conditioned stimulus. The process of fear conditioning involves interactions of the amygdala, insula, anterior cingulate cortex, and medial prefrontal cortex.

The process of unlearning fear is known as fear extinction.

Fear extinction does not consist of erasing old memories; rather it is the creation of new, benign associations. The underlying fear is still present, but successful fear extinction leads to a reduction in the amplitude and likelihood of a fearful response. This occurs when the once feared stimulus or situation no longer brings about any adverse consequences.

Fear extinction is a principal therapeutic component of exposure therapies for specific phobias and for PTSD, but learning to confront feared memories, situations, and people can be found in a broad range of psychotherapies.

Fear extinction requires a functional ventral-medial prefrontal cortex, rostral anterior cingulate cortex, and hippocampus [learning memory]. Activation of these regions leads to decreased amygdala activity. Clinical studies have demonstrated that the addition of D-cycloserine [caveat very very narrow therapeutic window between action and toxicity, strictly low dose one time, not chronic exposure, lacks general applicability], a partial N-methyl-D-aspartate (NMDA) glutamate agonist, may improve outcomes in exposure-based therapies for acrophobia and social phobias.21 Conversely, NMDA antagonists [Modafinil, ketamine], by decreasing NMDA activity, can inhibit the formation of long-term fear extinction. [ie blocks prevents psychotherapeutic learning to challenge erroneous beliefs]

While decreasing the activity in the amygdala leads to an acute reduction in perceived fear, the long-term persistence of fear extinction requires the activity of the ventral-medial prefrontal cortex [cognitive brain] and rostral anterior cingulate cortex. These appear to be vital in connecting the cognitive and emotional experiences and solidifying the learning.

The hippocampus [learning memory] aids in fear extinction by placing events into a context.

This context helps determine how generally the brain applies the new learning. [eg being fearful or being curious about something novel new unfamiliar, like plants animals people DVD Fading Gigolo John Turturro Vanessa Paradis Sharon Stone Sofia Vergara Woody Allen comedy] Because the previous fear is not erased, when the individual encounters the once feared stimuli there is activation of both the fearful and fear extinguished pathways. The context, provided by interactions between the hippocampus [learning memory] and ventromedial prefrontal cortex [cognition conscious awareness, mindfulness], determines which set of behaviors is predominately activated (Table 5).

The work of the psychotherapist is to help solidify the most healthy and adaptive responses.

Prediction of response to psychotherapy

Studies have begun to examine the ability to predict a patient’s response to psychotherapy based on neurobiological factors. One of the many changes that occur with depression is the elevation of metabolism in the posterior insula. Studies have found that changes in connectivity and activation of the insula predicted a positive response to psychotherapy in patients with depression.22-24 Another study found that increased metabolism in the subcollasal cingulate cortex and superior temporal sulcus was associated with no response to escitalopram or cognitive-behavior therapy treatment for depression.25 Conclusion

Although a precise description of the neurophysiological changes that occur during psychotherapy is currently impossible, it is likely that future imaging and neurobiological investigation will elucidate this process. The neurobiological correlates to many of the common elements of psychotherapy such as attachment, empathy, memory, learning, emotional regulation, and fear extinction are emerging. While we still cannot answer all of Freud’s questions, or our own questions, the artificial dichotomy between the functioning of the mind and brain during psychotherapy seems less imposing.

Dr Welton is Associate Professor of Psychiatry and Director of Residency Training and Dr Kay is Emeritus Professor of Psychiatry, Boonshoft School of Medicine, Wright State University, Dayton, OH.

1. Institute of Medicine. Psychosocial Interventions for Mental and Substance Use Disorders: A Framework for Establishing Evidence-Based Standards. Washington, DC: The National Academies Press; 2015:S1-S16.

2. Freud S. Beyond the pleasure principle. In: Strachey J, ed. The Standard Edition of the Complete Psychological Works of Sigmund Freud. Vol 18. London: Hogarth Press; 1955:1-64.

3. Bertsch K, Gamer M, Schmidt B, et al. Oxytocin and reduction of social threat hypersensitivity in women with borderline personality disorder. Am J Psychiatry. 2013;170:1169-1177.

4. Barr CS, Schwandt ML, Lindell SG, et al. Variation at the mu-opioid receptor gene (OPRM1) influences attachment behavior in infant primates. Proc Natl Acad Sci USA. 2008;105:5277-5281.

5. Clarici A, Pellizzoni S, Guaschino S, et al. Intranasal administration of oxytocin in postnatal depression: implications for psychodynamic psychotherapy from a randomized double-blind pilot study. Front Psychiatry. 2015;6:1-10.

6. MacDonald K, MacDonald TM, Brune M, et al. Oxytocin and psychotherapy: a pilot study of its physiological, behavioral and subjective effects in males with depression. Psychoneuroendocrinol. 2013;38:2831-2843.

7. Rizzolatti G, Fadiga L, Gallese V, Fogassi L. Premotor cortex and the recognition of motor actions. Cog Brain Res. 1996;3:131-141.

8. Iacoboni M. Face to face: the neural basis of social mirroring and empathy. Psychiatr Ann. 2007;37: 236-241.

9. Hutchison WD, Davis KD, Lozano AM, et al. Pain-related neurons in the human cingulate cortex. Nature Neurosci. 1999;2:403-405.

10. Wyk BC, Hudac CM, Carter EJ, et al. Action understanding in the superior temporal sulcus region. Psychol Sci. 2009;20:771-777.

11. Uzefovsky F, Shalev I, Israel S, et al. Oxytocin receptor and vasopressin receptor 1a genes are respectively associated with the emotional and cognitive empathy. Horm Behav. 2015;67:60-65.

12. Bliss TVP, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993;361:31-39.

13. Kandel ER. Psychotherapy and the single synapse: the impact of psychiatric thought on neurobiological research. J Neuropsychiatry Clin Neurosci. 2001;13:290-300.

14. Draganski B, Gaser C, Busch V, et al. Neuroplasticity: changes in grey matter induced by training. Nature. 2004;427:311-312.

15. Kuhn S, Gleich T, Lorenz RC, et al. Playing Super Mario induces structural brain plasticity: gray matter changes resulting from training with a commercial video game. Mol Psychiatry. 2014;19:272.

16. Ochsner KN, Ray RD, Cooper JC, et al. For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion. Neuroimage. 2004;23:483-499.

17. Buhle JT, Silvers JA, Wager TD, et al. Cognitive reappraisal of emotion: a meta-analysis of human neuroimaging studies. Cerebral Cortex. 2014;24: 2891-2890.

18. Levesque J, Eugene F, Joanette Y, et al. Neural circuitry underlying voluntary suppression of sadness. Biol Psychiatry. 2003;53:502-510.

19. Phan KL, Fitzgerald DA, Nathan PJ, et al. Neural substrates for voluntary suppression of negative affect: a functional magnetic resonance imaging study. Biol Psychiatry. 2005;57:210-219.

20. Goldin PR, McRae K, Ramel W, Gross JJ. The neural bases of emotion regulation: reappraisal and suppression of negative emotion. Biol Psychiatry. 2008;63:577-586.

21. Britton JC, Gold AL, Feczko EJ, et al. D-cycloserine inhibits amygdala responses during repeated presentations of faces. CNS Spect. 2007;12:600-605.

22. Roffman JL, Witte JM, Tanner AS, et al. Neural predictors of successful brief psychodynamic psychotherapy for persistent depression. Psychother Psychosom. 2014;83:364-370.

23. Crowther A, Smoski MJ, Minkel J, et al. Resting-state connectivity predictors of response to psychotherapy in major depressive disorder. Neuropsychopharmacol. 2015;40:1659-1673.

24. McGrath CL, Kelley ME, Holtzheimer PE 3rd, et al. Toward a neuroimaging treatment selection biomarker for major depressive disorder. JAMA Psychiatry. 2013;70:821-829.

25. McGrath CL, Kelley ME, Dunlop BW, et al. Pretreatment brain states identify likely nonresponse to standard treatments for depression. Biol Psychiatry. 2014;76:527-535.

Some issues to note about this otherwise very interesting article.

1. The Institute of Medicine report acknowledging the efficacy of a broad range of psychotherapy needs to be taken with a nuanced view (summary here: iom.nationalacademies.org/~/media/Files/Report%20Files/20....).

None of the claims of “evidence-base” here is based on a blinded clinical trial. Neither subjects nor treaters can feasibly be blind to the nature of the psychotherapy they receive in a clinical trial making these clinical trials poorly controlled. A masked rater only records the unblinded report of the subject and does not control for the lack of blinding. Many clinical trials done in this fashion do not make up for the lack of blinding because it is very easy to obtain non-inferiority and even superiority results in an unblinded trial of a psychiatric condition i.e., depression where endpoints are subjective-and blinding is a key element of any study with subjective endpoints where ratings may easily be swayed by hope and expectation. “Efficacy” and rigor in a clinical trial needs to be used by caution when studies do not have (can not possibly have) blind subjects or treaters.

2. The article’s statement that “A highly complex interaction of neurotransmitters allows the therapist to understand the patient’s experience”, is confusing. Do the authors mean that this research is valuable and heuristic (I would agree), or do they mean that a therapist can figure out how neurotransmitters are actually involved in a patient’s particular experience?- I think this kind of understanding is still very far away and the statement should be reworded.

3. Although the authors state that juggling and playing video games can make changes in the brain, in the next sentence they then move into the effects of psychotherapy making brain changes. Didn’t they just say that even juggling and video games can change the brain? The logic here seems to indicate that the brain is a plastic responsive organ easily changed by experience, but whether that experience (or therapy) is causing some therapeutic effect is still jump of logic away.

4. This study mentioned in the article: D-cycloserine inhibits amygdala responses during repeated presentations of faces. CNS Spectr 2007 Aug;12(8):600-5, only had 14 subjects randomly assigned to drug or placebo, i.e., 7 subj in each group. This “micro N” study needs to be taken with extreme caution, not noted like in this article to be that “Clinical studies have demonstrated…”

The article is an interesting discussion of behavior and biology, but neither the neurobiology of psychotherapy, nor the clinical trial validity of psychotherapy, is a conclusion that can be born from the discussion presented here.

Douglas Berger, MD, PhD.

US Board Certified Psychiatrist

Tokyo, Japan

Use sketches to educate and explain brain plasticity throughout the lifespan, continuing brain cell connection networks ramify and are pruned back continually, neurons (brain cells) interacting with astrocytes (Bergmann glia, Velate astrocytes) in constantly remodeling constellations to create new thought, attitude, behaviors with consequences for brain growth and development through adulthood. sciencemag.or 19Feb2016 Differences among astrocytes p813

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Brain changes with psychotherapy. Neurobiology of Psychotherapy

22Oct2015 Neuropsychiatry Major Depressive Disorder, Psychotherapy

Randon Welton, MD Jerald Kay, MD

The Neurobiology of Psychotherapy

Table 1. Main brain system involved in mediating attachment

Main brain system involved in mediating empathy

TABLE 2. Main brain system involved in mediating empathy

Main brain system involved in mediating learning

TABLE 3. Main brain system involved in mediating learning

Main brain system involved in mediating emotion regulation

TABLE 4. Main brain system involved in mediating emotion regulation

Main brain system involved in mediating fear extinction

TABLE 5. Main brain system involved in mediating fear extinction

A recent Institute of Medicine report acknowledges the efficacy of a broad range of psychosocial interventions.1 It challenges us to “identify key elements that drive an intervention’s effect.” The report describes key clinical tasks such as the therapist’s ability to engage with a patient, understand the patient’s worldview, and help the patient manage his or her emotional responses. The psychiatric community should also look into the neurobiological changes that accompany and may be responsible for an intervention’s effect. Although early psychoanalysts made little effort to connect functions of the mind to definable portions of the brain, from the beginning there was a belief that such a relationship may exist. Freud confidently predicted that one day there would be a neurological understanding of the work he initiated.

The deficiencies in our description would probably vanish if we were already in a position to replace psychological terms by physiological or chemical ones. Biology is truly a land of unlimited possibilities. We may expect it to give us the most surprising information and we cannot guess what answers it will return in a few dozen years to the questions we have put to it.2

Almost 100 years have passed since Freud wrote those words, and many of his questions remain unanswered. Steady progress, however, has been made in the development of a neurobiological understanding of what happens in the brain when the mind is engaged in psychotherapy. Advances in cognitive neuroscience and neuroimaging have facilitated a greater appreciation of the neuroanatomy and neurophysiology of the CNS. The technology to study the real-time functioning of the brain through measurement of blood flow or glucose uptake, for example, has been widely used for a quarter of a century. Numerous challenges endure, such as subtle individual variations of neural circuitry, uncertainty as to the proper area to study, and the possibility that differing forms of therapy affect the brain differently. Within the boundaries created by these limitations, however, there is an emerging understanding of the neurobiological correlates of some common psychotherapy elements.

Although different approaches utilize various terms and concepts, there are some components that are found in most forms of efficacious psychotherapy. There must be some emotional engagement (attachment) between the patient and therapist. The therapist will struggle to understand and express the patient’s experience (empathy). By learning about themselves and their environment, patients will decide to make changes. As therapy continues, they will develop new abilities to regulate their emotions. Many patients will be forced to face and overcome feared relationships or situations (fear extinction). There is a neurobiological literature developing on each of these common components of psychotherapy.

Attachment

Forming nurturing attachments with others remains a challenge throughout life especially for those with early trauma. The neurochemistry of attachment involves the neuropeptides oxytocin and arginine vasopressin. Both of these messengers are released from the hypothalamus by sexual stimulation and stress. In combination with estrogen, oxytocin helps induce maternal behavior, while the absence of oxytocin makes it more difficult for animals to adapt to social settings and leads to abnormal displays of aggression. Infusing or blocking oxytocin also causes dramatic changes in mating behaviors. Arginine vasopressin has myriad effects on normal mammals including altering displays of aggression and the animal’s tendency to affiliate with or protect others.

In humans, oxytocin is associated with a number of factors that affect attachment including trust, empathy, eye contact, and generosity. Oxytocin infusions in healthy individuals tend to decrease anxiety and the stress associated with social situations while shifting attention from negative to positive information. The reduction in distress appears related to a reduction in activity in the amygdala. In a study of women with borderline personality disorder, oxytocin infusion decreased their amygdala activation when exposed to angry faces.3 Although the effect is mediated by past experiences, intra-nasal infusion of oxytocin may increase an individual’s ability to infer the mental state and intention of others based on their facial expression. Oxytocin specifically aids in parent-child bonding. Administering oxytocin to parents increases the social engagement of the parent and child and leads to an increase in oxytocin in the child.

The mu-opioid receptor also appears to be involved in attachment. Activation of the mu-opioid receptor leads to a general sense of pleasure as well as analgesia. In animal models, removing the mother from the child leads to distress that is at least partially mediated through mu-opioid activity. Animals with an increased activation of the opioid system had more attachment behaviors and louder and more prolonged protests when separated. Their separation distress could be partially reversed by non-sedating opioid agonists.4 Patients with borderline personality disorder have differences in baseline mu-opioid receptor concentrations and in the endogenous opioid system response to negative emotional challenges. These differences might be related to their difficulty with emotion regulation.

Attachment therefore correlates with neurochemical changes within the brain. This might be most evidenced in parent-child interactions but may play a significant role in psychotherapy as well. A study of mothers with postpartum depression undergoing psychodynamic psychotherapy found that daily infusions of oxytocin over 12 weeks were associated with a decrease in narcissistic traits but not in depressive personality traits or depressive symptoms.5Depressed men who received oxytocin infusions while in psychotherapy performed better on tests of inferring the mental state of others but were more likely to experience anxiety during the session.6 These findings hint of a complex interaction between oxytocin and the therapist-patient relationship (Table 1).

