Dr Caroline Leaf and the struggle spiral

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In Proverbs 12:25, the incredibly wise King Solomon wrote that, “Worry weighs us down; a cheerful word picks us up.”

Today, Dr Leaf posted to her social media stream that “An undisciplined mind is filled with worries, fears and distorted perceptions – These lead to degeneration of the mind and body.”

Well, that’s about as uplifting as a lead balloon.

Dr Caroline Leaf is a communication pathologist and a self-titled cognitive neuroscientist.  I’m sure her heart was in the right place when she posted her latest jewel of wisdom, but it may not be as encouraging or as helpful as she may have intended.

The biggest problem is her opening premise, “An undisciplined mind is filled with worries, fears and distorted perceptions”.  So … that’s not really accurate. The normal human mind is filled with worries, fears and distorted perceptions. It really doesn’t matter whether you discipline your mind or not, you won’t shift these ‘negative’ thoughts.

That’s because we’re meant to experience appropriate levels of fear and worry.  They’re a survival mechanism.  Without a certain amount of fear, we’d end up as a Darwin Award.  And as human beings, we’re naturally inclined to so many different cognitive biases that there’s a very long list (although ironically, those with the strongest confirmation bias will probably be the least likely to accept this).

By erroneously linking normal cognitive function to the concept of mental ill-discipline, Dr Leaf is simply setting people up for an unrealistic struggle with their normal psyche as they unnecessarily try to discipline it.

And for the people who really do struggle with excessive or inappropriate worry, fear or incorrect perceptions – i.e. people who suffer from formal anxiety disorders – this sort of statement is misleading because again, their issue isn’t mental ill-discipline. Anxiety is the result of a genetic predisposition and increased vulnerability to stress.

The second part of Dr Leafs meme is as unhelpful as the first.  For a start, it’s not true that worries, fears and distorted perceptions cause degeneration of the mind and body.  There may be a correlation between stress and some long term health problems, but correlation does not equal causation.  As Cohen and colleagues noted, “Although stressors are often associated with illness, the majority of individuals confronted with traumatic events and chronic serious problems remain disease-free.” [1]  Dr Leaf’s claim seems little more than a scare tactic, which can only lead to increased anxiety not increased motivation.

The important things to remember here are:
1. Experiencing worries, fears and distorted perceptions is normal, and not something that can be changed by disciplining your mind.  Don’t fall into the trap of trying to treat something that isn’t a disease.
2. If you do suffer from an anxiety disorder, don’t blame yourself.  That sets up a spiral of struggle.  Thoughts are just words. They have no power over you unless you engage with them.  Instead of trying to repress every worry and every fear, allow your thoughts to bubble away in the background, and instead, focus your energy on taking values based committed action which will ultimately help you live a life of meaning, not just struggling.

References

[1]     Cohen S, Janicki-Deverts D, Miller GE. Psychological stress and disease. JAMA: the journal of the American Medical Association 2007;298(14):1685-87.

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Dr Caroline Leaf and the myth of optimism bias

“What are little girls are made of?  Sugar and spice, and all things nice.”

It sounds sweet doesn’t it?  We like to connect with these rosy little memes that warm our cockles and make us feel good about the world and ourselves.  We think of all of the examples in our own experience, which seems to confirm the saying.  We may think of a few examples that don’t quite fit, but they’re just the exception that proves the rule.

It doesn’t seem to matter what the saying or proverb is, we usually just assume it’s true.  Think of some other examples:
“Blondes have more fun.”
“Women can’t read maps.”
“White guys can’t dance.”

In all of these things, we tend to experience what psychologists call confirmation bias (Princeton University, 2014), our own mini-delusion in which we fool ourselves into believing a half-truth.  It looks right on first glance, and we can easily think of a few confirming examples, so without deeper inspection, we assume it must be true.

When Dr Leaf proclaims that,

“Science shows we are wired for love with a natural optimism bias”

the same process kicks in.  But in truth, science doesn’t show anything of the sort.  What science shows is that we learn love and fear, and our genetics influences the way we see the world, our personality.

