Neural Network Modulation by Trauma as a Marker of Resilience

Differences Between Veterans With Posttraumatic Stress Disorder and Resilient Controls

Lisa M. James, PhD; Brian E. Engdahl, PhD; Art C. Leuthold, PhD; Scott M. Lewis, MD, PhD; Emily Van Kampen, MS; Apostolos P. Georgopoulos, MD, PhD

Thanks Imran! A very interesting paper.

Maybe this review might be of interest for you:

Pitman et al (2012) Biological studies of post-traumatic stress disorder. Nat Rev Neurosci.

The relationship between inflammation and PTSD is a complex one, but we aren't yet at the point where we understand it well. One issue with CRP is its role in the innate immune system. The presence of an acute injury or infection, moderate to severe alcohol use disorder, depression, type II diabetes, or nicotine each are reported to increase CRP levels. That's tough to control in a clinical study.

On the other hand, elevated CRP levels are associated with obesity and cardiovascular disease, and PTSD has a known independent association with the presence and severity of cardiovascular disease (see, for example, Levine et al, Cardiology 2014;127:1-19 among others). But I don't think we know the specific pathophysiologic mechanisms that link PTSD to inflammation.

CRP is widely examined in a number of different medical conditions and that makes it an attractive molecule for a biomarker. Most likely, a good biomarker will be one that is slightly 'upstream' from CRP or a biomarker that is more specific to psychiatric illness.

Barry, new to this forum. This may provide a backbone, the inflammation hypothesis is very appealing. At the last annual meeting of the International Society of Psychoneuroendocrinology there was new research on this, see www.ispne.org. More will be coming out soon I guess.

I have been following the inflammation markers in a combined combat PTSD-primary care clinic. High CRPs are present in a significant minority but would not qualify clinically as a marker. They are also present in refractory depression so non-specific. Flattened diurnal variation of cortisol is a rather robust finding but not of great clinical use. I have found PRA/aldosterone ratios consistent with hyperreninemic hypoaldosteronism in a subtype of combat PTSD. Again, this is not consistent in the population but does appear to be associated with significant medical co-morbidity in the population. This population also is more likely to have positive inflammatory markers which would be consistent with an allostatic overload model of PTSD.

increased blood flow to the amygdala has been found to differentiate people with PTSD but like so many biological markers, it could not b e used to differentiate individual patients from normals. the diagnosis is essential a clinical one, and overlaps with anxiety disorders. the key feature is the experience of flashbacks, or reliving the event as if it was happening again in the hear and now.

See at http://alert.psychiatricnews.org/2014/02/study-finds-gene-methylation-marker-of.html

I have been looking for correlations between the shortened MAO-A genotype and PTSD. I have found a few things, but nothing directly researching the MAO-A genotype and PTSD.

This might be a good start:

"Classical twin designs can decompose genetic and environmental sources of variance. Such studies are reviewed extensively elsewhere, and we cover them only briefly in this review. Instead, we focus primarily on the identical co-twin control design. This design makes it possible to resolve the "chicken-egg" dilemma inherent in standard case-control designs, namely, distinguishing risk from sequelae."

"Abnormalities that are present in both the twin with PTSD and the unaffected co-twin suggest pre-existing vulnerability indicators. These include smaller hippocampal volume, large cavum septum pellucidum, more neurological soft signs, lower general intellectual ability, and poorer performance in the specific cognitive abilities of executive function, attention, declarative memory, and processing of contextual cues. In contrast, abnormalities in a twin with PTSD that are not present in the identical co-twin suggest consequences of PTSD or trauma exposure. These include psychophysiological responding, higher resting anterior cingulate metabolism, event-related potential abnormalities associated with attentional processes, recall intrusions, and possibly some types of chronic pain."

Kremen et al. (2012). Twin studies of posttraumatic stress disorder: differentiating vulnerability factors from sequelae. Neuropharmacology, 62, 647-653.

http://www.ncbi.nlm.nih.gov/pubmed/21443892

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3153636/pdf/nihms285297.pdf

There are clearly typical neural activation patterns in response to a variety of stimuli. In our work with mothers who suffer from interpersonal violence-related PTSD and their young children, we have published on such patterns and cite the many nice articles by Pittman, Shin, Rauch, Lanius and others who have defining this territory for the past decade or more. I also include our paper on autonomic nervous system. Our publications:

Moser DA, Aue T, Wang Z, Rusconi-Serpa S, Favez N., Peterson BS, Schechter DS (epub; 2014). Comorbid dissociation dampens limbic activation in violence-exposed mothers with PTSD who are exposed to video-clips of their child during separation. Stress.