Empathy [Narcissistic Personality Disorder NPD with conscious effort can evoke cognitive empathy but muted emotional empathy]

Empathy entails the ability to consider the world from another’s point of view and in some way to share his or her emotional experiences. Neurobiological correlates of empathy were first described in the early 1990s with the discovery of mirror neurons. Researchers who were studying the neuronal activity involved in organizing and monitoring movements noted that some of the same premotor cortex neurons were activated while observing others make corresponding movements.7,8 Neurons that were activated when a monkey grabbed food were activated when the researcher grabbed food but not when the researcher pushed or struck the food. These neurons were referred to as mirror neurons.

Mirror neurons in humans are not limited to simple movements. Watching dance leads to activation in the brains of other dancers. Greater activation occurs when dancers watch movements they already know. Mirror neurons activate while watching facial expressions and seem to be partially impaired in individuals with autistic disorders. Human mirroring networks also exist for pain and emotional distress. Researchers created pain by sticking subjects with a needle and monitored which areas of the brain were activated.9 Similar pathways were activated when the researchers brought the needle close to the subject but did not make contact and when subjects watched researchers pricking their own fingers. Witnessing others display disgust activates many of the same areas that are activated when one smells an unpleasant odor.

Mirroring neurons also fire when observing others being rejected or embarrassed. The areas most involved in mirroring physical pain, emotional distress, and social discomfort are the anterior cingulate cortex and insula. These areas help individuals automatically imagine themselves experiencing what they witness others experiencing. It should be noted that the studies of mirror neurons in humans are preliminary and not without controversy.

The posterior portions of the superior temporal sulcus have similar activities. This region activates when witnessing social behavior and predicting future actions. When a figure is walking toward you, activation of the superior temporal sulcus is greater when the figure is looking at you, which indicates the prospect of an upcoming interaction. Activation also increases when the other person’s behavior is different than expected. [attention focused through violated expectation]

In a study by Wyk and colleagues,10 an actor displayed pleasure or disgust to one of two identical objects and then randomly picked up one of the objects. When there was incongruent action (picking the object after showing disgust or not picking the object after a display of pleasure), there was increased activity in the observer’s posterior superior temporal sulcus region.

Experiencing empathy appears to require proper activation of portions of the insula and anterior cingulate cortex as we seek to understand the emotional experience of others. A properly functioning posterior superior temporal sulcus allows us to determine and predict the social actions of others, and will tend to activate when someone violates societal expectations. ][mutual respect dignity etiquette kindness helpfulness contribution to the common good]

Oxytocin and arginine vasopressin are also implicated in empathy. A study of polymorphisms in the genes of 367 young adults found that variations in the emotional aspect of empathy were associated with the oxytocin receptor gene, while the cognitive aspect of empathy was associated with the gene for the arginine vasopressin 1a receptor.11 A highly complex interaction of neurotransmitters and brain activation allows the therapist to understand the patient’s experience (Table 2).

Learning [hippocampus site of learning and memory]

Early in the 20th century Cajal proposed that the brain stored information by modifying neuronal connections. Learning involved changing individual neurons and their connections with each other. In the mid-20th century Hebb proposed his rule stating that when one neuron’s repeated excitation is involved in the excitation of a neighboring neuron, the connection between the two of them grows more efficient. Put colloquially, “Neurons that fire together wire together.” This implies that synapses change over time.

The first demonstration of this in the hippocampus occurred in 1973. After exposing neurons to strong, high-frequency stimulation, their connection to other neurons in the hippocampus became stronger.12 The discovery of hippocampal neurogenesis [new brain cell formation, constant baby brain cell creation which require 30 years to myelinate mature] established the process of neuronal plasticity [rewiring brain cell connections, augmentation bring in more brain cells for a particular circuit, or atrophy allowing connections to wither and die due to disuse like muscles in a broken arm unused in a cast become thinned from disuse atrophy] and upended the long-held belief that CNS cells were neurophysiologically and neuroanatomically incapable of growth.

Using the California sea slug (Aplysia californica), Kandel13 demonstrated that habituation [tolerance]—a decrease in response to a stimulus—could be attained with a single training session of 10 stimulations. These effects lasted minutes to hours and appeared to be a result of changes in the amount of neurotransmitter released with the stimulation. Training sessions on 4 consecutive days resulted in an effect that lasted weeks. This long-term learning was associated with changes in interneuronal connections. [rewiring, what we practice attending to, thinking and doing becomes stronger: self pity, helplessness, other blaming or personal responsibility, looking to the helpful hand at the end of own arm, choosing healthy vegetables fruits, sleep, physical activity, avoidance of recreational chemicals, engagement in meaningful work, continuity durability of healthy relationships, attitude, mental physical emotional social spiritual financial responsibility]

Preliminary studies in humans have found measurable changes in the brain based on learning stemming from juggling and playing video games.14,15 Experimental data demonstrate that the neurons in the brain are capable of learning-induced change. Psychotherapy includes components of experiential and didactic learning that is expected to create change in the patient’s brain. Many psychotherapies focus on thoughts or patterns that are initially outside the awareness of the patient. [precontemplation stage of change Motivational Interviewing Mindfulness Meditation introduces awareness that something is not comfortable] Therapy creates new memories to modify older, dysfunctional ones and in some cases creates new psychic structures. [children's literature bibliotherapy, cinematherapy, coming of age, shift POV point of view to allow reassessment reflection contemplation integration consolidation, openness to listening hearing another person social skill acquisition, appreciating own growth Good Job second grade social skill learning] This learning must involve changes in interneuronal connections (Table 3).

Emotion regulation [Sitting Still Like a Frog Eline Snell, Healing and the Mind Bill Moyers DVD 5 episodes, Stress Portrait of a Killer documentary, Dhamma Brothers Frontline 10 day meditation training years later follow up, Departures Oscar Best Foreign film learning forgiveness without apology]

Patients in psychotherapy are taught to understand, accept, or manage their emotional responses in new ways. Researchers are looking into how emotion regulation modifies brain activity.

One common strategy for altering emotions is reappraisal, when the individual deliberately tries to alter the meaning or relevance of an event. Reappraisal strategies link cognitive control with emotional experience. Attempts to deliberately decrease aversive emotions, sadness, and sexual arousal through cognitive reappraisal have found that reappraisal strategies most commonly activate multiple areas within the prefrontal cortex [behind forehead] and posterior parietal cortex. Activation of these areas during reappraisal leads to decreased activity in portions of the amygdala [anger anxiety]. These studies have demonstrated specific neuronal circuitry, for example, between the hippocampus [learning memory], prefrontal cortex [planning decision making analysis initiation motivation execution judgment financial literacy] , and amygdala anxiety anger], which are strengthened by psychotherapeutic treatment.16,17

Suppression, an intentional attempt to minimize the display of emotions, may also decrease the intensity of emotions. [role playing DVD Healing and the Mind Bill Moyers] Subjects were asked to suppress their emotions while observing sad pictures. When suppressing their emotions, there was an increase in activity in the right [emotional] orbitofrontal and dorsolateral prefrontal cortices.18 Other studies have found activation of the dorsal anterior cingulate cortex, dorsomedial prefrontal cortex [conscious decision effort], and lateral prefrontal cortex with suppression.19

Cognitive reappraisal and suppression seem to have distinctly different neurophysiological mechanisms. In a head-to-head study both strategies were successful at decreasing subjective emotional experience, but there were differences in brain activation.20

Reappraisal led to increased activity in the prefrontal cortex [cognition conscious choice awareness] and decreased activity in the right amygdala [anger anxiety emotional dysregulation] and left insula.

Suppression increased activity in the right ventral-lateral prefrontal cortex but did not decrease activity in the amygdala or insula (Table 4).

Fear extinction

Learning to be afraid, or fear conditioning, involves pairing a previously innocuous stimulus (conditioned stimulus) with an aversive stimulus (unconditioned stimulus). The mind begins to associate the previously benign stimulus with the unpleasant one, and the individual experiences heightened anxiety whenever presented with the new conditioned stimulus. The process of fear conditioning involves interactions of the amygdala, insula, anterior cingulate cortex, and medial prefrontal cortex.

The process of unlearning fear is known as fear extinction.

Fear extinction does not consist of erasing old memories; rather it is the creation of new, benign associations. The underlying fear is still present, but successful fear extinction leads to a reduction in the amplitude and likelihood of a fearful response. This occurs when the once feared stimulus or situation no longer brings about any adverse consequences.

Fear extinction is a principal therapeutic component of exposure therapies for specific phobias and for PTSD, but learning to confront feared memories, situations, and people can be found in a broad range of psychotherapies.

Fear extinction requires a functional ventral-medial prefrontal cortex, rostral anterior cingulate cortex, and hippocampus [learning memory]. Activation of these regions leads to decreased amygdala activity. Clinical studies have demonstrated that the addition of D-cycloserine [caveat very very narrow therapeutic window between action and toxicity, strictly low dose one time, not chronic exposure, lacks general applicability], a partial N-methyl-D-aspartate (NMDA) glutamate agonist, may improve outcomes in exposure-based therapies for acrophobia and social phobias.21 Conversely, NMDA antagonists [Modafinil, ketamine], by decreasing NMDA activity, can inhibit the formation of long-term fear extinction. [ie blocks prevents psychotherapeutic learning to challenge erroneous beliefs]

While decreasing the activity in the amygdala leads to an acute reduction in perceived fear, the long-term persistence of fear extinction requires the activity of the ventral-medial prefrontal cortex [cognitive brain] and rostral anterior cingulate cortex. These appear to be vital in connecting the cognitive and emotional experiences and solidifying the learning.

The hippocampus [learning memory] aids in fear extinction by placing events into a context.

This context helps determine how generally the brain applies the new learning. [eg being fearful or being curious about something novel new unfamiliar, like plants animals people DVD Fading Gigolo John Turturro Vanessa Paradis Sharon Stone Sofia Vergara Woody Allen comedy] Because the previous fear is not erased, when the individual encounters the once feared stimuli there is activation of both the fearful and fear extinguished pathways. The context, provided by interactions between the hippocampus [learning memory] and ventromedial prefrontal cortex [cognition conscious awareness, mindfulness], determines which set of behaviors is predominately activated (Table 5).

The work of the psychotherapist is to help solidify the most healthy and adaptive responses.

Prediction of response to psychotherapy

Studies have begun to examine the ability to predict a patient’s response to psychotherapy based on neurobiological factors. One of the many changes that occur with depression is the elevation of metabolism in the posterior insula. Studies have found that changes in connectivity and activation of the insula predicted a positive response to psychotherapy in patients with depression.22-24 Another study found that increased metabolism in the subcollasal cingulate cortex and superior temporal sulcus was associated with no response to escitalopram or cognitive-behavior therapy treatment for depression.25 Conclusion

Although a precise description of the neurophysiological changes that occur during psychotherapy is currently impossible, it is likely that future imaging and neurobiological investigation will elucidate this process. The neurobiological correlates to many of the common elements of psychotherapy such as attachment, empathy, memory, learning, emotional regulation, and fear extinction are emerging. While we still cannot answer all of Freud’s questions, or our own questions, the artificial dichotomy between the functioning of the mind and brain during psychotherapy seems less imposing.

Dr Welton is Associate Professor of Psychiatry and Director of Residency Training and Dr Kay is Emeritus Professor of Psychiatry, Boonshoft School of Medicine, Wright State University, Dayton, OH.

1. Institute of Medicine. Psychosocial Interventions for Mental and Substance Use Disorders: A Framework for Establishing Evidence-Based Standards. Washington, DC: The National Academies Press; 2015:S1-S16.

2. Freud S. Beyond the pleasure principle. In: Strachey J, ed. The Standard Edition of the Complete Psychological Works of Sigmund Freud. Vol 18. London: Hogarth Press; 1955:1-64.

3. Bertsch K, Gamer M, Schmidt B, et al. Oxytocin and reduction of social threat hypersensitivity in women with borderline personality disorder. Am J Psychiatry. 2013;170:1169-1177.

4. Barr CS, Schwandt ML, Lindell SG, et al. Variation at the mu-opioid receptor gene (OPRM1) influences attachment behavior in infant primates. Proc Natl Acad Sci USA. 2008;105:5277-5281.

5. Clarici A, Pellizzoni S, Guaschino S, et al. Intranasal administration of oxytocin in postnatal depression: implications for psychodynamic psychotherapy from a randomized double-blind pilot study. Front Psychiatry. 2015;6:1-10.

6. MacDonald K, MacDonald TM, Brune M, et al. Oxytocin and psychotherapy: a pilot study of its physiological, behavioral and subjective effects in males with depression. Psychoneuroendocrinol. 2013;38:2831-2843.

7. Rizzolatti G, Fadiga L, Gallese V, Fogassi L. Premotor cortex and the recognition of motor actions. Cog Brain Res. 1996;3:131-141.

8. Iacoboni M. Face to face: the neural basis of social mirroring and empathy. Psychiatr Ann. 2007;37: 236-241.

9. Hutchison WD, Davis KD, Lozano AM, et al. Pain-related neurons in the human cingulate cortex. Nature Neurosci. 1999;2:403-405.

10. Wyk BC, Hudac CM, Carter EJ, et al. Action understanding in the superior temporal sulcus region. Psychol Sci. 2009;20:771-777.

11. Uzefovsky F, Shalev I, Israel S, et al. Oxytocin receptor and vasopressin receptor 1a genes are respectively associated with the emotional and cognitive empathy. Horm Behav. 2015;67:60-65.

12. Bliss TVP, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993;361:31-39.

13. Kandel ER. Psychotherapy and the single synapse: the impact of psychiatric thought on neurobiological research. J Neuropsychiatry Clin Neurosci. 2001;13:290-300.

14. Draganski B, Gaser C, Busch V, et al. Neuroplasticity: changes in grey matter induced by training. Nature. 2004;427:311-312.

15. Kuhn S, Gleich T, Lorenz RC, et al. Playing Super Mario induces structural brain plasticity: gray matter changes resulting from training with a commercial video game. Mol Psychiatry. 2014;19:272.

16. Ochsner KN, Ray RD, Cooper JC, et al. For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion. Neuroimage. 2004;23:483-499.

17. Buhle JT, Silvers JA, Wager TD, et al. Cognitive reappraisal of emotion: a meta-analysis of human neuroimaging studies. Cerebral Cortex. 2014;24: 2891-2890.

18. Levesque J, Eugene F, Joanette Y, et al. Neural circuitry underlying voluntary suppression of sadness. Biol Psychiatry. 2003;53:502-510.

19. Phan KL, Fitzgerald DA, Nathan PJ, et al. Neural substrates for voluntary suppression of negative affect: a functional magnetic resonance imaging study. Biol Psychiatry. 2005;57:210-219.

20. Goldin PR, McRae K, Ramel W, Gross JJ. The neural bases of emotion regulation: reappraisal and suppression of negative emotion. Biol Psychiatry. 2008;63:577-586.

21. Britton JC, Gold AL, Feczko EJ, et al. D-cycloserine inhibits amygdala responses during repeated presentations of faces. CNS Spect. 2007;12:600-605.

22. Roffman JL, Witte JM, Tanner AS, et al. Neural predictors of successful brief psychodynamic psychotherapy for persistent depression. Psychother Psychosom. 2014;83:364-370.

23. Crowther A, Smoski MJ, Minkel J, et al. Resting-state connectivity predictors of response to psychotherapy in major depressive disorder. Neuropsychopharmacol. 2015;40:1659-1673.

24. McGrath CL, Kelley ME, Holtzheimer PE 3rd, et al. Toward a neuroimaging treatment selection biomarker for major depressive disorder. JAMA Psychiatry. 2013;70:821-829.

25. McGrath CL, Kelley ME, Dunlop BW, et al. Pretreatment brain states identify likely nonresponse to standard treatments for depression. Biol Psychiatry. 2014;76:527-535.

