Stress can kill you and that’s no metaphor

85heart - CopyThe term ‘heartbreak’ is used as a metaphor to describe the intense feeling of loss, sometimes also called emotional pain. But what if the metaphor has roots into something more tangible than a feeling, that of the actual muscular organ giving signs of failure?

Although there have been previous reports that found stress causes cardiovascular problems, including myocardial infarction, Graff et al. (2016) conducted the largest study to date that investigated this link: they had almost 1 million subjects. That’s right, 1 million people (well, actually 974 732). Out of these, almost 20% of them had a partner who died between 1995 and 2014. The chosen stressor was the loss of a loved one because “the loss of a partner is considered one of the most severely stressful life events and is likely to affect most people, independently of coping mechanisms” (p. 1-2). The authors looked at Danish hospital records for people who were diagnosed with atrial fibrillation (AF) for the first time and correlated that data with bereavement information. AF increases the risk of death due to stroke or heart failure.

The people who underwent loss had an increased risk to develop AF for 1 year after the loss. The risk was more pronounced in the first 8-14 days after the loss, the bereaved people having a 90% higher risk of developing AF than non-bereaved people. By the end of the first month the risk had declined, but still was a whooping 41% higher than the average. Only 1 year after the loss the risk of developing AF was similar to that of non-bereaved people.

The risk was even higher in young people or if the death of the partner was unexpected. The authors also looked to see if other variables play a role in the risk, like gender, civil status, education, diabetes, or cardiovascular medication and none influenced the results.

I suspect the number of people that have heart problems after major stress is actually a lot higher because of the under-reporting bias. In other words, not everybody who feels their heart aching would go to the hospital, particularly in the first couple of weeks after losing a loved one.

As for the mechanism, there is some data pointing to some stress hormones (like adrenaline or cortisol) which can damage the heart. Other substances released in abundance during stress and likely to act in concert with the stress hormones are proinflamatory cytokines which also can lead to arrhythmias.

Reference: Graff S, Fenger-Grøn M, Christensen B, Søndergaard Pedersen H, Christensen J, Li J, & Vestergaard M (2016). Long-term risk of atrial fibrillation after the death of a partner. Open Heart, 3: e000367. doi:10.1136/openhrt-2015-000367. Article  | FREE FULTEXT PDF

By Neuronicus, 16 April 2016

Advertisements

Mechanisms of stress resilience

71 stress - CopyLast year a new peer-reviewed journal called Neurobiology of Stress made its debut. The journal is published by Elsevier, who, in an uncharacteristic move, has provided Open Access for its first three issues. So hurry up and download the papers.

The very first issue is centered around the idea of resilience. That is, exposed to the same stressors, some people are more likely to develop stress-induced diseases, whereas others seem to be immune to the serious effects of stress.

Much research has been carried out to uncover the effects of chronic stress or of an exposure to a single severe stressor, which vary from cardiovascular disorders, obesity, irritable bowel syndrome, immune system dysfunctions to posttraumatic stress disorder, generalized anxiety, specific phobias, or depression. By comparison, there is little, but significant data on resilience: the ability to NOT develop those nasty stress-induced disorders. Without doubt, one reason for this scarcity is the difficulty in finding such rare subjects in our extremely stressful society. Therefore most of the papers in this issue focus on animal models.

Nevertheless, there is enough data on resilience to lead to no less that twenty reviews on the subject. It was difficult to choose one as most are very interesting, tackling various aspects of resilience, from sex differences to prenatal exposure to stress, from epigenetic to neurochemical modifications, from social inequalities to neurogenesis and so on.

So I chose for today a more general review of Pfau & Russo (2015), entitled “Peripheral and central mechanisms of stress resilience”. After it introduces the reader to four animal models of resilience, the paper looks at the neruoendocrine responses to stress and identifies some possible chemical mediators of resilience (like certain hormones), then at the immune responses to stress (bad, bad cytokines), and finally at the brain responses to stress (surprisingly, not focusing on amygdala, hypothalamus or hippocampus, but on the dopamine system originating from ventral tegmental area).