We are prewired to LEARN to love and fear.  It doesn’t come naturally.  We require exposure to both love and to fear for these emotions to develop.  The Bucharest Early Intervention Project is a study looking at the long-term psychological and physical health of children in Bucharest, one group who remained in an orphanage, and the other, a group of children that were eventually adopted.  Analysis of the cohort of the two groups of children showed that negative affect was the same for both groups.  However positive affect and emotional reactivity was significantly reduced in the institutionalised children (Bos et al., 2011).  This shows that children who lived in an institution all of their lives and given limited emotional stimulation had lower levels of positive affect (ie: love, happiness) compared to a child that was adopted.

The children in the institution did not have high positive affect because they were not shown love.  Those children who were adopted were higher on positive affect because they were shown love by their adopted parents.  Both groups were exposed to distress and fear during their time in the orphanage, so their negative affect was the same across both groups.  Thus, love and fear don’t come naturally.  They need to be learned.

Personality is “the combination of characteristics or qualities that form an individuals distinctive character.” (“Oxford Dictionary of English – 3rd Edition,” 2010) As Professor Greg Henriques wrote in psychology today, “Personality traits are longstanding patterns of thoughts, feelings, and actions which tend to stabilize in adulthood and remain relatively fixed. There are five broad trait domains, one of which is labeled Neuroticism, and it generally corresponds to the sensitivity of the negative affect system, where a person high in Neuroticism is someone who is a worrier, easily upset, often down or irritable, and demonstrates high emotional reactivity to stress.” (Henriques, 2012) Personality is heavily influenced by genetics, with up to 60% of our personality pre-determined by our genes (Vinkhuyzen et al., 2012), expressed through the function of the serotonin and dopamine transporter systems in our brain (Caspi, Hariri, Holmes, Uher, & Moffitt, 2010; Chen et al., 2011; Felten, Montag, Markett, Walter, & Reuter, 2011).

So some people *ARE* natural optimists – their genetic heritage blessed them with a rosy outlook and their early life experiences cemented it in.  These naturally optimistic people, and the people who know them, are the ones who take Dr Leaf’s word as truth because they see it in themselves or their friends.  But the fact that some people are naturally wired for pessimism or a neurotic personality disproves Dr Leaf’s assertion.

Its important that Dr Leaf’s misleading meme is seen for what it is.  If we assume that we’re all pre-wired for love and optimism, then those who are pessimistic must be deficient or deviant, and the fact they can’t change must mean they are incompetent or lazy.  If we know the truth, those who are less optimistic won’t be unnecessarily judged or marginalised.

I should point out that what I’ve said isn’t a free licence to be cranky or sullen all the time.  The natural pessimist still needs to be able to negotiate their way through life, and being a misery-guts makes it hard to get what you need from other people in any business, social or interpersonal relationship.  We have the ability to learn, and the person with a neurotic personality can still learn ways of dealing with people in a positive way.

But if you naturally see the glass half-empty, don’t tell yourself that you’re abnormal, or that you aren’t good enough.  You are who you are.  Accept who you are, because while there are weaknesses inherent to having neurotic personality traits, there are also strengths, such as the enhanced awareness of deception, or protection from gullibility (Forgas & East, 2008).

A good thing to have when searching for the truth.

 References

Bos, K., Zeanah, C. H., Fox, N. A., Drury, S. S., McLaughlin, K. A., & Nelson, C. A. (2011). Psychiatric outcomes in young children with a history of institutionalization. Harv Rev Psychiatry, 19(1), 15-24. doi: 10.3109/10673229.2011.549773

Caspi, A., Hariri, A. R., Holmes, A., Uher, R., & Moffitt, T. E. (2010). Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am J Psychiatry, 167(5), 509-527. doi: 10.1176/appi.ajp.2010.09101452

Chen, C., Chen, C., Moyzis, R., Stern, H., He, Q., Li, H., . . . Dong, Q. (2011). Contributions of dopamine-related genes and environmental factors to highly sensitive personality: a multi-step neuronal system-level approach. PLoS One, 6(7), e21636. doi: 10.1371/journal.pone.0021636

Felten, A., Montag, C., Markett, S., Walter, N. T., & Reuter, M. (2011). Genetically determined dopamine availability predicts disposition for depression. Brain Behav, 1(2), 109-118. doi: 10.1002/brb3.20

Forgas, J. P., & East, R. (2008). On being happy and gullible: Mood effects on skepticism and the detection of deception. Journal of Experimental Social Psychology, 44, 1362-1367.