Some issues to note about this otherwise very interesting article.

1. The Institute of Medicine report acknowledging the efficacy of a broad range of psychotherapy needs to be taken with a nuanced view (summary here: iom.nationalacademies.org/~/media/Files/Report%20Files/20....).

None of the claims of “evidence-base” here is based on a blinded clinical trial. Neither subjects nor treaters can feasibly be blind to the nature of the psychotherapy they receive in a clinical trial making these clinical trials poorly controlled. A masked rater only records the unblinded report of the subject and does not control for the lack of blinding. Many clinical trials done in this fashion do not make up for the lack of blinding because it is very easy to obtain non-inferiority and even superiority results in an unblinded trial of a psychiatric condition i.e., depression where endpoints are subjective-and blinding is a key element of any study with subjective endpoints where ratings may easily be swayed by hope and expectation. “Efficacy” and rigor in a clinical trial needs to be used by caution when studies do not have (can not possibly have) blind subjects or treaters.

2. The article’s statement that “A highly complex interaction of neurotransmitters allows the therapist to understand the patient’s experience”, is confusing. Do the authors mean that this research is valuable and heuristic (I would agree), or do they mean that a therapist can figure out how neurotransmitters are actually involved in a patient’s particular experience?- I think this kind of understanding is still very far away and the statement should be reworded.

3. Although the authors state that juggling and playing video games can make changes in the brain, in the next sentence they then move into the effects of psychotherapy making brain changes. Didn’t they just say that even juggling and video games can change the brain? The logic here seems to indicate that the brain is a plastic responsive organ easily changed by experience, but whether that experience (or therapy) is causing some therapeutic effect is still jump of logic away.

4. This study mentioned in the article: D-cycloserine inhibits amygdala responses during repeated presentations of faces. CNS Spectr 2007 Aug;12(8):600-5, only had 14 subjects randomly assigned to drug or placebo, i.e., 7 subj in each group. This “micro N” study needs to be taken with extreme caution, not noted like in this article to be that “Clinical studies have demonstrated…”

The article is an interesting discussion of behavior and biology, but neither the neurobiology of psychotherapy, nor the clinical trial validity of psychotherapy, is a conclusion that can be born from the discussion presented here.

Douglas Berger, MD, PhD.

US Board Certified Psychiatrist

Tokyo, Japan

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Brain change with psychotherapy. Neurobiology of Psychotherapy

22Oct2015 Neuropsychiatry Major Depressive Disorder, Psychotherapy

Randon Welton, MD Jerald Kay, MD

The Neurobiology of Psychotherapy

Table 1. Main brain system involved in mediating attachment

Main brain system involved in mediating empathy

TABLE 2. Main brain system involved in mediating empathy

Main brain system involved in mediating learning

TABLE 3. Main brain system involved in mediating learning

Main brain system involved in mediating emotion regulation

TABLE 4. Main brain system involved in mediating emotion regulation

Main brain system involved in mediating fear extinction

TABLE 5. Main brain system involved in mediating fear extinction

A recent Institute of Medicine report acknowledges the efficacy of a broad range of psychosocial interventions.1 It challenges us to “identify key elements that drive an intervention’s effect.” The report describes key clinical tasks such as the therapist’s ability to engage with a patient, understand the patient’s worldview, and help the patient manage his or her emotional responses. The psychiatric community should also look into the neurobiological changes that accompany and may be responsible for an intervention’s effect. Although early psychoanalysts made little effort to connect functions of the mind to definable portions of the brain, from the beginning there was a belief that such a relationship may exist. Freud confidently predicted that one day there would be a neurological understanding of the work he initiated.

The deficiencies in our description would probably vanish if we were already in a position to replace psychological terms by physiological or chemical ones. Biology is truly a land of unlimited possibilities. We may expect it to give us the most surprising information and we cannot guess what answers it will return in a few dozen years to the questions we have put to it.2

Almost 100 years have passed since Freud wrote those words, and many of his questions remain unanswered. Steady progress, however, has been made in the development of a neurobiological understanding of what happens in the brain when the mind is engaged in psychotherapy. Advances in cognitive neuroscience and neuroimaging have facilitated a greater appreciation of the neuroanatomy and neurophysiology of the CNS. The technology to study the real-time functioning of the brain through measurement of blood flow or glucose uptake, for example, has been widely used for a quarter of a century. Numerous challenges endure, such as subtle individual variations of neural circuitry, uncertainty as to the proper area to study, and the possibility that differing forms of therapy affect the brain differently. Within the boundaries created by these limitations, however, there is an emerging understanding of the neurobiological correlates of some common psychotherapy elements.

Although different approaches utilize various terms and concepts, there are some components that are found in most forms of efficacious psychotherapy. There must be some emotional engagement (attachment) between the patient and therapist. The therapist will struggle to understand and express the patient’s experience (empathy). By learning about themselves and their environment, patients will decide to make changes. As therapy continues, they will develop new abilities to regulate their emotions. Many patients will be forced to face and overcome feared relationships or situations (fear extinction). There is a neurobiological literature developing on each of these common components of psychotherapy.

Attachment

Forming nurturing attachments with others remains a challenge throughout life especially for those with early trauma. The neurochemistry of attachment involves the neuropeptides oxytocin and arginine vasopressin. Both of these messengers are released from the hypothalamus by sexual stimulation and stress. In combination with estrogen, oxytocin helps induce maternal behavior, while the absence of oxytocin makes it more difficult for animals to adapt to social settings and leads to abnormal displays of aggression. Infusing or blocking oxytocin also causes dramatic changes in mating behaviors. Arginine vasopressin has myriad effects on normal mammals including altering displays of aggression and the animal’s tendency to affiliate with or protect others.

In humans, oxytocin is associated with a number of factors that affect attachment including trust, empathy, eye contact, and generosity. Oxytocin infusions in healthy individuals tend to decrease anxiety and the stress associated with social situations while shifting attention from negative to positive information. The reduction in distress appears related to a reduction in activity in the amygdala. In a study of women with borderline personality disorder, oxytocin infusion decreased their amygdala activation when exposed to angry faces.3 Although the effect is mediated by past experiences, intra-nasal infusion of oxytocin may increase an individual’s ability to infer the mental state and intention of others based on their facial expression. Oxytocin specifically aids in parent-child bonding. Administering oxytocin to parents increases the social engagement of the parent and child and leads to an increase in oxytocin in the child.

The mu-opioid receptor also appears to be involved in attachment. Activation of the mu-opioid receptor leads to a general sense of pleasure as well as analgesia. In animal models, removing the mother from the child leads to distress that is at least partially mediated through mu-opioid activity. Animals with an increased activation of the opioid system had more attachment behaviors and louder and more prolonged protests when separated. Their separation distress could be partially reversed by non-sedating opioid agonists.4 Patients with borderline personality disorder have differences in baseline mu-opioid receptor concentrations and in the endogenous opioid system response to negative emotional challenges. These differences might be related to their difficulty with emotion regulation.

Attachment therefore correlates with neurochemical changes within the brain. This might be most evidenced in parent-child interactions but may play a significant role in psychotherapy as well. A study of mothers with postpartum depression undergoing psychodynamic psychotherapy found that daily infusions of oxytocin over 12 weeks were associated with a decrease in narcissistic traits but not in depressive personality traits or depressive symptoms.5Depressed men who received oxytocin infusions while in psychotherapy performed better on tests of inferring the mental state of others but were more likely to experience anxiety during the session.6 These findings hint of a complex interaction between oxytocin and the therapist-patient relationship (Table 1).

Empathy [Narcissistic Personality Disorder NPD with conscious effort can evoke cognitive empathy but muted emotional empathy]

Empathy entails the ability to consider the world from another’s point of view and in some way to share his or her emotional experiences. Neurobiological correlates of empathy were first described in the early 1990s with the discovery of mirror neurons. Researchers who were studying the neuronal activity involved in organizing and monitoring movements noted that some of the same premotor cortex neurons were activated while observing others make corresponding movements.7,8 Neurons that were activated when a monkey grabbed food were activated when the researcher grabbed food but not when the researcher pushed or struck the food. These neurons were referred to as mirror neurons.

Mirror neurons in humans are not limited to simple movements. Watching dance leads to activation in the brains of other dancers. Greater activation occurs when dancers watch movements they already know. Mirror neurons activate while watching facial expressions and seem to be partially impaired in individuals with autistic disorders. Human mirroring networks also exist for pain and emotional distress. Researchers created pain by sticking subjects with a needle and monitored which areas of the brain were activated.9 Similar pathways were activated when the researchers brought the needle close to the subject but did not make contact and when subjects watched researchers pricking their own fingers. Witnessing others display disgust activates many of the same areas that are activated when one smells an unpleasant odor.

Mirroring neurons also fire when observing others being rejected or embarrassed. The areas most involved in mirroring physical pain, emotional distress, and social discomfort are the anterior cingulate cortex and insula. These areas help individuals automatically imagine themselves experiencing what they witness others experiencing. It should be noted that the studies of mirror neurons in humans are preliminary and not without controversy.

The posterior portions of the superior temporal sulcus have similar activities. This region activates when witnessing social behavior and predicting future actions. When a figure is walking toward you, activation of the superior temporal sulcus is greater when the figure is looking at you, which indicates the prospect of an upcoming interaction. Activation also increases when the other person’s behavior is different than expected. [attention focused through violated expectation]

In a study by Wyk and colleagues,10 an actor displayed pleasure or disgust to one of two identical objects and then randomly picked up one of the objects. When there was incongruent action (picking the object after showing disgust or not picking the object after a display of pleasure), there was increased activity in the observer’s posterior superior temporal sulcus region.

Experiencing empathy appears to require proper activation of portions of the insula and anterior cingulate cortex as we seek to understand the emotional experience of others. A properly functioning posterior superior temporal sulcus allows us to determine and predict the social actions of others, and will tend to activate when someone violates societal expectations. ][mutual respect dignity etiquette kindness helpfulness contribution to the common good]

Oxytocin and arginine vasopressin are also implicated in empathy. A study of polymorphisms in the genes of 367 young adults found that variations in the emotional aspect of empathy were associated with the oxytocin receptor gene, while the cognitive aspect of empathy was associated with the gene for the arginine vasopressin 1a receptor.11 A highly complex interaction of neurotransmitters and brain activation allows the therapist to understand the patient’s experience (Table 2).

Learning [hippocampus site of learning and memory]

Early in the 20th century Cajal proposed that the brain stored information by modifying neuronal connections. Learning involved changing individual neurons and their connections with each other. In the mid-20th century Hebb proposed his rule stating that when one neuron’s repeated excitation is involved in the excitation of a neighboring neuron, the connection between the two of them grows more efficient. Put colloquially, “Neurons that fire together wire together.” This implies that synapses change over time.

The first demonstration of this in the hippocampus occurred in 1973. After exposing neurons to strong, high-frequency stimulation, their connection to other neurons in the hippocampus became stronger.12 The discovery of hippocampal neurogenesis [new brain cell formation, constant baby brain cell creation which require 30 years to myelinate mature] established the process of neuronal plasticity [rewiring brain cell connections, augmentation bring in more brain cells for a particular circuit, or atrophy allowing connections to wither and die due to disuse like muscles in a broken arm unused in a cast become thinned from disuse atrophy] and upended the long-held belief that CNS cells were neurophysiologically and neuroanatomically incapable of growth.

Using the California sea slug (Aplysia californica), Kandel13 demonstrated that habituation [tolerance]—a decrease in response to a stimulus—could be attained with a single training session of 10 stimulations. These effects lasted minutes to hours and appeared to be a result of changes in the amount of neurotransmitter released with the stimulation. Training sessions on 4 consecutive days resulted in an effect that lasted weeks. This long-term learning was associated with changes in interneuronal connections. [rewiring, what we practice attending to, thinking and doing becomes stronger: self pity, helplessness, other blaming or personal responsibility, looking to the helpful hand at the end of own arm, choosing healthy vegetables fruits, sleep, physical activity, avoidance of recreational chemicals, engagement in meaningful work, continuity durability of healthy relationships, attitude, mental physical emotional social spiritual financial responsibility]

Preliminary studies in humans have found measurable changes in the brain based on learning stemming from juggling and playing video games.14,15 Experimental data demonstrate that the neurons in the brain are capable of learning-induced change. Psychotherapy includes components of experiential and didactic learning that is expected to create change in the patient’s brain. Many psychotherapies focus on thoughts or patterns that are initially outside the awareness of the patient. [precontemplation stage of change Motivational Interviewing Mindfulness Meditation introduces awareness that something is not comfortable] Therapy creates new memories to modify older, dysfunctional ones and in some cases creates new psychic structures. [children's literature bibliotherapy, cinematherapy, coming of age, shift POV point of view to allow reassessment reflection contemplation integration consolidation, openness to listening hearing another person social skill acquisition, appreciating own growth Good Job second grade social skill learning] This learning must involve changes in interneuronal connections (Table 3).

Emotion regulation [Sitting Still Like a Frog Eline Snell, Healing and the Mind Bill Moyers DVD 5 episodes, Stress Portrait of a Killer documentary, Dhamma Brothers Frontline 10 day meditation training years later follow up, Departures Oscar Best Foreign film learning forgiveness without apology]

Patients in psychotherapy are taught to understand, accept, or manage their emotional responses in new ways. Researchers are looking into how emotion regulation modifies brain activity.

One common strategy for altering emotions is reappraisal, when the individual deliberately tries to alter the meaning or relevance of an event. Reappraisal strategies link cognitive control with emotional experience. Attempts to deliberately decrease aversive emotions, sadness, and sexual arousal through cognitive reappraisal have found that reappraisal strategies most commonly activate multiple areas within the prefrontal cortex [behind forehead] and posterior parietal cortex. Activation of these areas during reappraisal leads to decreased activity in portions of the amygdala [anger anxiety]. These studies have demonstrated specific neuronal circuitry, for example, between the hippocampus [learning memory], prefrontal cortex [planning decision making analysis initiation motivation execution judgment financial literacy] , and amygdala anxiety anger], which are strengthened by psychotherapeutic treatment.16,17

Suppression, an intentional attempt to minimize the display of emotions, may also decrease the intensity of emotions. [role playing DVD Healing and the Mind Bill Moyers] Subjects were asked to suppress their emotions while observing sad pictures. When suppressing their emotions, there was an increase in activity in the right [emotional] orbitofrontal and dorsolateral prefrontal cortices.18 Other studies have found activation of the dorsal anterior cingulate cortex, dorsomedial prefrontal cortex [conscious decision effort], and lateral prefrontal cortex with suppression.19

Cognitive reappraisal and suppression seem to have distinctly different neurophysiological mechanisms. In a head-to-head study both strategies were successful at decreasing subjective emotional experience, but there were differences in brain activation.20

Reappraisal led to increased activity in the prefrontal cortex [cognition conscious choice awareness] and decreased activity in the right amygdala [anger anxiety emotional dysregulation] and left insula.

Suppression increased activity in the right ventral-lateral prefrontal cortex but did not decrease activity in the amygdala or insula (Table 4).

Fear extinction

Learning to be afraid, or fear conditioning, involves pairing a previously innocuous stimulus (conditioned stimulus) with an aversive stimulus (unconditioned stimulus). The mind begins to associate the previously benign stimulus with the unpleasant one, and the individual experiences heightened anxiety whenever presented with the new conditioned stimulus. The process of fear conditioning involves interactions of the amygdala, insula, anterior cingulate cortex, and medial prefrontal cortex.

The process of unlearning fear is known as fear extinction.

Fear extinction does not consist of erasing old memories; rather it is the creation of new, benign associations. The underlying fear is still present, but successful fear extinction leads to a reduction in the amplitude and likelihood of a fearful response. This occurs when the once feared stimulus or situation no longer brings about any adverse consequences.