I catalogue the review as a medium difficulty read because it requires a certain amount of knowledge of the stress field beforehand. But do check out the other ones in the issue, too!

Reference: Pfau ML & Russo SJ (1 Jan 2015). Peripheral and central mechanisms of stress resilience. Neurobiology of Stress, 1:66-79. PMID: 25506605, PMCID: PMC4260357, DOI: 10.1016/j.ynstr.2014.09.004. Article | FREE FULLTEXT PDF

By Neuronicus, 24 January 2016

Terrorist attacks increase the male fetal loss

effelThe odds of having a baby boy decreases after terrorist attacks, natural or man-made disasters, or economical depression. There are several studies worldwide that support this finding. This is somewhat counter-intuitive, because there are anecdotal accounts that report an increase in male births after a war, presumably to make up for the lost men.

Bruckner et al. (2010) wanted to see if this decrease in the odds of a male births, also called the secondary sex ratio, is due to a failure to conceive male babies or the male fetuses die in the womb before birth. They looked at the public databases from 1996-2002 fetal deaths and births from the U.S. National Center for Health Statistics.

The results showed that in the months following the September 11, 2001 terrorist attacks the deaths of male fetuses older that 20 weeks increased significantly. The authors make reference to the communal bereavement hypothesis, which stipulates that stress increases in persons not directly affected by a tragedy. Although the effects of stress on pregnant females is well documented, why the male fetuses seem to be more susceptible to mother’s stress is unknown.

I chose to feature this paper because of the recent Paris atrocities.

Reference: Bruckner TA, Catalano R, & Ahern J. (25 May 2010). Male fetal loss in the U.S. following the terrorist attacks of September 11, 2001. BMC Public Health.;10:273. doi: 10.1186/1471-2458-10-273. Article | FREE FULLTEXT PDF

By Neuronicus, 15 November 2015

The F in memory

"Figure 2. Ephs and ephrins mediate molecular events that may be involved in memory formation. Evidence shows that memory formation involves alterations of presynaptic neurotransmitter release, activation of glutamate receptors, and neuronal morphogenesis. Eph receptors regulate synaptic transmission by regulating synaptic release, glutamate reuptake from the synapse (via astrocytes), and glutamate receptor conductance and trafficking. Ephs and ephrins also regulate neuronal morphogenesis of axons and dendritic spines through controlling the actin cytoskeleton structure and dynamics" (Dines & Lamprecht, 2015, p. 3).
“Figure 2. Ephs and ephrins mediate molecular events that may be involved in memory formation. Evidence shows that memory formation involves alterations of presynaptic neurotransmitter release, activation of glutamate receptors, and neuronal morphogenesis. Eph receptors regulate synaptic transmission by regulating synaptic release, glutamate reuptake from the synapse (via astrocytes), and glutamate receptor conductance and trafficking. Ephs and ephrins also regulate neuronal morphogenesis of axons and dendritic spines through controlling the actin cytoskeleton structure and dynamics” (Dines & Lamprecht, 2015, p. 3).

When thinking about long-term memory formation, most people immediately picture glutamate synapses. Dines & Lamprecht (2015) review the role of a family of little known players, but with big roles in learning and long-term memory consolidation: the ephs and the ephrines.

Ephs (the name comes from erythropoietin-producing human hepatocellular, the cancer line from which the first member was isolated) are transmembranal tyrosine kinase receptors. Ephrines (Eph receptor interacting protein) bind to them. Ephrines are also membrane-bound proteins, which means that in order for the aforementioned binding to happen, cells must touch each other, or at least be in a very very cozy vicinity. They are expressed in many regions of the brain like hippocampus, amygdala, or cortex.

The authors show that “interruption of Ephs/ephrins mediated functions is sufficient for disruption of memory formation” (p. 7) by reviewing a great deal of genetic, pharmacologic, and electrophysiological studies employing a variety of behavioral tasks, from spatial memory to fear conditioning. The final sections of the review focus on the involvement of ephs/ephrins in Alzheimer’s and anxiety disorders, suggesting that drugs that reverse the impairment on eph/ephrin signaling in these brain diseases may lead to an eventual cure.