Henriques, G. (2012). (When) Are You Neurotic?  Retrieved from http://www.psychologytoday.com/blog/theory-knowledge/201211/when-are-you-neurotic

Oxford Dictionary of English – 3rd Edition. (2010)   (3rd edition ed.). Oxford, UK: Oxford University Press.

Princeton University. (2014). Confirmation bias.   Retrieved January 10, 2014, from http://www.princeton.edu/~achaney/tmve/wiki100k/docs/Confirmation_bias.html

Vinkhuyzen, A. A., Pedersen, N. L., Yang, J., Lee, S. H., Magnusson, P. K., Iacono, W. G., . . . Wray, N. R. (2012). Common SNPs explain some of the variation in the personality dimensions of neuroticism and extraversion. Transl Psychiatry, 2, e102. doi: 10.1038/tp.2012.27

Dr Caroline Leaf – Contradicted by the latest research

This is my most popular post by far.  I truly appreciate the support and interest in this post, but I’ve discovered and documented a lot more about Dr Leaf’s ministry in the last two years.  I welcome you to read this post, but if you’d like a more current review of the ministry of Dr Caroline Leaf, a new and improved version is here:
Dr Caroline Leaf – Still Contradicted by the Latest Evidence, Scripture & Herself

* * * * *

Mr Mac Leaf, the husband of Dr Caroline Leaf, kindly took the time to respond to my series of posts on the teachings of Dr Leaf at Kings Christian Centre, on the Gold Coast, Australia, earlier this month. As I had intended, and as Mr Leaf requested, I published his  reply, complete and unabridged (here).

This blog is my reply.  It is heavily researched and thoroughly referenced.  I think it’s fair to say that while Dr Leaf draws her conclusions from some scientific documents, there is more than enough research that contradicts her statements and opinions.  I have only listed a small fraction, and only on some of the points she raised.

In fairness, the fields of neurology and neuroscience are vast and rapidly expanding, and it is impossible for one person to cover all of the literature on every subject.  This applies to myself and Dr Leaf.  However, I believe that the information I have read, and referenced from the latest peer-reviewed scholarly works, do not support Dr Leaf’s fundamental premises.  If I am correct, then the strength and validity of Dr Leaf’s published works should be called into question.

As before, I welcome any reply or rebuttal that Dr Leaf wishes to make, which I will publish in full if she requests.  In the interests of healthy public debate, and encouraging people to make their own informed decisions on the teachings of Dr Leaf, any comments regarding the response of Mr Leaf, Dr Leaf or myself, are welcome provided they are constructive.

This is a bit of a lengthy read, but I hope it is worthwhile.

Dear Mr Leaf,

Thank you very much for taking the time out to reply to some of the points raised in my blog.  I am more than happy to publish your response, and to publish any response you wish to make public.

ON INFORMED DECISIONS

I published my blog posts to open up discussion on the statements made by Dr Leaf at the two meetings that I attended at Kings Christian Centre on the Gold Coast.  As you rightly point out, people should be able to make informed decisions.  A robust discussion provides the information required for people to make an informed choice.  Any contributions to this discussion from either yourself or Dr Leaf would be most welcome.

I apologise if you interpreted my blogs as judgemental, or if you believe there are any misunderstandings.  You may or may not have read my final two paragraphs from the third post, in which I acknowledged that I may have misunderstood where she was coming from, but that I would welcome her response.  If there were any misunderstandings, it is likely because Dr Leaf did not make any attempt to reference any of the statements she made on the day.  You may argue that she was speaking to a lay audience, and referencing is therefore not necessary.  However, I have been to many workshops for the lay public by university professors, who have extensively referenced their information during their presentations.  A lay audience does not preclude providing references.  Rather, it augments the speakers authority and demonstrates the depth of their knowledge on the subject at hand.