Fear extinction is a principal therapeutic component of exposure therapies for specific phobias and for PTSD, but learning to confront feared memories, situations, and people can be found in a broad range of psychotherapies.

Fear extinction requires a functional ventral-medial prefrontal cortex, rostral anterior cingulate cortex, and hippocampus [learning memory]. Activation of these regions leads to decreased amygdala activity. Clinical studies have demonstrated that the addition of D-cycloserine [caveat very very narrow therapeutic window between action and toxicity, strictly low dose one time, not chronic exposure, lacks general applicability], a partial N-methyl-D-aspartate (NMDA) glutamate agonist, may improve outcomes in exposure-based therapies for acrophobia and social phobias.21 Conversely, NMDA antagonists [Modafinil, ketamine], by decreasing NMDA activity, can inhibit the formation of long-term fear extinction. [ie blocks prevents psychotherapeutic learning to challenge erroneous beliefs]

While decreasing the activity in the amygdala leads to an acute reduction in perceived fear, the long-term persistence of fear extinction requires the activity of the ventral-medial prefrontal cortex [cognitive brain] and rostral anterior cingulate cortex. These appear to be vital in connecting the cognitive and emotional experiences and solidifying the learning.

The hippocampus [learning memory] aids in fear extinction by placing events into a context.

This context helps determine how generally the brain applies the new learning. [eg being fearful or being curious about something novel new unfamiliar, like plants animals people DVD Fading Gigolo John Turturro Vanessa Paradis Sharon Stone Sofia Vergara Woody Allen comedy] Because the previous fear is not erased, when the individual encounters the once feared stimuli there is activation of both the fearful and fear extinguished pathways. The context, provided by interactions between the hippocampus [learning memory] and ventromedial prefrontal cortex [cognition conscious awareness, mindfulness], determines which set of behaviors is predominately activated (Table 5).

The work of the psychotherapist is to help solidify the most healthy and adaptive responses.

Prediction of response to psychotherapy

Studies have begun to examine the ability to predict a patient’s response to psychotherapy based on neurobiological factors. One of the many changes that occur with depression is the elevation of metabolism in the posterior insula. Studies have found that changes in connectivity and activation of the insula predicted a positive response to psychotherapy in patients with depression.22-24 Another study found that increased metabolism in the subcollasal cingulate cortex and superior temporal sulcus was associated with no response to escitalopram or cognitive-behavior therapy treatment for depression.25 Conclusion

Although a precise description of the neurophysiological changes that occur during psychotherapy is currently impossible, it is likely that future imaging and neurobiological investigation will elucidate this process. The neurobiological correlates to many of the common elements of psychotherapy such as attachment, empathy, memory, learning, emotional regulation, and fear extinction are emerging. While we still cannot answer all of Freud’s questions, or our own questions, the artificial dichotomy between the functioning of the mind and brain during psychotherapy seems less imposing.

Dr Welton is Associate Professor of Psychiatry and Director of Residency Training and Dr Kay is Emeritus Professor of Psychiatry, Boonshoft School of Medicine, Wright State University, Dayton, OH.

1. Institute of Medicine. Psychosocial Interventions for Mental and Substance Use Disorders: A Framework for Establishing Evidence-Based Standards. Washington, DC: The National Academies Press; 2015:S1-S16.

2. Freud S. Beyond the pleasure principle. In: Strachey J, ed. The Standard Edition of the Complete Psychological Works of Sigmund Freud. Vol 18. London: Hogarth Press; 1955:1-64.

3. Bertsch K, Gamer M, Schmidt B, et al. Oxytocin and reduction of social threat hypersensitivity in women with borderline personality disorder. Am J Psychiatry. 2013;170:1169-1177.

4. Barr CS, Schwandt ML, Lindell SG, et al. Variation at the mu-opioid receptor gene (OPRM1) influences attachment behavior in infant primates. Proc Natl Acad Sci USA. 2008;105:5277-5281.

5. Clarici A, Pellizzoni S, Guaschino S, et al. Intranasal administration of oxytocin in postnatal depression: implications for psychodynamic psychotherapy from a randomized double-blind pilot study. Front Psychiatry. 2015;6:1-10.

6. MacDonald K, MacDonald TM, Brune M, et al. Oxytocin and psychotherapy: a pilot study of its physiological, behavioral and subjective effects in males with depression. Psychoneuroendocrinol. 2013;38:2831-2843.

7. Rizzolatti G, Fadiga L, Gallese V, Fogassi L. Premotor cortex and the recognition of motor actions. Cog Brain Res. 1996;3:131-141.

8. Iacoboni M. Face to face: the neural basis of social mirroring and empathy. Psychiatr Ann. 2007;37: 236-241.

9. Hutchison WD, Davis KD, Lozano AM, et al. Pain-related neurons in the human cingulate cortex. Nature Neurosci. 1999;2:403-405.

10. Wyk BC, Hudac CM, Carter EJ, et al. Action understanding in the superior temporal sulcus region. Psychol Sci. 2009;20:771-777.

11. Uzefovsky F, Shalev I, Israel S, et al. Oxytocin receptor and vasopressin receptor 1a genes are respectively associated with the emotional and cognitive empathy. Horm Behav. 2015;67:60-65.

12. Bliss TVP, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993;361:31-39.

13. Kandel ER. Psychotherapy and the single synapse: the impact of psychiatric thought on neurobiological research. J Neuropsychiatry Clin Neurosci. 2001;13:290-300.

14. Draganski B, Gaser C, Busch V, et al. Neuroplasticity: changes in grey matter induced by training. Nature. 2004;427:311-312.

15. Kuhn S, Gleich T, Lorenz RC, et al. Playing Super Mario induces structural brain plasticity: gray matter changes resulting from training with a commercial video game. Mol Psychiatry. 2014;19:272.

16. Ochsner KN, Ray RD, Cooper JC, et al. For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion. Neuroimage. 2004;23:483-499.

17. Buhle JT, Silvers JA, Wager TD, et al. Cognitive reappraisal of emotion: a meta-analysis of human neuroimaging studies. Cerebral Cortex. 2014;24: 2891-2890.

18. Levesque J, Eugene F, Joanette Y, et al. Neural circuitry underlying voluntary suppression of sadness. Biol Psychiatry. 2003;53:502-510.

19. Phan KL, Fitzgerald DA, Nathan PJ, et al. Neural substrates for voluntary suppression of negative affect: a functional magnetic resonance imaging study. Biol Psychiatry. 2005;57:210-219.

20. Goldin PR, McRae K, Ramel W, Gross JJ. The neural bases of emotion regulation: reappraisal and suppression of negative emotion. Biol Psychiatry. 2008;63:577-586.

21. Britton JC, Gold AL, Feczko EJ, et al. D-cycloserine inhibits amygdala responses during repeated presentations of faces. CNS Spect. 2007;12:600-605.

22. Roffman JL, Witte JM, Tanner AS, et al. Neural predictors of successful brief psychodynamic psychotherapy for persistent depression. Psychother Psychosom. 2014;83:364-370.

23. Crowther A, Smoski MJ, Minkel J, et al. Resting-state connectivity predictors of response to psychotherapy in major depressive disorder. Neuropsychopharmacol. 2015;40:1659-1673.

24. McGrath CL, Kelley ME, Holtzheimer PE 3rd, et al. Toward a neuroimaging treatment selection biomarker for major depressive disorder. JAMA Psychiatry. 2013;70:821-829.

25. McGrath CL, Kelley ME, Dunlop BW, et al. Pretreatment brain states identify likely nonresponse to standard treatments for depression. Biol Psychiatry. 2014;76:527-535.

Some issues to note about this otherwise very interesting article.

1. The Institute of Medicine report acknowledging the efficacy of a broad range of psychotherapy needs to be taken with a nuanced view (summary here: iom.nationalacademies.org/~/media/Files/Report%20Files/20....).

None of the claims of “evidence-base” here is based on a blinded clinical trial. Neither subjects nor treaters can feasibly be blind to the nature of the psychotherapy they receive in a clinical trial making these clinical trials poorly controlled. A masked rater only records the unblinded report of the subject and does not control for the lack of blinding. Many clinical trials done in this fashion do not make up for the lack of blinding because it is very easy to obtain non-inferiority and even superiority results in an unblinded trial of a psychiatric condition i.e., depression where endpoints are subjective-and blinding is a key element of any study with subjective endpoints where ratings may easily be swayed by hope and expectation. “Efficacy” and rigor in a clinical trial needs to be used by caution when studies do not have (can not possibly have) blind subjects or treaters.

2. The article’s statement that “A highly complex interaction of neurotransmitters allows the therapist to understand the patient’s experience”, is confusing. Do the authors mean that this research is valuable and heuristic (I would agree), or do they mean that a therapist can figure out how neurotransmitters are actually involved in a patient’s particular experience?- I think this kind of understanding is still very far away and the statement should be reworded.

3. Although the authors state that juggling and playing video games can make changes in the brain, in the next sentence they then move into the effects of psychotherapy making brain changes. Didn’t they just say that even juggling and video games can change the brain? The logic here seems to indicate that the brain is a plastic responsive organ easily changed by experience, but whether that experience (or therapy) is causing some therapeutic effect is still jump of logic away.

4. This study mentioned in the article: D-cycloserine inhibits amygdala responses during repeated presentations of faces. CNS Spectr 2007 Aug;12(8):600-5, only had 14 subjects randomly assigned to drug or placebo, i.e., 7 subj in each group. This “micro N” study needs to be taken with extreme caution, not noted like in this article to be that “Clinical studies have demonstrated…”

The article is an interesting discussion of behavior and biology, but neither the neurobiology of psychotherapy, nor the clinical trial validity of psychotherapy, is a conclusion that can be born from the discussion presented here.

Douglas Berger, MD, PhD.

US Board Certified Psychiatrist

Tokyo, Japan

History physical exam lab EKG x-ray assessment, symptoms, neuropsychiatric neuropsychological testing, assessm risk for addiction at EACH VISIT, differential diagnosis dDx, options for treatment, relative risk for harm and benefit of treatment or watchful waiting, rationale for selection of working diagnosis Dx, extensive discussion with patient of perceived symptoms, therapeutic goals, patient values, discuss ways patient believes this behavior is helping, offer alternative diagnoses dDx and options for care, comparative risks benefit analysis discussion. Palliative euphoriant marijuana helpful in dementia to curb striking out, anger tantrums, irritability with euphoriant sedative complacency, illusion of well-being while accumulating neuronal brain cell loss, accelerating progressive cognitive impairment dementia.

Brain changes with psychotherapy. Neurobiology of Psychotherapy

22Oct2015 Neuropsychiatry Major Depressive Disorder, Psychotherapy

Randon Welton, MD Jerald Kay, MD

The Neurobiology of Psychotherapy

Table 1. Main brain system involved in mediating attachment

Main brain system involved in mediating empathy

TABLE 2. Main brain system involved in mediating empathy

Main brain system involved in mediating learning

TABLE 3. Main brain system involved in mediating learning

Main brain system involved in mediating emotion regulation

TABLE 4. Main brain system involved in mediating emotion regulation

Main brain system involved in mediating fear extinction

TABLE 5. Main brain system involved in mediating fear extinction

A recent Institute of Medicine report acknowledges the efficacy of a broad range of psychosocial interventions.1 It challenges us to “identify key elements that drive an intervention’s effect.” The report describes key clinical tasks such as the therapist’s ability to engage with a patient, understand the patient’s worldview, and help the patient manage his or her emotional responses. The psychiatric community should also look into the neurobiological changes that accompany and may be responsible for an intervention’s effect. Although early psychoanalysts made little effort to connect functions of the mind to definable portions of the brain, from the beginning there was a belief that such a relationship may exist. Freud confidently predicted that one day there would be a neurological understanding of the work he initiated.

The deficiencies in our description would probably vanish if we were already in a position to replace psychological terms by physiological or chemical ones. Biology is truly a land of unlimited possibilities. We may expect it to give us the most surprising information and we cannot guess what answers it will return in a few dozen years to the questions we have put to it.2

Almost 100 years have passed since Freud wrote those words, and many of his questions remain unanswered. Steady progress, however, has been made in the development of a neurobiological understanding of what happens in the brain when the mind is engaged in psychotherapy. Advances in cognitive neuroscience and neuroimaging have facilitated a greater appreciation of the neuroanatomy and neurophysiology of the CNS. The technology to study the real-time functioning of the brain through measurement of blood flow or glucose uptake, for example, has been widely used for a quarter of a century. Numerous challenges endure, such as subtle individual variations of neural circuitry, uncertainty as to the proper area to study, and the possibility that differing forms of therapy affect the brain differently. Within the boundaries created by these limitations, however, there is an emerging understanding of the neurobiological correlates of some common psychotherapy elements.

Although different approaches utilize various terms and concepts, there are some components that are found in most forms of efficacious psychotherapy. There must be some emotional engagement (attachment) between the patient and therapist. The therapist will struggle to understand and express the patient’s experience (empathy). By learning about themselves and their environment, patients will decide to make changes. As therapy continues, they will develop new abilities to regulate their emotions. Many patients will be forced to face and overcome feared relationships or situations (fear extinction). There is a neurobiological literature developing on each of these common components of psychotherapy.

Attachment

Forming nurturing attachments with others remains a challenge throughout life especially for those with early trauma. The neurochemistry of attachment involves the neuropeptides oxytocin and arginine vasopressin. Both of these messengers are released from the hypothalamus by sexual stimulation and stress. In combination with estrogen, oxytocin helps induce maternal behavior, while the absence of oxytocin makes it more difficult for animals to adapt to social settings and leads to abnormal displays of aggression. Infusing or blocking oxytocin also causes dramatic changes in mating behaviors. Arginine vasopressin has myriad effects on normal mammals including altering displays of aggression and the animal’s tendency to affiliate with or protect others.

In humans, oxytocin is associated with a number of factors that affect attachment including trust, empathy, eye contact, and generosity. Oxytocin infusions in healthy individuals tend to decrease anxiety and the stress associated with social situations while shifting attention from negative to positive information. The reduction in distress appears related to a reduction in activity in the amygdala. In a study of women with borderline personality disorder, oxytocin infusion decreased their amygdala activation when exposed to angry faces.3 Although the effect is mediated by past experiences, intra-nasal infusion of oxytocin may increase an individual’s ability to infer the mental state and intention of others based on their facial expression. Oxytocin specifically aids in parent-child bonding. Administering oxytocin to parents increases the social engagement of the parent and child and leads to an increase in oxytocin in the child.

The mu-opioid receptor also appears to be involved in attachment. Activation of the mu-opioid receptor leads to a general sense of pleasure as well as analgesia. In animal models, removing the mother from the child leads to distress that is at least partially mediated through mu-opioid activity. Animals with an increased activation of the opioid system had more attachment behaviors and louder and more prolonged protests when separated. Their separation distress could be partially reversed by non-sedating opioid agonists.4 Patients with borderline personality disorder have differences in baseline mu-opioid receptor concentrations and in the endogenous opioid system response to negative emotional challenges. These differences might be related to their difficulty with emotion regulation.

Attachment therefore correlates with neurochemical changes within the brain. This might be most evidenced in parent-child interactions but may play a significant role in psychotherapy as well. A study of mothers with postpartum depression undergoing psychodynamic psychotherapy found that daily infusions of oxytocin over 12 weeks were associated with a decrease in narcissistic traits but not in depressive personality traits or depressive symptoms.5Depressed men who received oxytocin infusions while in psychotherapy performed better on tests of inferring the mental state of others but were more likely to experience anxiety during the session.6 These findings hint of a complex interaction between oxytocin and the therapist-patient relationship (Table 1).