Reference: Dines M & Lamprecht R (8 Oct 2015, Epub 13 Sept 2015). The Role of Ephs and Ephrins in Memory Formation. International Journal of Neuropsychopharmacology, 1-14. doi:10.1093/ijnp/pyv106. Article | FREE FULLTEXT PDF

By Neuronicus, 26 October 2015

Cell phones give you hallucinations

A young businessman in a suit screaming at a cell phone. By: Benjamin Miller. License FSP Standard FreeStockPhotos.biz
Photo by Benjamin Miller. License: FSP Standard FreeStockPhotos.biz

Medical doctors (MD) are overworked, particularly when they are hatchlings (i.e. Medical School students) and fledglings (interns and residents). So overworked, that in many countries is routine to have 80-hour weeks and 30-hour shifts as residents and interns. This is a concern as it has been shown that sleep deprivation impairs learning (which is the whole point of residency) and increases the number of medical mistakes (the lack of which is the whole point of their profession).

Lin et al. (2013) show that it can do more than that. Couple internship and cell phones and you get… hallucinations. That’s right. The authors asked 73 medical interns to complete some tests before their internship, then every third, sixth, and twelfth months of their internship, and after the internship. The questionnaires were on anxiety, depression, personality, and cell phone habits and hallucinations. That is: the sensation that your cell phone is vibrating or ringing when, in fact, it is not (which fully corresponds to the definition of hallucination). And here is what they found:

 Before internship, 78% of MDs experienced phantom vibration and 27% experienced phantom ringing.
 During their 1-year internship, about 85 to 95% of MDs experienced phantom vibration and phantom ringing.
 After the internship when the MDs did no work for two weeks, 50% still had these hallucinations.

Composite figure from Lin et al. (2015) showing the interns' depression (above) and anxiety (below) scores before, during, and after internship. The differences are statistically significant.
Fig. 1. Composite figure from Lin et al. (2015) showing the interns’ depression (above) and anxiety (below) scores before, during, and after internship. The differences are statistically significant.

The MDs’ depression and anxiety were also elevated more during the internship than before or after (see Fig. 1), but there was no correlation between the hallucinations and the depression and anxiety scores.

These findings are disturbing on so many levels… Should we be worried that prolonged exposure to cell phones can produce hallucinations? Or that o good portion of the MDs have hallucinations before going to internship? Or that 90% the people in charge with your life or your child’s life are so overworked that are hallucinating on a regular basis? Fine, fine, believing that your phone is ringing or vibrating may not be such a big deal of a hallucination, compared with, let’s say, “the voices told me to give you a lethal dose of morphine”, but as a neuroscientist I beg the question: is there a common mechanism between these two types of hallucinations and, if so, what ELSE is the MD hallucinating about while reassuring you that your CAT scan is normal? Or, forget about the hallucinations, should we worry that your MD is probably more depressed and anxious than you? Or, the “good” news, that the medical interns provide “a model of stress-induced psychotic symptoms” better that previous models, as the authors put it (p. 5)? I really wish there was more research on positive things (… that was a pun; hallucinations are a positive schizophrenic symptom, look it up 🙂 ).

Reference: Lin YH, Lin SH, Li P, Huang WL, & Chen CY. (10 June 2013). Prevalent hallucinations during medical internships: phantom vibration and ringing syndromes. PLoS One, 8(6): e65152. doi: 10.1371/journal.pone.0065152. Article | FREE PDF | First time the phenomenon was documented in press

By Neuronicus, 14 October 2015

Stressed out? Blame your amygdalae

amygdala
Clipart: Royalty free from http://www.cliparthut.com. Text: Neuronicus.

Sooner or later, everyone is exposed to high amounts of stress, whether it is in the form losing someone dear, financial insecurity, or health problems and so on. Most of us manage to bounce right up and continue with our lives, but there is a considerable segment of the population who do not and develop all sorts of problems, from autoimmune disorders to severe depression and anxiety. What makes those people more susceptible to stress? And, more importantly, can we do something about it (yeah, besides making the world a less stressful place)?