YOUR DEFENCE

It’s interesting that you feel the need to resort to defence by association, and Ad Hominem dismissal as your primary counter to the points I raised.

Can you clarify how attending the same university as Dr Christaan Barnard, or a Nobel laureate, endorses her arguments or precludes her from criticism?  I attended the University of Queensland where Professor Ian Frazer was based.  He developed the Human Papilloma Virus vaccine and was the 2006 Australian of the Year.  Does that association enhance my argument?

Can you also clarify why a reference from a colleague was preferred to letting Dr Leaf’s statements and conclusions speak for themselves?  Dr Amua-Quarshie’s CV is certainly very impressive, no doubt about that, although he doesn’t list the papers he’s published.  (I’m assuming that to hold the title of Adjunct Professor, he’s published peer-reviewed articles.  Is he willing to list them, for the record?)

Whatever his credentials, his endorsement means very little, since both Dr Leaf and Dr Amua-Quarshie would know from their experience in research that expert opinion is one of the lowest forms of evidence, second worst only to testimonials [1].  Further, both he and Dr Leaf are obviously close friends which introduces possible bias.  His endorsement is noteworthy, but it can not validate every statement made by Dr Leaf.  Her statements should stand up on their own through the rigors of critical analysis.

On the subject of evidence, disparaging your critics is not a substitute for answering their criticism.  Your statement, “By your comments it is obvious that you have not kept up to date with the latest Scientific research” is an assumption that is somewhat arrogant, and ironic since Dr Leaf is content to use superseded references dating back to 1979 to justify her current hypotheses.

DR LEAF’S EVIDENCE

In the blog to which you referred, Dr Leaf makes a number of statements that are intended to support her case.  These include the following.

“A study by the American Medical Association found that stress is a factor in 75% of all illnesses and diseases that people suffer from today.”  She fails to reference this study.

“The association between stress and disease is a colossal 85% (Dr Brian Luke Seaward).”   But again, she fails to reference the quote.

“The International Agency for Research on Cancer and the World Health Organization has concluded that 80% of cancers are due to lifestyles and are not genetic, and they say this is a conservative number (Cancer statistics and views of causes Science News Vol.115, No 2 (Jan.13 1979), p.23).”  It’s good that she provides a reference to her statement.  However, referencing a journal on genetics from 1979 is the equivalent of attempting to use the land-speed record from 1979 to justify your current preference of car.  The technology has advanced significantly, and genetic discoveries are lightyears ahead of where they were more than three decades ago.

“According to Dr Bruce Lipton (The Biology of Belief, 2008), gene disorders like Huntington’s chorea, beta thalassemia, cystic fibrosis, to name just a few, affect less than 2% of the population. This means the vast majority of the worlds population come into this world with genes that should enable the to live a happy and healthy life. He says a staggering 98% of diseases are lifestyle choices and therefore, thinking.”  Even if it’s true that Huntingtons, CF etc account for 2% of all illnesses, they account for only a tiny fraction of genetic disease.  And concluding that the remaining 98% must therefore be lifestyle related is overly simplistic.  It ignores the genetic influence on all other diseases, other congenital, and environmental causes of disease.  I will fully outline this point soon.

Similarly, “According to W.C Willett (balancing lifestyle and genomics research for disease prevention Science (296) p 695-698, 2002) only 5% of cancer and cardiovascular patients can attribute their disease to hereditary factors.”  Science is clear that genes play a significant role in the development of cardiovascular disease and most cancers, certainly greater than 5%.  Again, I will discuss this further soon.

“According to the American Institute of health, it has been estimated that 75 – 90% of all visits to primary care physicians are for stress related problems (http://www.stress.org/americas.htm). Some of the latest stress statistics causing illness as a result of toxic thinking can be found at: http://www.naturalwellnesscare.com/stress-statistics.html”  These websites not peer-reviewed, and both suffer from a blatant pro-stress bias.

You’ll also have to forgive my confusion, but Dr Leaf also wrote, “Dr H.F. Nijhout (Metaphors and the Role of Genes and Development, 1990) genes control biology and not the other way around.”  So is she saying that genes DO control development?