Empathy [Narcissistic Personality Disorder NPD with conscious effort can evoke cognitive empathy but muted emotional empathy]

Empathy entails the ability to consider the world from another’s point of view and in some way to share his or her emotional experiences. Neurobiological correlates of empathy were first described in the early 1990s with the discovery of mirror neurons. Researchers who were studying the neuronal activity involved in organizing and monitoring movements noted that some of the same premotor cortex neurons were activated while observing others make corresponding movements.7,8 Neurons that were activated when a monkey grabbed food were activated when the researcher grabbed food but not when the researcher pushed or struck the food. These neurons were referred to as mirror neurons.

Mirror neurons in humans are not limited to simple movements. Watching dance leads to activation in the brains of other dancers. Greater activation occurs when dancers watch movements they already know. Mirror neurons activate while watching facial expressions and seem to be partially impaired in individuals with autistic disorders. Human mirroring networks also exist for pain and emotional distress. Researchers created pain by sticking subjects with a needle and monitored which areas of the brain were activated.9 Similar pathways were activated when the researchers brought the needle close to the subject but did not make contact and when subjects watched researchers pricking their own fingers. Witnessing others display disgust activates many of the same areas that are activated when one smells an unpleasant odor.

Mirroring neurons also fire when observing others being rejected or embarrassed. The areas most involved in mirroring physical pain, emotional distress, and social discomfort are the anterior cingulate cortex and insula. These areas help individuals automatically imagine themselves experiencing what they witness others experiencing. It should be noted that the studies of mirror neurons in humans are preliminary and not without controversy.

The posterior portions of the superior temporal sulcus have similar activities. This region activates when witnessing social behavior and predicting future actions. When a figure is walking toward you, activation of the superior temporal sulcus is greater when the figure is looking at you, which indicates the prospect of an upcoming interaction. Activation also increases when the other person’s behavior is different than expected. [attention focused through violated expectation]

In a study by Wyk and colleagues,10 an actor displayed pleasure or disgust to one of two identical objects and then randomly picked up one of the objects. When there was incongruent action (picking the object after showing disgust or not picking the object after a display of pleasure), there was increased activity in the observer’s posterior superior temporal sulcus region.

Experiencing empathy appears to require proper activation of portions of the insula and anterior cingulate cortex as we seek to understand the emotional experience of others. A properly functioning posterior superior temporal sulcus allows us to determine and predict the social actions of others, and will tend to activate when someone violates societal expectations. ][mutual respect dignity etiquette kindness helpfulness contribution to the common good]

Oxytocin and arginine vasopressin are also implicated in empathy. A study of polymorphisms in the genes of 367 young adults found that variations in the emotional aspect of empathy were associated with the oxytocin receptor gene, while the cognitive aspect of empathy was associated with the gene for the arginine vasopressin 1a receptor.11 A highly complex interaction of neurotransmitters and brain activation allows the therapist to understand the patient’s experience (Table 2).

Learning [hippocampus site of learning and memory]

Early in the 20th century Cajal proposed that the brain stored information by modifying neuronal connections. Learning involved changing individual neurons and their connections with each other. In the mid-20th century Hebb proposed his rule stating that when one neuron’s repeated excitation is involved in the excitation of a neighboring neuron, the connection between the two of them grows more efficient. Put colloquially, “Neurons that fire together wire together.” This implies that synapses change over time.

The first demonstration of this in the hippocampus occurred in 1973. After exposing neurons to strong, high-frequency stimulation, their connection to other neurons in the hippocampus became stronger.12 The discovery of hippocampal neurogenesis [new brain cell formation, constant baby brain cell creation which require 30 years to myelinate mature] established the process of neuronal plasticity [rewiring brain cell connections, augmentation bring in more brain cells for a particular circuit, or atrophy allowing connections to wither and die due to disuse like muscles in a broken arm unused in a cast become thinned from disuse atrophy] and upended the long-held belief that CNS cells were neurophysiologically and neuroanatomically incapable of growth.

Using the California sea slug (Aplysia californica), Kandel13 demonstrated that habituation [tolerance]—a decrease in response to a stimulus—could be attained with a single training session of 10 stimulations. These effects lasted minutes to hours and appeared to be a result of changes in the amount of neurotransmitter released with the stimulation. Training sessions on 4 consecutive days resulted in an effect that lasted weeks. This long-term learning was associated with changes in interneuronal connections. [rewiring, what we practice attending to, thinking and doing becomes stronger: self pity, helplessness, other blaming or personal responsibility, looking to the helpful hand at the end of own arm, choosing healthy vegetables fruits, sleep, physical activity, avoidance of recreational chemicals, engagement in meaningful work, continuity durability of healthy relationships, attitude, mental physical emotional social spiritual financial responsibility]

Preliminary studies in humans have found measurable changes in the brain based on learning stemming from juggling and playing video games.14,15 Experimental data demonstrate that the neurons in the brain are capable of learning-induced change. Psychotherapy includes components of experiential and didactic learning that is expected to create change in the patient’s brain. Many psychotherapies focus on thoughts or patterns that are initially outside the awareness of the patient. [precontemplation stage of change Motivational Interviewing Mindfulness Meditation introduces awareness that something is not comfortable] Therapy creates new memories to modify older, dysfunctional ones and in some cases creates new psychic structures. [children's literature bibliotherapy, cinematherapy, coming of age, shift POV point of view to allow reassessment reflection contemplation integration consolidation, openness to listening hearing another person social skill acquisition, appreciating own growth Good Job second grade social skill learning] This learning must involve changes in interneuronal connections (Table 3).

Emotion regulation [Sitting Still Like a Frog Eline Snell, Healing and the Mind Bill Moyers DVD 5 episodes, Stress Portrait of a Killer documentary, Dhamma Brothers Frontline 10 day meditation training years later follow up, Departures Oscar Best Foreign film learning forgiveness without apology]

Patients in psychotherapy are taught to understand, accept, or manage their emotional responses in new ways. Researchers are looking into how emotion regulation modifies brain activity.

One common strategy for altering emotions is reappraisal, when the individual deliberately tries to alter the meaning or relevance of an event. Reappraisal strategies link cognitive control with emotional experience. Attempts to deliberately decrease aversive emotions, sadness, and sexual arousal through cognitive reappraisal have found that reappraisal strategies most commonly activate multiple areas within the prefrontal cortex [behind forehead] and posterior parietal cortex. Activation of these areas during reappraisal leads to decreased activity in portions of the amygdala [anger anxiety]. These studies have demonstrated specific neuronal circuitry, for example, between the hippocampus [learning memory], prefrontal cortex [planning decision making analysis initiation motivation execution judgment financial literacy] , and amygdala anxiety anger], which are strengthened by psychotherapeutic treatment.16,17

Suppression, an intentional attempt to minimize the display of emotions, may also decrease the intensity of emotions. [role playing DVD Healing and the Mind Bill Moyers] Subjects were asked to suppress their emotions while observing sad pictures. When suppressing their emotions, there was an increase in activity in the right [emotional] orbitofrontal and dorsolateral prefrontal cortices.18 Other studies have found activation of the dorsal anterior cingulate cortex, dorsomedial prefrontal cortex [conscious decision effort], and lateral prefrontal cortex with suppression.19

Cognitive reappraisal and suppression seem to have distinctly different neurophysiological mechanisms. In a head-to-head study both strategies were successful at decreasing subjective emotional experience, but there were differences in brain activation.20

Reappraisal led to increased activity in the prefrontal cortex [cognition conscious choice awareness] and decreased activity in the right amygdala [anger anxiety emotional dysregulation] and left insula.

Suppression increased activity in the right ventral-lateral prefrontal cortex but did not decrease activity in the amygdala or insula (Table 4).

Fear extinction

Learning to be afraid, or fear conditioning, involves pairing a previously innocuous stimulus (conditioned stimulus) with an aversive stimulus (unconditioned stimulus). The mind begins to associate the previously benign stimulus with the unpleasant one, and the individual experiences heightened anxiety whenever presented with the new conditioned stimulus. The process of fear conditioning involves interactions of the amygdala, insula, anterior cingulate cortex, and medial prefrontal cortex.

The process of unlearning fear is known as fear extinction.

Fear extinction does not consist of erasing old memories; rather it is the creation of new, benign associations. The underlying fear is still present, but successful fear extinction leads to a reduction in the amplitude and likelihood of a fearful response. This occurs when the once feared stimulus or situation no longer brings about any adverse consequences.

Fear extinction is a principal therapeutic component of exposure therapies for specific phobias and for PTSD, but learning to confront feared memories, situations, and people can be found in a broad range of psychotherapies.

Fear extinction requires a functional ventral-medial prefrontal cortex, rostral anterior cingulate cortex, and hippocampus [learning memory]. Activation of these regions leads to decreased amygdala activity. Clinical studies have demonstrated that the addition of D-cycloserine [caveat very very narrow therapeutic window between action and toxicity, strictly low dose one time, not chronic exposure, lacks general applicability], a partial N-methyl-D-aspartate (NMDA) glutamate agonist, may improve outcomes in exposure-based therapies for acrophobia and social phobias.21 Conversely, NMDA antagonists [Modafinil, ketamine], by decreasing NMDA activity, can inhibit the formation of long-term fear extinction. [ie blocks prevents psychotherapeutic learning to challenge erroneous beliefs]

While decreasing the activity in the amygdala leads to an acute reduction in perceived fear, the long-term persistence of fear extinction requires the activity of the ventral-medial prefrontal cortex [cognitive brain] and rostral anterior cingulate cortex. These appear to be vital in connecting the cognitive and emotional experiences and solidifying the learning.

The hippocampus [learning memory] aids in fear extinction by placing events into a context.

This context helps determine how generally the brain applies the new learning. [eg being fearful or being curious about something novel new unfamiliar, like plants animals people DVD Fading Gigolo John Turturro Vanessa Paradis Sharon Stone Sofia Vergara Woody Allen comedy] Because the previous fear is not erased, when the individual encounters the once feared stimuli there is activation of both the fearful and fear extinguished pathways. The context, provided by interactions between the hippocampus [learning memory] and ventromedial prefrontal cortex [cognition conscious awareness, mindfulness], determines which set of behaviors is predominately activated (Table 5).

The work of the psychotherapist is to help solidify the most healthy and adaptive responses.

Prediction of response to psychotherapy

Studies have begun to examine the ability to predict a patient’s response to psychotherapy based on neurobiological factors. One of the many changes that occur with depression is the elevation of metabolism in the posterior insula. Studies have found that changes in connectivity and activation of the insula predicted a positive response to psychotherapy in patients with depression.22-24 Another study found that increased metabolism in the subcollasal cingulate cortex and superior temporal sulcus was associated with no response to escitalopram or cognitive-behavior therapy treatment for depression.25 Conclusion

Although a precise description of the neurophysiological changes that occur during psychotherapy is currently impossible, it is likely that future imaging and neurobiological investigation will elucidate this process. The neurobiological correlates to many of the common elements of psychotherapy such as attachment, empathy, memory, learning, emotional regulation, and fear extinction are emerging. While we still cannot answer all of Freud’s questions, or our own questions, the artificial dichotomy between the functioning of the mind and brain during psychotherapy seems less imposing.

Dr Welton is Associate Professor of Psychiatry and Director of Residency Training and Dr Kay is Emeritus Professor of Psychiatry, Boonshoft School of Medicine, Wright State University, Dayton, OH.

1. Institute of Medicine. Psychosocial Interventions for Mental and Substance Use Disorders: A Framework for Establishing Evidence-Based Standards. Washington, DC: The National Academies Press; 2015:S1-S16.

2. Freud S. Beyond the pleasure principle. In: Strachey J, ed. The Standard Edition of the Complete Psychological Works of Sigmund Freud. Vol 18. London: Hogarth Press; 1955:1-64.

3. Bertsch K, Gamer M, Schmidt B, et al. Oxytocin and reduction of social threat hypersensitivity in women with borderline personality disorder. Am J Psychiatry. 2013;170:1169-1177.

4. Barr CS, Schwandt ML, Lindell SG, et al. Variation at the mu-opioid receptor gene (OPRM1) influences attachment behavior in infant primates. Proc Natl Acad Sci USA. 2008;105:5277-5281.

5. Clarici A, Pellizzoni S, Guaschino S, et al. Intranasal administration of oxytocin in postnatal depression: implications for psychodynamic psychotherapy from a randomized double-blind pilot study. Front Psychiatry. 2015;6:1-10.

6. MacDonald K, MacDonald TM, Brune M, et al. Oxytocin and psychotherapy: a pilot study of its physiological, behavioral and subjective effects in males with depression. Psychoneuroendocrinol. 2013;38:2831-2843.

7. Rizzolatti G, Fadiga L, Gallese V, Fogassi L. Premotor cortex and the recognition of motor actions. Cog Brain Res. 1996;3:131-141.

8. Iacoboni M. Face to face: the neural basis of social mirroring and empathy. Psychiatr Ann. 2007;37: 236-241.

9. Hutchison WD, Davis KD, Lozano AM, et al. Pain-related neurons in the human cingulate cortex. Nature Neurosci. 1999;2:403-405.

10. Wyk BC, Hudac CM, Carter EJ, et al. Action understanding in the superior temporal sulcus region. Psychol Sci. 2009;20:771-777.

11. Uzefovsky F, Shalev I, Israel S, et al. Oxytocin receptor and vasopressin receptor 1a genes are respectively associated with the emotional and cognitive empathy. Horm Behav. 2015;67:60-65.

12. Bliss TVP, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993;361:31-39.

13. Kandel ER. Psychotherapy and the single synapse: the impact of psychiatric thought on neurobiological research. J Neuropsychiatry Clin Neurosci. 2001;13:290-300.

14. Draganski B, Gaser C, Busch V, et al. Neuroplasticity: changes in grey matter induced by training. Nature. 2004;427:311-312.

15. Kuhn S, Gleich T, Lorenz RC, et al. Playing Super Mario induces structural brain plasticity: gray matter changes resulting from training with a commercial video game. Mol Psychiatry. 2014;19:272.

16. Ochsner KN, Ray RD, Cooper JC, et al. For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion. Neuroimage. 2004;23:483-499.

17. Buhle JT, Silvers JA, Wager TD, et al. Cognitive reappraisal of emotion: a meta-analysis of human neuroimaging studies. Cerebral Cortex. 2014;24: 2891-2890.

18. Levesque J, Eugene F, Joanette Y, et al. Neural circuitry underlying voluntary suppression of sadness. Biol Psychiatry. 2003;53:502-510.

19. Phan KL, Fitzgerald DA, Nathan PJ, et al. Neural substrates for voluntary suppression of negative affect: a functional magnetic resonance imaging study. Biol Psychiatry. 2005;57:210-219.

20. Goldin PR, McRae K, Ramel W, Gross JJ. The neural bases of emotion regulation: reappraisal and suppression of negative emotion. Biol Psychiatry. 2008;63:577-586.

21. Britton JC, Gold AL, Feczko EJ, et al. D-cycloserine inhibits amygdala responses during repeated presentations of faces. CNS Spect. 2007;12:600-605.

22. Roffman JL, Witte JM, Tanner AS, et al. Neural predictors of successful brief psychodynamic psychotherapy for persistent depression. Psychother Psychosom. 2014;83:364-370.

23. Crowther A, Smoski MJ, Minkel J, et al. Resting-state connectivity predictors of response to psychotherapy in major depressive disorder. Neuropsychopharmacol. 2015;40:1659-1673.

24. McGrath CL, Kelley ME, Holtzheimer PE 3rd, et al. Toward a neuroimaging treatment selection biomarker for major depressive disorder. JAMA Psychiatry. 2013;70:821-829.

25. McGrath CL, Kelley ME, Dunlop BW, et al. Pretreatment brain states identify likely nonresponse to standard treatments for depression. Biol Psychiatry. 2014;76:527-535.

Some issues to note about this otherwise very interesting article.