Swartz et al. (2015) scanned the brain of 753 healthy young adults (18-22 yrs) while performing a widely used paradigm that elicits amygdalar activation (brain structure, see pic): the subjects had to match a face appearing in the upper part of the screen with one of the faces in the lower part of the screen. The faces looked fearful, angry, surprised, or neutral and amygdalae are robustly activated when matching the fearful face. Then the authors had the participants fill out questionnaires regarding their life events and perceived stress level every 3 months over a period of 2 years (they say 4 years everywhere else in the paper minus Methods & Results, which are the sections that count if one wants to replicate; maybe this is only half of the study and they intend to follow-up to 4 years?).

The higher your baseline amygdalar activation, the higher the risk to develop anxiety disorders later on if expossed to life stressors. Yellow = amygdala. Photo credit: https://www.youtube.com/watch?v=JD44PbAOTy8, presumably copyrighted to Duke University.
The higher your baseline amygdalar activation, the higher the risk to develop anxiety disorders later on if expossed to life stressors. Yellow = amygdala. Photo credit: https://www.youtube.com/watch?v=JD44PbAOTy8, presumably copyrighted to Duke University.

The finding of the study is this: baseline amygdalar activation can predict who will develop anxiety later on. In other words, if your natural, healthy, non-stressed self has a an overactive amygdala, you will develop some anxiety disorder later on if exposed to stressors (and who isn’t?). The good news is that knowing this, the owner of the super-sensitive amygdalae, even if s/he may not be able to protect her/himself from stressors, at least can engage in some preventative therapy or counseling to be better equipped with adaptive coping mechanisms when the bad things come. Probably we could all benefit from being “better equipped with adaptive coping mechanisms”, feisty amygdalae or not. Oh, well…

Reference: Swartz, J.R., Knodt, A.R., Radtke, S.R., & Hariri, A.R. (2015). A neural biomarker of psychological vulnerability to future life stress. Neuron, 85, 505-511. doi: 10.1016/j.neuron.2014.12.055. Article | PDF | Video

By Neuronicus, 12 October 2015

Stress can get you fat. And then kill you.

stress meSome people lose weight under stressful conditions and some gain weight. How does that play into the risk for the cardiovascular disease and subsequent mortality? Medical doctors keep warning us that fat people are at risk for diabetes and heart disease. Turns out that being a little on the heavy side might actually not be that bad. It all depends on what kind of fat and where it is.

The paper featured today reviews a series of interesting articles with surprising results. Peters & McEwen (2015) identify three distinct phenotypes:

1) The good stress leads to well-proportionate body shape. People who live in safe environments, they do well socioeconomically, they have good self-esteem, and they have a fulfilling social and family life. They experience low levels of stress, they are well proportionate, and have a low mortality rate due to cardiovascular disease. Might as well call these ones the lucky ones.

2) The tolerable stress leads to corpulent-but-narrow-waisted body shape. People who experience stress but in order to cope with it they supply the brain with more energy by eating more. So they become more corpulent, gaining subcutaneous fat, but their cardiovascular mortality risk remains low.

3) The toxic stress leads to lean-but-wide-waisted body shape. People who experience prolonged stress exposure to uncertain socioeconomic conditions, poor work, or family life. They have low self-esteem, often associated with depressive periods. They are or become lean, but they accumulate large visceral fat deposits (as opposed to subcutaneous), and their cardiovascular mortality risk is the highest. They also are at risk for other physical and mental disorders. The phenotype 3 people have a wider waist relative to their body mass index and height.

Source: Peters & McEwen (2015, p.144)
Source: Peters & McEwen (2015, p.144)

Thus, the authors propose that instead or along with the body mass index, another metric should be used to identify the ones in dire need of help: the body shape index. Also, the review outlines the mechanisms responsible for these findings.

So next time you see a not so well-proportionate person, smile. Maybe even offer to help or chat; you don’t know what they’re going through.

Reference: Peters, A. & McEwen, B. S. (September 2015, Epub 3 July 2015). Stress habituation, body shape and cardiovascular mortality. Neuroscience Biobehavioral Reviews, 56:139-50. doi: 10.1016/j.neubiorev.2015.07.001. Article | FREE PDF

By Neuronicus, 5 October 2015