EVIDENCE CONTRADICTING DR LEAF

Influence Of Thought On Health

Dr Leaf has categorically stated that “75 to 98% of all illnesses are the result of our thought life” on a number of occasions.  She repeated the same statement in her most recent book so it is something she is confident in.  However, in order to be true, this fact must be consistent across the whole of humanity.

And yet, in a recent peer-reviewed publication, Mara et al state, “At any given time close to half of the urban populations of Africa, Asia, and Latin America have a disease associated with poor sanitation, hygiene, and water.” [2]  Bartram and Cairncross write that “While rarely discussed alongside the ‘big three’ attention-seekers of the international public health community—HIV/AIDS, tuberculosis, and malaria—one disease alone kills more young children each year than all three combined. It is diarrhoea, and the key to its control is hygiene, sanitation, and water.” [3]  Hunter et al state that, “diarrhoeal disease is the second most common contributor to the disease burden in developing countries (as measured by disability-adjusted life years [DALYs]), and poor-quality drinking water is an important risk factor for diarrhoea.” [4]

Toilets and clean running water have nothing to do with stress or thought.  We live in a society that essentially prevents more than half of our illnesses because of internal plumbing, with additional benefits from vaccination and population screening.  If thoughts have any effect on our health, they are artificially magnified by our clean water and sewerage systems.  Remove those factors and any effects of thought on our health disappear from significance.  Dr Leaf’s assertion that 75 to 98% of human illness is thought-related is a clear exaggeration.

Let me be clear – I understand the significance of stress on health and the economy, but it is not the cause of 75-98% of all illnesses.  I’m not sure if there is a similar study in the US, but the latest Australian data suggests that all psychological illness only counts for 8% of visits to Australian primary care physicians [5].

In terms of cancer, I don’t have time to exhaustively list every cancer but of the top four listed in the review “Cancer Statistics 2013” [6] , here are the articles that list the gene x environment interactions:

  1. PROSTATE – There are only two risk factors for prostate cancer, familial aggregation and ethnic origin. No dietary or environmental cause has yet been identified [7].  It is most likely caused by multiple genes at various loci [8].
  2. BREAST – Genes make up 25% of the risk factors for breast cancer, and significantly interacted with parity (number of children born) [9].
  3. LUNG/BRONCHUS – Lung cancer is almost exclusively linked to smoking, but nicotine addiction has a strong hereditary link (50-75% genetic susceptibility) [10].
  4. COLORECTUM – Approximately one third of colorectal cancer is genetically linked [11].

So the most common cancer is not linked to any environmental factors at all, and the others have genetic influences of 25% to more than 50%.  This is far from being 2% or 5% as Dr Leaf’s sources state.

Also in terms of heart disease, the INTERHEART trial [12] lists the following as significant risk factors, and I have listed the available gene x environment interaction studies that have been done on these too:

  1. HIGH CHOLESTEROL – Genetic susceptibility accounts for 40-60% of the risk for high cholesterol [13].
  2. DIABETES – Genetic factors account for 88% of the risk for type 1 diabetes [14].  There is a strong genetic component of the risk of type 2 diabetes with 62-70% being attributable to genetics [15, 16].
  3. SMOKING – nicotine addiction has a strong hereditary link (50-75% genetic susceptibility) [10].
  4. HYPERTENSION – While part of a much greater mix of variables, genetics are still thought to contribute between 30% and 50% to the risk of developing high blood pressure [17].

So again, while genes are a part of a complex system, it is clear from the most recent evidence that genetics account for about 50% of the risk for cardiovascular disease, which again is a marked difference between the figures that Dr Leaf is using to base her assertions on.