1. The Institute of Medicine report acknowledging the efficacy of a broad range of psychotherapy needs to be taken with a nuanced view (summary here: iom.nationalacademies.org/~/media/Files/Report%20Files/20....).

None of the claims of “evidence-base” here is based on a blinded clinical trial. Neither subjects nor treaters can feasibly be blind to the nature of the psychotherapy they receive in a clinical trial making these clinical trials poorly controlled. A masked rater only records the unblinded report of the subject and does not control for the lack of blinding. Many clinical trials done in this fashion do not make up for the lack of blinding because it is very easy to obtain non-inferiority and even superiority results in an unblinded trial of a psychiatric condition i.e., depression where endpoints are subjective-and blinding is a key element of any study with subjective endpoints where ratings may easily be swayed by hope and expectation. “Efficacy” and rigor in a clinical trial needs to be used by caution when studies do not have (can not possibly have) blind subjects or treaters.

2. The article’s statement that “A highly complex interaction of neurotransmitters allows the therapist to understand the patient’s experience”, is confusing. Do the authors mean that this research is valuable and heuristic (I would agree), or do they mean that a therapist can figure out how neurotransmitters are actually involved in a patient’s particular experience?- I think this kind of understanding is still very far away and the statement should be reworded.

3. Although the authors state that juggling and playing video games can make changes in the brain, in the next sentence they then move into the effects of psychotherapy making brain changes. Didn’t they just say that even juggling and video games can change the brain? The logic here seems to indicate that the brain is a plastic responsive organ easily changed by experience, but whether that experience (or therapy) is causing some therapeutic effect is still jump of logic away.

4. This study mentioned in the article: D-cycloserine inhibits amygdala responses during repeated presentations of faces. CNS Spectr 2007 Aug;12(8):600-5, only had 14 subjects randomly assigned to drug or placebo, i.e., 7 subj in each group. This “micro N” study needs to be taken with extreme caution, not noted like in this article to be that “Clinical studies have demonstrated…”

The article is an interesting discussion of behavior and biology, but neither the neurobiology of psychotherapy, nor the clinical trial validity of psychotherapy, is a conclusion that can be born from the discussion presented here.

Douglas Berger, MD, PhD.

US Board Certified Psychiatrist

Tokyo, Japan

The sins of the flesh are bad but they are the least bad of all sins. All the worse pleasures are purely spiritual: the pleasure of putting other people in the wrong, of bossing and patronizing and spoiling sport, and back-biting, and the pleasures of power, of hatred. CS Lewis

book The Illustrated Book of Bad Arguments Ali Almossawi cartoon explanation of Attacking Faulty Reasoning: T. Edward Damer

DVD Temple Grandin. book The Center Cannot Hold Elyn Saks. Brain changes with psychotherapy. Neurobiology of Psychotherapy

22Oct2015 Neuropsychiatry Major Depressive Disorder, Psychotherapy

Randon Welton, MD Jerald Kay, MD

The Neurobiology of Psychotherapy

Table 1. Main brain system involved in mediating attachment

TABLE 2. Main brain system involved in mediating empathy

TABLE 3. Main brain system involved in mediating learning

TABLE 4. Main brain system involved in mediating emotion regulation

TABLE 5. Main brain system involved in mediating fear extinction

A recent Institute of Medicine report acknowledges the efficacy of a broad range of psychosocial interventions.1 It challenges us to “identify key elements that drive an intervention’s effect.” The report describes key clinical tasks such as the therapist’s ability to engage with a patient, understand the patient’s worldview, and help the patient manage his or her emotional responses. The psychiatric community should also look into the neurobiological changes that accompany and may be responsible for an intervention’s effect. Although early psychoanalysts made little effort to connect functions of the mind to definable portions of the brain, from the beginning there was a belief that such a relationship may exist. Freud confidently predicted that one day there would be a neurological understanding of the work he initiated.

The deficiencies in our description would probably vanish if we were already in a position to replace psychological terms by physiological or chemical ones. Biology is truly a land of unlimited possibilities. We may expect it to give us the most surprising information and we cannot guess what answers it will return in a few dozen years to the questions we have put to it.2

Almost 100 years have passed since Freud wrote those words, and many of his questions remain unanswered. Steady progress, however, has been made in the development of a neurobiological understanding of what happens in the brain when the mind is engaged in psychotherapy. Advances in cognitive neuroscience and neuroimaging have facilitated a greater appreciation of the neuroanatomy and neurophysiology of the CNS. The technology to study the real-time functioning of the brain through measurement of blood flow or glucose uptake, for example, has been widely used for a quarter of a century. Numerous challenges endure, such as subtle individual variations of neural circuitry, uncertainty as to the proper area to study, and the possibility that differing forms of therapy affect the brain differently. Within the boundaries created by these limitations, however, there is an emerging understanding of the neurobiological correlates of some common psychotherapy elements.

Although different approaches utilize various terms and concepts, there are some components that are found in most forms of efficacious psychotherapy. There must be some emotional engagement (attachment) between the patient and therapist. The therapist will struggle to understand and express the patient’s experience (empathy). By learning about themselves and their environment, patients will decide to make changes. As therapy continues, they will develop new abilities to regulate their emotions. Many patients will be forced to face and overcome feared relationships or situations (fear extinction). There is a neurobiological literature developing on each of these common components of psychotherapy.

Attachment

Forming nurturing attachments with others remains a challenge throughout life especially for those with early trauma. The neurochemistry of attachment involves the neuropeptides oxytocin and arginine vasopressin. Both of these messengers are released from the hypothalamus by sexual stimulation and stress. In combination with estrogen, oxytocin helps induce maternal behavior, while the absence of oxytocin makes it more difficult for animals to adapt to social settings and leads to abnormal displays of aggression. Infusing or blocking oxytocin also causes dramatic changes in mating behaviors. Arginine vasopressin has myriad effects on normal mammals including altering displays of aggression and the animal’s tendency to affiliate with or protect others.

In humans, oxytocin is associated with a number of factors that affect attachment including trust, empathy, eye contact, and generosity. Oxytocin infusions in healthy individuals tend to decrease anxiety and the stress associated with social situations while shifting attention from negative to positive information. The reduction in distress appears related to a reduction in activity in the amygdala. In a study of women with borderline personality disorder, oxytocin infusion decreased their amygdala activation when exposed to angry faces.3 Although the effect is mediated by past experiences, intra-nasal infusion of oxytocin may increase an individual’s ability to infer the mental state and intention of others based on their facial expression. Oxytocin specifically aids in parent-child bonding. Administering oxytocin to parents increases the social engagement of the parent and child and leads to an increase in oxytocin in the child.

The mu-opioid receptor also appears to be involved in attachment. Activation of the mu-opioid receptor leads to a general sense of pleasure as well as analgesia. In animal models, removing the mother from the child leads to distress that is at least partially mediated through mu-opioid activity. Animals with an increased activation of the opioid system had more attachment behaviors and louder and more prolonged protests when separated. Their separation distress could be partially reversed by non-sedating opioid agonists.4 Patients with borderline personality disorder have differences in baseline mu-opioid receptor concentrations and in the endogenous opioid system response to negative emotional challenges. These differences might be related to their difficulty with emotion regulation.

Attachment therefore correlates with neurochemical changes within the brain. This might be most evidenced in parent-child interactions but may play a significant role in psychotherapy as well. A study of mothers with postpartum depression undergoing psychodynamic psychotherapy found that daily infusions of oxytocin over 12 weeks were associated with a decrease in narcissistic traits but not in depressive personality traits or depressive symptoms.5Depressed men who received oxytocin infusions while in psychotherapy performed better on tests of inferring the mental state of others but were more likely to experience anxiety during the session.6 These findings hint of a complex interaction between oxytocin and the therapist-patient relationship (Table 1).

Empathy [Narcissistic Personality Disorder NPD with conscious effort can evoke cognitive empathy but muted emotional empathy]

Empathy entails the ability to consider the world from another’s point of view and in some way to share his or her emotional experiences. Neurobiological correlates of empathy were first described in the early 1990s with the discovery of mirror neurons. Researchers who were studying the neuronal activity involved in organizing and monitoring movements noted that some of the same premotor cortex neurons were activated while observing others make corresponding movements.7,8 Neurons that were activated when a monkey grabbed food were activated when the researcher grabbed food but not when the researcher pushed or struck the food. These neurons were referred to as mirror neurons.

Mirror neurons in humans are not limited to simple movements. Watching dance leads to activation in the brains of other dancers. Greater activation occurs when dancers watch movements they already know. Mirror neurons activate while watching facial expressions and seem to be partially impaired in individuals with autistic disorders. Human mirroring networks also exist for pain and emotional distress. Researchers created pain by sticking subjects with a needle and monitored which areas of the brain were activated.9 Similar pathways were activated when the researchers brought the needle close to the subject but did not make contact and when subjects watched researchers pricking their own fingers. Witnessing others display disgust activates many of the same areas that are activated when one smells an unpleasant odor.

Mirroring neurons also fire when observing others being rejected or embarrassed. The areas most involved in mirroring physical pain, emotional distress, and social discomfort are the anterior cingulate cortex and insula. These areas help individuals automatically imagine themselves experiencing what they witness others experiencing. It should be noted that the studies of mirror neurons in humans are preliminary and not without controversy.

The posterior portions of the superior temporal sulcus have similar activities. This region activates when witnessing social behavior and predicting future actions. When a figure is walking toward you, activation of the superior temporal sulcus is greater when the figure is looking at you, which indicates the prospect of an upcoming interaction. Activation also increases when the other person’s behavior is different than expected. [attention focused through violated expectation]

In a study by Wyk and colleagues,10 an actor displayed pleasure or disgust to one of two identical objects and then randomly picked up one of the objects. When there was incongruent action (picking the object after showing disgust or not picking the object after a display of pleasure), there was increased activity in the observer’s posterior superior temporal sulcus region.

Experiencing empathy appears to require proper activation of portions of the insula and anterior cingulate cortex as we seek to understand the emotional experience of others. A properly functioning posterior superior temporal sulcus allows us to determine and predict the social actions of others, and will tend to activate when someone violates societal expectations. ][mutual respect dignity etiquette kindness helpfulness contribution to the common good]

Oxytocin and arginine vasopressin are also implicated in empathy. A study of polymorphisms in the genes of 367 young adults found that variations in the emotional aspect of empathy were associated with the oxytocin receptor gene, while the cognitive aspect of empathy was associated with the gene for the arginine vasopressin 1a receptor.11 A highly complex interaction of neurotransmitters and brain activation allows the therapist to understand the patient’s experience (Table 2).

Learning [hippocampus site of learning and memory]

Early in the 20th century Cajal proposed that the brain stored information by modifying neuronal connections. Learning involved changing individual neurons and their connections with each other. In the mid-20th century Hebb proposed his rule stating that when one neuron’s repeated excitation is involved in the excitation of a neighboring neuron, the connection between the two of them grows more efficient. Put colloquially, “Neurons that fire together wire together.” This implies that synapses change over time.

The first demonstration of this in the hippocampus occurred in 1973. After exposing neurons to strong, high-frequency stimulation, their connection to other neurons in the hippocampus became stronger.12 The discovery of hippocampal neurogenesis [new brain cell formation, constant baby brain cell creation which require 30 years to myelinate mature] established the process of neuronal plasticity [rewiring brain cell connections, augmentation bring in more brain cells for a particular circuit, or atrophy allowing connections to wither and die due to disuse like muscles in a broken arm unused in a cast become thinned from disuse atrophy] and upended the long-held belief that CNS cells were neurophysiologically and neuroanatomically incapable of growth.

Using the California sea slug (Aplysia californica), Kandel13 demonstrated that habituation [tolerance]—a decrease in response to a stimulus—could be attained with a single training session of 10 stimulations. These effects lasted minutes to hours and appeared to be a result of changes in the amount of neurotransmitter released with the stimulation. Training sessions on 4 consecutive days resulted in an effect that lasted weeks. This long-term learning was associated with changes in interneuronal connections. [rewiring, what we practice attending to, thinking and doing becomes stronger: self pity, helplessness, other blaming or personal responsibility, looking to the helpful hand at the end of own arm, choosing healthy vegetables fruits, sleep, physical activity, avoidance of recreational chemicals, engagement in meaningful work, continuity durability of healthy relationships, attitude, mental physical emotional social spiritual financial responsibility]

Preliminary studies in humans have found measurable changes in the brain based on learning stemming from juggling and playing video games.14,15 Experimental data demonstrate that the neurons in the brain are capable of learning-induced change. Psychotherapy includes components of experiential and didactic learning that is expected to create change in the patient’s brain. Many psychotherapies focus on thoughts or patterns that are initially outside the awareness of the patient. [precontemplation stage of change Motivational Interviewing Mindfulness Meditation introduces awareness that something is not comfortable] Therapy creates new memories to modify older, dysfunctional ones and in some cases creates new psychic structures. [children's literature bibliotherapy, cinematherapy, coming of age, shift POV point of view to allow reassessment reflection contemplation integration consolidation, openness to listening hearing another person social skill acquisition, appreciating own growth Good Job second grade social skill learning] This learning must involve changes in interneuronal connections (Table 3).

Emotion regulation [Sitting Still Like a Frog Eline Snell, Healing and the Mind Bill Moyers DVD 5 episodes, Stress Portrait of a Killer documentary, Dhamma Brothers Frontline 10 day meditation training years later follow up, Departures Oscar Best Foreign film learning forgiveness without apology]

Patients in psychotherapy are taught to understand, accept, or manage their emotional responses in new ways. Researchers are looking into how emotion regulation modifies brain activity.

One common strategy for altering emotions is reappraisal, when the individual deliberately tries to alter the meaning or relevance of an event. Reappraisal strategies link cognitive control with emotional experience. Attempts to deliberately decrease aversive emotions, sadness, and sexual arousal through cognitive reappraisal have found that reappraisal strategies most commonly activate multiple areas within the prefrontal cortex [behind forehead] and posterior parietal cortex. Activation of these areas during reappraisal leads to decreased activity in portions of the amygdala [anger anxiety]. These studies have demonstrated specific neuronal circuitry, for example, between the hippocampus [learning memory], prefrontal cortex [planning decision making analysis initiation motivation execution judgment financial literacy] , and amygdala anxiety anger], which are strengthened by psychotherapeutic treatment.16,17

Suppression, an intentional attempt to minimize the display of emotions, may also decrease the intensity of emotions. [role playing DVD Healing and the Mind Bill Moyers] Subjects were asked to suppress their emotions while observing sad pictures. When suppressing their emotions, there was an increase in activity in the right [emotional] orbitofrontal and dorsolateral prefrontal cortices.18 Other studies have found activation of the dorsal anterior cingulate cortex, dorsomedial prefrontal cortex [conscious decision effort], and lateral prefrontal cortex with suppression.19

Cognitive reappraisal and suppression seem to have distinctly different neurophysiological mechanisms. In a head-to-head study both strategies were successful at decreasing subjective emotional experience, but there were differences in brain activation.20

Reappraisal led to increased activity in the prefrontal cortex [cognition conscious choice awareness] and decreased activity in the right amygdala [anger anxiety emotional dysregulation] and left insula.

Suppression increased activity in the right ventral-lateral prefrontal cortex but did not decrease activity in the amygdala or insula (Table 4).

Fear extinction

Learning to be afraid, or fear conditioning, involves pairing a previously innocuous stimulus (conditioned stimulus) with an aversive stimulus (unconditioned stimulus). The mind begins to associate the previously benign stimulus with the unpleasant one, and the individual experiences heightened anxiety whenever presented with the new conditioned stimulus. The process of fear conditioning involves interactions of the amygdala, insula, anterior cingulate cortex, and medial prefrontal cortex.

The process of unlearning fear is known as fear extinction.