Atrial Natriuretic Peptide

I am aware of research that’s studied the anxiolytic properties of Atrial Natriuretic Peptide.  For example, Wiedemann et al [18] did a trial using ANP to truncate panic attacks.  However, these experiments were done on only nine subjects, and the panic attacks were induced by cholecystokinin.  As such, the numbers are too small to have any real meaning.  And the settling is completely artificial.  Just as CCK excretion does not cause us all to have panic attacks every time we eat, ANP does not provide anxiolysis in normal day to day situations.  Besides, if ANP were really effective at reducing anxiety, then why do people suffering from congestive cardiac failure, who have supraphysiological levels of circulating ANP [19] , also suffer from a higher rate of anxiety and panic disorders than the general population? [20]

The Heart As A Mini-Brain

As for Heartmath, they advance the notion of the heart being a mini-brain to give themselves credibility.  It’s really no different to an article that I read the other day from a group of gut researchers [21] – “‘The gut is really your second brain,’ Greenblatt said. ‘There are more neurons in the GI tract than anywhere else except the brain.’”  The heart as a mini-brain and the gut as a mini-brain are both figurative expressions.  Neither are meant to be taken literally.  I welcome Dr Leaf to tender any further evidence in support of her claim.

Hard-Wired For Optimism

As for being wired for optimism, the brain is likely pre-wired with a template for all actions and emotions, which is the theory of protoconsciousness [22].  Indeed, neonatal reflexes often reflect common motor patterns.  If this is true, then the brain is pre-wired for both optimism and love, but also fear.  This explains the broad role of the amygdala in emotional learning [23] including fear learning.  It also means that a neonate needs to develop both love and fear.

A recent paper showed that the corticosterone response required to learn fear is suppressed in the neonate to facilitate attachment, but with enough stress, the corticosterone levels build to the point where amygdala fear learning can commence [24].  The fear circuits are already present, only their development is suppressed.  Analysis of the cohort of children in the Bucharest Early Intervention Project showed that negative affect was the same for both groups.  However positive affect and emotional reactivity was significantly reduced in the institutionalised children [25].  If the brain is truly wired for optimism and only fear is learned, then positive emotional reactivity should be the same in both groups and the negative affect should be enhanced in the institutionalised cohort.  That the result is reversed confirms that neonates and infants require adequate stimulation of both fear and love pathways to grow into an emotionally robust child, because the brain is pre-wired for both but requires further stimulation for adequate development.

The Mind-Brain Link

If the mind controls the brain and not the other way around as Dr Leaf suggests, why do anti-depressant medications correct depression or anxiety disorders?  There is high-level evidence to show this to be true [26-28].  The same can be said for recent research to show that medications which enhance NDMA receptors have been shown to improve the extinction of fear in anxiety disorders such as panic disorder, OCD, Social Anxiety Disorder, and PTSD [29].

If the mind controls the brain and not the other way around as Dr Leaf suggests, why do some people with acquired brain injuries or brain tumours develop acute personality changes or thought disorders?  Dr Leaf has done PhD research on patients with closed head injuries and treated them in clinical settings according to her CV.  She must be familiar with this effect.

One can only conclude that there is a bi-directional effect between the brain and the stream of thought, which is at odds with Dr Leaf’s statement that the mind controls the brain and not the other way around.

FURTHER CLARIFICATION

One further thing.  Can you clarify which of Dr Leaf’s peer-reviewed articles have definitively shown the academic improvement in the cohort of 100,000 students, as you and your referee have stated?  And can you provide a list of articles which have cited Dr Leaf’s Geodesic Information Processing Model?  Google Scholar did not display any articles that had cited it, which must be an error on Google’s part.  If her theory is widely used as you say, it must have been extensively cited.

I understand that you are both busy, but I believe that I have documented a number of observations, backed by recent peer-reviewed scientific literature, which directly contradict Dr Leaf’s teaching.  I have not had a chance to touch on many, many other points of disagreement.

For the benefit of Dr Leaf’s followers, and for the scientific and Christian community at large, I would appreciate your response.

I would be grateful if you could respond to the points raised and the literature which supports it, rather than an Ad Hominem dismissal or further defense by association.

Dr C. Edward Pitt

REFERENCES

1. Fowler, G., Evidence-based practice: Tools and techniques. Systems, settings, people: Workforce development challenges for the alcohol and other drugs field, 2001: 93-107.

2. Mara, D., et al., Sanitation and health. PLoS Med, 2010. 7(11): e1000363.

3. Bartram, J. and Cairncross, S., Hygiene, sanitation, and water: forgotten foundations of health. PLoS Med, 2010. 7(11): e1000367.