Fear extinction does not consist of erasing old memories; rather it is the creation of new, benign associations. The underlying fear is still present, but successful fear extinction leads to a reduction in the amplitude and likelihood of a fearful response. This occurs when the once feared stimulus or situation no longer brings about any adverse consequences.

Fear extinction is a principal therapeutic component of exposure therapies for specific phobias and for PTSD, but learning to confront feared memories, situations, and people can be found in a broad range of psychotherapies.

Fear extinction requires a functional ventral-medial prefrontal cortex, rostral anterior cingulate cortex, and hippocampus [learning memory]. Activation of these regions leads to decreased amygdala activity. Clinical studies have demonstrated that the addition of D-cycloserine [caveat very very narrow therapeutic window between action and toxicity, strictly low dose one time, not chronic exposure, lacks general applicability], a partial N-methyl-D-aspartate (NMDA) glutamate agonist, may improve outcomes in exposure-based therapies for acrophobia and social phobias.21 Conversely, NMDA antagonists [Modafinil, ketamine], by decreasing NMDA activity, can inhibit the formation of long-term fear extinction. [ie blocks prevents psychotherapeutic learning to challenge erroneous beliefs]

While decreasing the activity in the amygdala leads to an acute reduction in perceived fear, the long-term persistence of fear extinction requires the activity of the ventral-medial prefrontal cortex [cognitive brain] and rostral anterior cingulate cortex. These appear to be vital in connecting the cognitive and emotional experiences and solidifying the learning.

The hippocampus [learning memory] aids in fear extinction by placing events into a context.

This context helps determine how generally the brain applies the new learning. [eg being fearful or being curious about something novel new unfamiliar, like plants animals people DVD Fading Gigolo John Turturro Vanessa Paradis Sharon Stone Sofia Vergara Woody Allen comedy] Because the previous fear is not erased, when the individual encounters the once feared stimuli there is activation of both the fearful and fear extinguished pathways. The context, provided by interactions between the hippocampus [learning memory] and ventromedial prefrontal cortex [cognition conscious awareness, mindfulness], determines which set of behaviors is predominately activated (Table 5).

The work of the psychotherapist is to help solidify the most healthy and adaptive responses.

Prediction of response to psychotherapy

Studies have begun to examine the ability to predict a patient’s response to psychotherapy based on neurobiological factors. One of the many changes that occur with depression is the elevation of metabolism in the posterior insula. Studies have found that changes in connectivity and activation of the insula predicted a positive response to psychotherapy in patients with depression.22-24 Another study found that increased metabolism in the subcollasal cingulate cortex and superior temporal sulcus was associated with no response to escitalopram or cognitive-behavior therapy treatment for depression.25 Conclusion

Although a precise description of the neurophysiological changes that occur during psychotherapy is currently impossible, it is likely that future imaging and neurobiological investigation will elucidate this process. The neurobiological correlates to many of the common elements of psychotherapy such as attachment, empathy, memory, learning, emotional regulation, and fear extinction are emerging. While we still cannot answer all of Freud’s questions, or our own questions, the artificial dichotomy between the functioning of the mind and brain during psychotherapy seems less imposing.

Dr Welton is Associate Professor of Psychiatry and Director of Residency Training and Dr Kay is Emeritus Professor of Psychiatry, Boonshoft School of Medicine, Wright State University, Dayton, OH.

1. Institute of Medicine. Psychosocial Interventions for Mental and Substance Use Disorders: A Framework for Establishing Evidence-Based Standards. Washington, DC: The National Academies Press; 2015:S1-S16.

2. Freud S. Beyond the pleasure principle. In: Strachey J, ed. The Standard Edition of the Complete Psychological Works of Sigmund Freud. Vol 18. London: Hogarth Press; 1955:1-64.

3. Bertsch K, Gamer M, Schmidt B, et al. Oxytocin and reduction of social threat hypersensitivity in women with borderline personality disorder. Am J Psychiatry. 2013;170:1169-1177.

4. Barr CS, Schwandt ML, Lindell SG, et al. Variation at the mu-opioid receptor gene (OPRM1) influences attachment behavior in infant primates. Proc Natl Acad Sci USA. 2008;105:5277-5281.

5. Clarici A, Pellizzoni S, Guaschino S, et al. Intranasal administration of oxytocin in postnatal depression: implications for psychodynamic psychotherapy from a randomized double-blind pilot study. Front Psychiatry. 2015;6:1-10.

6. MacDonald K, MacDonald TM, Brune M, et al. Oxytocin and psychotherapy: a pilot study of its physiological, behavioral and subjective effects in males with depression. Psychoneuroendocrinol. 2013;38:2831-2843.

7. Rizzolatti G, Fadiga L, Gallese V, Fogassi L. Premotor cortex and the recognition of motor actions. Cog Brain Res. 1996;3:131-141.

8. Iacoboni M. Face to face: the neural basis of social mirroring and empathy. Psychiatr Ann. 2007;37: 236-241.

9. Hutchison WD, Davis KD, Lozano AM, et al. Pain-related neurons in the human cingulate cortex. Nature Neurosci. 1999;2:403-405.

10. Wyk BC, Hudac CM, Carter EJ, et al. Action understanding in the superior temporal sulcus region. Psychol Sci. 2009;20:771-777.

11. Uzefovsky F, Shalev I, Israel S, et al. Oxytocin receptor and vasopressin receptor 1a genes are respectively associated with the emotional and cognitive empathy. Horm Behav. 2015;67:60-65.

12. Bliss TVP, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993;361:31-39.

13. Kandel ER. Psychotherapy and the single synapse: the impact of psychiatric thought on neurobiological research. J Neuropsychiatry Clin Neurosci. 2001;13:290-300.

14. Draganski B, Gaser C, Busch V, et al. Neuroplasticity: changes in grey matter induced by training. Nature. 2004;427:311-312.

15. Kuhn S, Gleich T, Lorenz RC, et al. Playing Super Mario induces structural brain plasticity: gray matter changes resulting from training with a commercial video game. Mol Psychiatry. 2014;19:272.

16. Ochsner KN, Ray RD, Cooper JC, et al. For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion. Neuroimage. 2004;23:483-499.

17. Buhle JT, Silvers JA, Wager TD, et al. Cognitive reappraisal of emotion: a meta-analysis of human neuroimaging studies. Cerebral Cortex. 2014;24: 2891-2890.

18. Levesque J, Eugene F, Joanette Y, et al. Neural circuitry underlying voluntary suppression of sadness. Biol Psychiatry. 2003;53:502-510.

19. Phan KL, Fitzgerald DA, Nathan PJ, et al. Neural substrates for voluntary suppression of negative affect: a functional magnetic resonance imaging study. Biol Psychiatry. 2005;57:210-219.

20. Goldin PR, McRae K, Ramel W, Gross JJ. The neural bases of emotion regulation: reappraisal and suppression of negative emotion. Biol Psychiatry. 2008;63:577-586.

21. Britton JC, Gold AL, Feczko EJ, et al. D-cycloserine inhibits amygdala responses during repeated presentations of faces. CNS Spect. 2007;12:600-605.

22. Roffman JL, Witte JM, Tanner AS, et al. Neural predictors of successful brief psychodynamic psychotherapy for persistent depression. Psychother Psychosom. 2014;83:364-370.

23. Crowther A, Smoski MJ, Minkel J, et al. Resting-state connectivity predictors of response to psychotherapy in major depressive disorder. Neuropsychopharmacol. 2015;40:1659-1673.

24. McGrath CL, Kelley ME, Holtzheimer PE 3rd, et al. Toward a neuroimaging treatment selection biomarker for major depressive disorder. JAMA Psychiatry. 2013;70:821-829.

25. McGrath CL, Kelley ME, Dunlop BW, et al. Pretreatment brain states identify likely nonresponse to standard treatments for depression. Biol Psychiatry. 2014;76:527-535.

Some issues to note about this otherwise very interesting article.

1. The Institute of Medicine report acknowledging the efficacy of a broad range of psychotherapy needs to be taken with a nuanced view (summary here: iom.nationalacademies.org/~/media/Files/Report%20Files/20....).

None of the claims of “evidence-base” here is based on a blinded clinical trial. Neither subjects nor treaters can feasibly be blind to the nature of the psychotherapy they receive in a clinical trial making these clinical trials poorly controlled. A masked rater only records the unblinded report of the subject and does not control for the lack of blinding. Many clinical trials done in this fashion do not make up for the lack of blinding because it is very easy to obtain non-inferiority and even superiority results in an unblinded trial of a psychiatric condition i.e., depression where endpoints are subjective-and blinding is a key element of any study with subjective endpoints where ratings may easily be swayed by hope and expectation. “Efficacy” and rigor in a clinical trial needs to be used by caution when studies do not have (can not possibly have) blind subjects or treaters.

2. The article’s statement that “A highly complex interaction of neurotransmitters allows the therapist to understand the patient’s experience”, is confusing. Do the authors mean that this research is valuable and heuristic (I would agree), or do they mean that a therapist can figure out how neurotransmitters are actually involved in a patient’s particular experience?- I think this kind of understanding is still very far away and the statement should be reworded.

3. Although the authors state that juggling and playing video games can make changes in the brain, in the next sentence they then move into the effects of psychotherapy making brain changes. Didn’t they just say that even juggling and video games can change the brain? The logic here seems to indicate that the brain is a plastic responsive organ easily changed by experience, but whether that experience (or therapy) is causing some therapeutic effect is still jump of logic away.

4. This study mentioned in the article: D-cycloserine inhibits amygdala responses during repeated presentations of faces. CNS Spectr 2007 Aug;12(8):600-5, only had 14 subjects randomly assigned to drug or placebo, i.e., 7 subj in each group. This “micro N” study needs to be taken with extreme caution, not noted like in this article to be that “Clinical studies have demonstrated…”

The article is an interesting discussion of behavior and biology, but neither the neurobiology of psychotherapy, nor the clinical trial validity of psychotherapy, is a conclusion that can be born from the discussion presented here.

Douglas Berger, MD, PhD.

US Board Certified Psychiatrist

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Title: The Biological bulletin

Identifier: biologicalbullet177mari

Year: (s)

Authors: Marine Biological Laboratory (Woods Hole, Mass. ); Marine Biological Laboratory (Woods Hole, Mass. ). Annual report 1907/08-1952; Lillie, Frank Rattray, 1870-1947; Moore, Carl Richard, 1892-; Redfield, Alfred Clarence, 1890-1983

Subjects: Biology; Zoology; Biology; Marine Biology

Publisher: Woods Hole, Mass. : Marine Biological Laboratory

Contributing Library: MBLWHOI Library

Digitizing Sponsor: MBLWHOI Library

  

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144

 

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Figure 4. (a) Longitudinal section of radial nerve with cell bodies in both ectoncural (EN) and hyponeural (H N) systems as well as beaded fibers in the axonal region (arrows). BM, basement membrane. Primary antibody, L135, with PAP labelling. Scale bar = 100 urn. (b) Transverse section of regenerating radial nerve to show dense concentration of immunoreactive fibers (arrows). The absence of im- munoreactive cell bodies suggests these fibers are derived from cells distal to the region of growth. Primary antibody, LI 35, with PAP label- ling. Scale bar = 100 ^m. (c) Longitudinal section of the radial nerve cord showing hyponeu- ral cell bodies, one with a process (arrow) directed toward the basement membrane (BM). Primary antibody, 1 171, with FITC labelling. Scale bar = 25 pm. tebrates. the characterization of the FMRFamide-Iike peptides in echinoderms would provide a further test of the notion that the F(X)RFamide peptides are peculiar to protostomes. M. R. ELPHICK ET AL Echinoderm neurobiology Our current understanding of echinoderm neurobiol- ogy is far behind that of most of the other major inverte- brate phyla (see Cobb, 1987, 1988). Only one native echinoderm neuropeptide has ever been thoroughly in- vestigated: gonad stimulating substance (GSS) (see Ka- natani. 1979). Discovered thirty years ago (Chaet and McConnaughy, 1959), GSS has only recently (and par- tially) been sequenced (Shirai, 1987). This is the first extensive study of peptidergic neurons in an echinoderm. The distribution of FMRFamide-like immunoreactivity in the nervous system may provide some clues as to the function of these peptides in starfish. The abundance of immunoreactivity and its presence in both the ectoneural and hyponeural systems suggests that the peptides may have a general transmitter-like role. However, the immunoreactivity is particularly as- sociated with the innervation of the tube feet. Thus the sub-epithelial nerve plexus of the tube feet contains nu- merous immunoreactive fibers, whereas the soma of these neurons appear to lie within the adjacent nerve cord or ring. Florey and Cahill (1980) demonstrated that the tube feet of sea urchins are under cholinergic motor control. Their evidence indicates that chemical transmission in- volves the diffusion of acetylcholine (ACh) from nerve terminals of the sub-epithelial plexus to the musculature, across the intervening connective tissue layer. Peptides produced by the immunoreactive neurons described here may be modulating the motor control of tube foot activity. Some circumstantial support for this idea comes from Unger's work (1960, 1962). Using simple chro- matographic methods, this author isolated two physio- logically active substances from the radial nerve cords of Asterias glacialis. In addition to effecting color changes, both factors induced movement in whole animals, as well as in isolated arms, and one of them strongly exci- tated the Helix heart. These effects were clearly distin- guishable from those of ACh, serotonin, adrenalin, nor- adrenalin, and histamine, and we speculate that the ex- tracts may have contained peptidic factors, including FMRFamide-like molecules. The immunocytochemical data presented in this re- port shows us relatively little about the chemical nature of the immunoreactive peptides since any peptide with a C-terminal sequence similar to that of FMRFamide might cross-react with the antisera. A good example is the family of pancreatic polypeptide-related peptides (PP-RP) which terminates in Arg-Tyr-amide (see Thorn- dyke, 1986, for a more complete discussion of this problem). Experiments designed to isolate and sequence the FMRFamide-like peptides in Asterias are currently un-

  

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Title: The Biological bulletin

Identifier: biologicalbullet177mari

Year: (s)

Authors: Marine Biological Laboratory (Woods Hole, Mass. ); Marine Biological Laboratory (Woods Hole, Mass. ). Annual report 1907/08-1952; Lillie, Frank Rattray, 1870-1947; Moore, Carl Richard, 1892-; Redfield, Alfred Clarence, 1890-1983

Subjects: Biology; Zoology; Biology; Marine Biology

Publisher: Woods Hole, Mass. : Marine Biological Laboratory

Contributing Library: MBLWHOI Library

Digitizing Sponsor: MBLWHOI Library

  

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About This Book: Catalog Entry

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Figure 2. (a) Transverse section of radial nerve showing distribu- tion of immunoreactivity in the ectoneural (EN) and hyponeural (HN) systems. Primary antibody. 1171, with PAP labelling. Scale bar = 100 (b) Longitudinal section ofcircumoral ring and part of tube foot epi- thelium showing lateral concentration of ectoneural cell bodies (triple arrows) and distinctive tube foot sub-epithelial nerve plexus (TFP). Pri- mary antibody. 1 171. with PAP labelling. Scale bar = lOO^m. (c) Longitudinal section of radial nerve cord showing bipolar ecto- neural cell bodies (white arrows) interspersed between supporting cells (black arrows) of the epithelium. Primary antibody, I 171, with PAP labelling. Scale bar = 30 ^m. (d) Transverse section of lateral region of the radial nerve cord near junction with tube foot showing increased concentration of immunore- active ectoneural cell bodies and fibers (arrows). Primary antibody, L135, with PAP labelling. Scale bar = 30 Mm. basement membrane, although no fibers appeared to cross it in either direction (Fig. 4a, c). In preliminary experiments designed to investigate the pattern of neuronal regeneration in previously sectioned arms, the concentration of immunoreactive fibers in the ectoneural system of the regenerates was noticeably in- creased (Fig. 4b). Both FMRFamide antisera used gave positive results, but all of the control experiments, including those using antisera previously absorbed with FMRFamide, proved negative. Discussion This investigation records for the first time, the occur- rence of immunoreactive FMRFamide-like molecules in the nervous system of an echinoderm. These findings have implications for both neuropeptide phylogeny and echinoderm neurobiology. Neuropeptide phylogeny Over the last decade, FMRFamide-like peptides have been characterized in a variety of species and appear, at present, to fall into two distinct groups. First, those iso- lated from protostome phyla (Nematoda, Annelida. Mollusca, and Arthropoda) share with FMRFamide the general C-terminal sequence: F(X)RFamide, where X can be methionine, leucine, or isoleucine. Second, those peptides isolated from non-protostomes (Coelenterata and Chordata) usually share with FMRFamide only the C-terminal RFamide. Greenberg et al (1988) suggested that the protosto- mian peptides are homologous, whereas the sharing of the RFamide C-terminus with FMRFamide among the non-protostomian peptides "may merely reflect general characteristics of associations between peptides and pro- teins. If there is a homology, it is likely to reside with the class of membrane proteins comprising peptide recep- tors." Since the echinoderms are deuterostomian inver-

 

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Figure 3. (a) Oblique section through radial nerve cord. Hyponeu- ral cell bodies (HN) are clearly evident as is the sub-epithelial plexus in adjacent tube feet (arrows). Notice the high concentration of immuno- reactive cells where the nerve cord branches to innervate the tube feet (arrow heads). Primary antiserum, 1171, with PAP labelling. Scale bar = 100 ^m. (b) Transverse section of marginal nerve cord (MN) and adjacent tube foot (TF). Immunoreactive fibers in the sub-epithelial plexus are clearly evident (arrow). Primary antiserum, 1 171, with PAP labelling. Scale bar = 30 ^m.

  

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Title: The Biological bulletin

Identifier: biologicalbullet202mari

Year: (s)

Authors: Marine Biological Laboratory (Woods Hole, Mass. ); Marine Biological Laboratory (Woods Hole, Mass. ). Annual report 1907/08-1952; Lillie, Frank Rattray, 1870-1947; Moore, Carl Richard, 1892-; Redfield, Alfred Clarence, 1890-1983

Subjects: Biology; Zoology; Biology; Marine Biology

Publisher: Woods Hole, Mass. : Marine Biological Laboratory

Contributing Library: MBLWHOI Library

Digitizing Sponsor: MBLWHOI Library

  

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CRUSTACEAN LIMB AUTOTOMY FACTOR 209 0) •o c

 

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Days Before or After First Injection Figure 7. Effects of injection of limb bud extracts on I limb bud growth. Proecdysial animals (K index 13-15) were injected with extracts of either 1° LBs (•) or 2° LBs (open symbols) three times at 2-day intervals beginning at Day 0 (arrow). Each injection contained two LB equivalents (see Materials and Methods). The effect of injections was determined by monitoring (he R index of the R2 1 LB. The injection of 2° LB extracts inhibited 1° LB growth (animals #124, #386, and #341), whereas injection of 1° LB extract had no effect (#331). ing injection (P < 0.005; n = 12). The 1° LB growth rates of animals injected with 1° LB extracts were the same before and during the injection series (P < 0.86: n = 10). For animals that were allowed to complete proecdysis and molt, injection of 2° LB extract delayed ecdysis about 6 days. The interval between the first injection to ecdysis was 16 to 18 days for three animals injected with 1° LB extract and 22 to 24 days for three animals injected with 2° LB extract. Characterization of linih autotomy factor—proecdysis The reduction in hemolymph ecdysteroid concentration after LBA suggested that LAFpro. like MIH. inhibits ecdy- steroid secretion by the Y-organs. Consequently, we deter- mined whether LAFpro shared physical and chemical prop- erties with MIH. MIH is a neuropeptide that is resistant to boiling in deionized water or acids, but is inactivated by proteases (Ranga Rao. 1965; Freeman and Costlow, 1979; Webster, 1986; Webster and Keller, 1986: Chang ct <//.. 1990). To determine the properties of LAFpro, 2° LB extracts were either boiled in deionized water, boiled in 0.1 N acetic acid, or incubated with proteinase K. An injection series consisted of three injections at 2-day intervals; each injec- tion contained one LB equivalent (because we found that one LB equivalent was as effective as two, we used one LB equivalent to conserve material). The growth of the R2 1° LB was measured for the week before and the week after the first injection. The thermal stability of LAFpro was deter- mined by heating 2° LB extracts in a boiling water bath for 15 min. The denatured protein was removed by centrifuga- tion, and the supernatant fraction was injected into proec- dysial animals. The boiled extract significantly inhibited 1° LB growth by 68%. indicating that the factor was heat- stable (Fig. 9). In a second set of experiments, the injection of extracts boiled in 0.1 N acetic acid had no effect on 1° LB growth, while the positive control (2° LB extracts from the same animal boiled 15 min in deionized water) inhibited growth (Fig. 9). In a third set of experiments, incubation of 2° LB extracts with proteinase K also destroyed LAFpm activity, as injection of treated extracts did not inhibit 1° LB growth (Fig. 9). Positive controls, in which untreated 2° LB extracts from the same animals were injected, inhibited 1 LB growth (data not shown). Discussion Since LB growth in decapod crustaceans is restricted to the proecdysial stage, limb regeneration must be coordi- nated and integrated with other physiological processes for an animal to molt successfully. In various decapod species, multiple leg autotomy (MLA) acts as a potent inducer of precocious molting, probably due to the need to restore functional appendages as quickly as possible (Skinner and Graham, 1970, 1972: Holland and Skinner. 1976; see Skin- ner. 1985, for additional references). Limb bud autotomy (LBA) can delay molting so that animals will molt with a E3 Growth rate betore injection • Growth rate during injection 0) TJ C re DC O i_ O

  

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Title: The Biological bulletin

Identifier: biologicalbullet184mari

Year: (s)

Authors: Marine Biological Laboratory (Woods Hole, Mass. ); Marine Biological Laboratory (Woods Hole, Mass. ). Annual report 1907/08-1952; Lillie, Frank Rattray, 1870-1947; Moore, Carl Richard, 1892-; Redfield, Alfred Clarence, 1890-1983

Subjects: Biology; Zoology; Biology; Marine Biology

Publisher: Woods Hole, Mass. : Marine Biological Laboratory

Contributing Library: MBLWHOI Library

Digitizing Sponsor: MBLWHOI Library

  

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NEUROPEPTIDES ISOLATED FROM LIMl'LUS 325 GHSLLHFa \ 1.0 i GGRSPSLRLRFa j

 

Text Appearing After Image:

0.0 0 5 10 15 20 Time (min) Figure 1. RIA analysis of the initial HPLC fractionation of a Limulus CNS extract (second experiment). Half-minute fractions were collected, and 2-jjl aliquots were taken from each fraction for the RIA using the Q2 antiserum. The immunoreactive peaks containing peptides LPI-LP4 are indicated: * (LP1. LP2, LP3): « (LP4). In a previous purification, the Limulus head peptide (Lip-HP) was isolated from the second peak (**). The elution times of LP2 (GHSLLHFamide) and Lip-HP (GGRSPSLRLRFamide) are indicated with arrows. The sequences and molecular ions of all of the peptides are listed in Table II. sequence GHSLLHF. This sequence is in agreement with the calculated molecular weight of 808 for GHSLLHF, assuming an amidated carboxyl terminus (Gly-His-Ser- Leu-Leu-His-Phe-NH2). The remaining three peaks contained insufficient ma- terial for either microsequencing or FABms. We therefore prepared a new extract to resolve the ambiguities left by the first experiment. The first HPLC fractionation of this new CNS extract, after RIA analysis with the Q2 antiserum, showed im- munoreactive peaks (Fig. 1) similar to those in the RIA profile obtained from the earlier CNS extracts. When the S253 antiserum was used, some peaks were more clearly defined than in the previous experiment. Two peptides (LP3 and LP4) that reacted only with the Q2, and that had not been identified earlier, were isolated and identi- fied. In addition, the identification of LP1 was completed with the new extract. The details of these findings are set out below. After oxidation, peak LP3 eluted almost 8 min earlier; shifts of this magnitude are indicative of more than one methionyl residue. A prominent monoisotopic protonated ion was found at an m/z ratio of 1109.2, and automated Edman degradation of 125 pmol of peptide yielded the sequence PDHHMMYF (Pro-Asp-His-His-Met-Met-Tyr- Phe). This sequence is consistent with the calculated mo- lecular weight of 1108 for LP3, assuming an amidated 60 -, T3 3 = 40 20 - [GHSLLHFa] (nM) Figure 2. Dose-response relationship of the effect of GHSLLHFamide (LP2) on the isolated Limulus heart. LP2 decreases the amplitude of the beat with a threshold of 4 nM (Nine or ten determinations on five dif- ferent hearts; SEM < 2°;). The measurement of the response, the per- centage of amplitude relative to that of the control beat, is described in Materials and Methods. carboxyl terminus and both methionyl residues as the sulfoxides. The elution time of LP4 also shifted after oxidation, though not as much as that of LP3. FABms analysis of the immunoreactive peak revealed a prominent proton- ated molecular ion at an m/z ratio of 1011.2. Further analysis of the fragment ions yielded the sequence DHGNMLYFamide (Asp-His-Gly-Asn-Met-Leu-Tyr- Phe-NH2). Finally, the molecular ion for LP1 was obtained (1155.8), and fragment ions indicative of an N-terminal aspartic acid residue were also found. So the sequence of this peptide was deduced to be: DEGHKMLYFamide. Peptide synthesis The synthetic peptides GGRSPSLRLRFamide and GHSLLHFamide were purified by HPLC. Amino acid GHSLLHFa 2x10 8 M 4x1 O8 M 2x107 M 1 min Figure 3. LP2-induced decreases in strength and rate of contractions of the isolated Limulus heart. Whereas the effect on the heart rate is long-lasting, the amplitude starts to increase again 4-5 min after peptide application.

  

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Title: The Biological bulletin

Identifier: biologicalbullet191mari

Year: (s)

Authors: Marine Biological Laboratory (Woods Hole, Mass. ); Marine Biological Laboratory (Woods Hole, Mass. ). Annual report 1907/08-1952; Lillie, Frank Rattray, 1870-1947; Moore, Carl Richard, 1892-; Redfield, Alfred Clarence, 1890-1983

Subjects: Biology; Zoology; Biology; Marine Biology

Publisher: Woods Hole, Mass. : Marine Biological Laboratory

Contributing Library: MBLWHOI Library

Digitizing Sponsor: MBLWHOI Library

  

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pQFYRFa B 1.5mM K

 

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Figure 6. Effects of pQFYRFamide on a Cl neuron from the cere- bral ganglia of Hcli\ IM/KV.WJ (A) Examples of the currents evoked by the peptide at different holding potentials (Vh). In the top record, the voltage was periodically stepped to -50 mV to monitor the conduc- tance: note that the current pulses in response to the -5 mV steps are about twice as large at the peak of the response as in the control. (B) Relationship between peak evoked current and holding potential for responses in physiological solutions containing normal (5 m.M. circles) or reduced (1.5 mM, squares) concentrations of potassium. The data shown in the graph were taken from an experiment on a singled neu- ron. A second experiment gave the same result. Discussion We have sequenced the 5' end of the cDNA encoding the FMRFamide precursor of Helix aspersa. and so the entire sequence is now complete. The general organiza- tion of this precursor is similar to that of the two other completely sequenced FMRFamide precursors: Lym- naea stagnalis (reviewed by Benjamin and Burke, 1994) and Aplysia californica (see Taussig and Scheller, 1986). The similarity is manifest in both the splicing pattern and in the linear arrangement of landmark sequences in the precursor. The mRNA encoding the FMRFamide precursor in all three species is composed of at least two exons, and in all three the splice junction is in a roughly similar posi- tion. In both Lymnut'ii and Helix the first exon of the FMRFamide precursor is alternatively spliced to give an- other neuropeptide precursor (that of the FLRFamide- related heptapeptides), but no alternatively spliced prod- uct has ever been found in Aplysin. Vh= -45 mV pQFYRFa

  

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When a person uses creative visualization imagery and self-suggestion to visualize and change their emotions, this process has an actual physical affect on the body.

How Creative Visualization and Emotions Heal

The hypothalamus is the emotional center of the brain and changes emotions into physical responses.

 

The hypothalamus also controls other bodily functions such as the body temperature; blood sugar levels; appetite; adrenal and pituitary gland; heart; lungs; and the circulatory and digestive systems.

 

The hypothalamus is the neuropeptide receptor, and neuropeptides are a chemical messenger hormone that transports emotions back and forth between the mind and body. They link perceptions in the brain to the body using organs, cellular activity and hormones. Neuropeptides also influence every major section of the immune system, making the mind and body work together as one unit.

With creative visualization a person uses this mind and body connection to induce healing.

[caption id="attachment_514" align="alignright" width="250" caption="Creative Visualization"][/caption]

 

Everything in the universe is connected and each thought, action or event is connected and influences one another.

 

Every thought and action a person has, causes a reaction and has repercussions.

Each thought a person has arouses an associated emotion and if this emotion is strong enough, it stimulates actions.

 

Thus, positive thoughts and emotions are vital in producing a positive outcome.

 

Negative thoughts and emotions actually lower a person’s immune system and positive thoughts enhance the immune system.

 

With this connection idea in mind, creative visualization believes that if a person can visualize something, they can achieve it.

 

This is equally true with health and well being as well.

This Awesome Video Shows A Patient Actually Healing

In this video the healing helpers and the patient are using the power of the imagination and are generating positive emotions which induces the healing. The patient and the helping healers "see" the patient as healed in their minds eye. This is a type of creative visualization.

 

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Creative Visualization Transports a Person To a Whole New World of Health and Well Being

 

[caption id="attachment_535" align="alignright" width="135" caption="VISUALIZATION"][/caption]

 

When using creative visualization, a person can be transported from a place of fear, stress and illness to a place of peace, calm and

 

wellness.

 

One of the multitude of positive effects of creative visualization is that the body goes limp and loose as it enters a relaxed state. This is the perfect state for a person to learn, focus on goals and heal. Creative

 

visualization can be done sitting or laying down and even with eyes open. The key is in focusing the minds eye.

 

Using creative visualization along with guided relaxation a person can experience further relaxation of the body and enhance healing.

Creative Visualization Quietens The Mind And Allows Easy Focus On Healing and Well Being

Everyone has an internal critic, which is that part of our mind that uses past experiences to reject unfamiliar information without further evaluation.

 

Studies show that creative visualization along with guided relaxation help to subdue this internal critic, making a person open to new ideas.

 

This allows a person to experience appropriate and positive ways to imagine a personal goal.

 

As a result, using creative visualization, a person can remain optimistic and motivated toward their healing and well being goals.

Creative Visualization Targets The Mind Body Connection In A Focused and Positive Way

[caption id="attachment_530" align="alignleft" width="300" caption="Creative Visualization For Health And Well Being"][/caption]

 

In conclusion, we have known for centuries that there is mind and body connection.

 

From the scientific perspective we understand that creative visualization directly and powerfully impacts a body’s neurological system. It also has a direct impact on all levels physical body

 

What we can visualize, we can achieve whether it be a certain goal or something as critical as healing our bodies of disease.

 

Creative visualization is one of the most powerful techniques that a person can use to relax and heal.

 

Guided visualization is a perfect way to to start learning and practicing creative visualization.

 

To find out more about learning creative visualization visit the "Visualization Store" and read other highly informative articles on this website. You may also wish to investigate some of the courses and ebooks that teach you "How To Visualize"

 

We hope that you enjoyed this article about creative visualization. @identi @kewego @myspace @plerb @soundcloud @sugarsync @tinypic @wordpress @zooomr

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