4. Hunter, P.R., et al., Water supply and health. PLoS Med, 2010. 7(11): e1000361.

5. FMRC. Public BEACH data. 2010  16JUL13]; Available from: <http://sydney.edu.au/medicine/fmrc/beach/data-reports/public&gt;.

6. Siegel, R., et al., Cancer statistics, 2013. CA Cancer J Clin, 2013. 63(1): 11-30.

7. Cussenot, O. and Valeri, A., Heterogeneity in genetic susceptibility to prostate cancer. Eur J Intern Med, 2001. 12(1): 11-6.

8. Alberti, C., Hereditary/familial versus sporadic prostate cancer: few indisputable genetic differences and many similar clinicopathological features. Eur Rev Med Pharmacol Sci, 2010. 14(1): 31-41.

9. Nickels, S., et al., Evidence of gene-environment interactions between common breast cancer susceptibility loci and established environmental risk factors. PLoS Genet, 2013. 9(3): e1003284.

10. Berrettini, W.H. and Doyle, G.A., The CHRNA5-A3-B4 gene cluster in nicotine addiction. Mol Psychiatry, 2012. 17(9): 856-66.

11. Hutter, C.M., et al., Characterization of gene-environment interactions for colorectal cancer susceptibility loci. Cancer Res, 2012. 72(8): 2036-44.

12. Yusuf, S., et al., Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet, 2004. 364(9438): 937-52.

13. Asselbergs, F.W., et al., Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci. Am J Hum Genet, 2012. 91(5): 823-38.

14. Wu, Y.L., et al., Risk factors and primary prevention trials for type 1 diabetes. Int J Biol Sci, 2013. 9(7): 666-79.

15. Ali, O., Genetics of type 2 diabetes. World J Diabetes, 2013. 4(4): 114-23.

16. Murea, M., et al., Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications. Rev Diabet Stud, 2012. 9(1): 6-22.

17. Kunes, J. and Zicha, J., The interaction of genetic and environmental factors in the etiology of hypertension. Physiol Res, 2009. 58 Suppl 2: S33-41.

18. Wiedemann, K., et al., Anxiolyticlike effects of atrial natriuretic peptide on cholecystokinin tetrapeptide-induced panic attacks: preliminary findings. Arch Gen Psychiatry, 2001. 58(4): 371-7.

19. Ronco, C., Fluid overload : diagnosis and management. Contributions to nephrology,. 2010, Basel Switzerland ; New York: Karger. viii, 243 p.

20. Riegel, B., et al., State of the science: promoting self-care in persons with heart failure: a scientific statement from the American Heart Association. Circulation, 2009. 120(12): 1141-63.

21. Arnold, C. Gut feelings: the future of psychiatry may be inside your stomach. 2013  [cited 2013 Aug 22]; Available from: http://www.theverge.com/2013/8/21/4595712/gut-feelings-the-future-of-psychiatry-may-be-inside-your-stomach.

22. Hobson, J.A., REM sleep and dreaming: towards a theory of protoconsciousness. Nat Rev Neurosci, 2009. 10(11): 803-13.

23. Dalgleish, T., The emotional brain. Nat Rev Neurosci, 2004. 5(7): 583-9.

24. Landers, M.S. and Sullivan, R.M., The development and neurobiology of infant attachment and fear. Dev Neurosci, 2012. 34(2-3): 101-14.

25. Bos, K., et al., Psychiatric outcomes in young children with a history of institutionalization. Harv Rev Psychiatry, 2011. 19(1): 15-24.

26. Arroll, B., et al., Antidepressants versus placebo for depression in primary care. Cochrane Database Syst Rev, 2009(3): CD007954.

27. Soomro, G.M., et al., Selective serotonin re-uptake inhibitors (SSRIs) versus placebo for obsessive compulsive disorder (OCD). Cochrane Database Syst Rev, 2008(1): CD001765.

28. Kapczinski, F., et al., Antidepressants for generalized anxiety disorder. Cochrane Database Syst Rev, 2003(2): CD003592.

29. Davis, M., NMDA receptors and fear extinction: implications for cognitive behavioral therapy. Dialogues Clin Neurosci, 2011. 13(4): 463-74.