Schechter DS, Moser DA, McCaw JE, Myers MM (epub 11.06.2013). Autonomic functioning in mothers with interpersonal violence-exposure related posttraumatic stress disorder in response to the stressor of separation-reunion. Developmental Psychobiology.

Schechter DS, Moser D, Wang Z, Marsh R, Hao XJ, Duan Y, Yu S, Gunter B, Murphy D, McCaw J, Kangarlu A, Willheim E, Myers M, Hofer M, Peterson BS (2012 epub 22.10.11). An fMRI study of the brain responses of traumatized mothers to viewing their toddlers during separation and play. Journal of Social, Cognitive and Affective Neuroscience, 7(8),969-79.

I seem to remember a dissertation by Thomas Rinne (NL) in which he found two subtypes of Borderline Personality Disorder: one with biological PTSD markers and one without.

Please see the paper of Zoladz PR et al. Current status on behavioral and biological markers of PTSD: a search for clarity in a conflicting literature.

http://www.ncbi.nlm.nih.gov/pubmed/23567521

There are a lot of physiological and even anatomic findings that "go with" PTSD but they are mostly not exclusive to PTSD. So extremely high levels of cortisol and other stress chemicals, exaggerated stress responses to future stressors, decreased hippocampal volume can be seen as common findings among people with apparent PTSD... but some of these things can be found in other people who don't have PTSD and some people with lots of apparent PTSD don't exhibit a lot of these findings.

Thanks Dick. As the great range of answers show the research is full of confounding variables which is why I asked the question. I watched a film from the end of WW1 in which a young soldier was shown with vivid neurological symptoms (Private Eagerfield (War Hyperthyroidism and Hyperadrenalism) (General Adaptational Syndrome). Eagerfield's facial expression indicates von Graefe's syndrome (immobility of the upper eyelid and downward rotation of the eye) This extreme reaction to psychiatric trauma is of interest and must somewhere have a biological factor and extreme levels of cortisol looks like the prime suspect. Obviously many other factors are at play here and it might be impossible to ever pin down any particular causes.

I see there are several paper which are mentioned above. As a sleep physician I know that these patients have increased REM density and decreased REM latency. Contrary to common sense, these patients have increased arousal threshold.

Imram, could the increased arousal threshold be due to the state of hypervigelence. characteristic of PTSD?

So here we go in a nutshell without me forwarding you to any articles because you can find those by a simple Google scholar search; and, I need to finish some other work with a deadline. Apologize for that.

We all know I'm assuming, that PTSD can result from years of repressed or regressed memories that are normally hidden away in the brains of children and adults, traumas being given life by therapy that was intended to deal with other issues, incessantly re-experiencing an event or the events that initially resulted in the changes in neural and chemical responses of the brain to potential and current stimuli believed to be similar, or could be linked to the trauma, and other environmental and psychological factors that could be, but may not necessarily be related, but trigger a response from the brain just constantly being in a state of hyper-vigilance, etc........

The thing with PTSD is that it is almost like having a guard on watch who is constantly looking to avoid situations that brings about known stimuli that will result in the individual going into a panic. The same can be said about our war zones heroes, sexual abuse victims, and the constant fears that are associated with numerous traumas experienced over a period of time. It is my belief that the totality of the traumatic experiences will ultimately determine the extent of the PTSD and whether other comorbid disorders will surface, like Borderline Personality Disorder, GERD, etc.

Noteworthy is the fact that there are in fact biological markers with just about any disorder that depletes an individual to the point of a lower functioning, and that is utterly disruptive to their lives, affecting social and personal relationships to the point that they cannot even hold down a job or personal relationships for any period of time without a support system. if you know what to look for and where to look, PTSD would be showing biological markers like any of the disorders that can be considered disorders from a medical standpoint. However, the problem that I think many run into, and that causes so many challenges to those who have the disorder, and those who are trying to understand it, is which marker/s ultimately apply to what disorder foreseen or undiagnosed, since PTSD is typically present with other comorbid disorder/s. Additionally, PTSD has resulted in individuals actually having other comorbid disorders, so which is responsible for any biological markers associated with PTSD and that has been identified (the comorbid disorder or PTSD?). So, in essence, there are biological markers. The real conundrum is pinpointing it or them, and not confusing it with other psychological disorders that have similar markers. Well, I am turning this into a book, so need to run. I am already hurting for time on my current project.

For more insight into the PTSD - inflammation relationship, look at the literature on sleep disturbances and inflammation. VanCauter et al (2009) reported insomnia is associated with reduced slow wave sleep (Stage 3-4 NREM sleep), endocrine changes that stimulate daytime appetite, weight gain, and insulin resistance. Polysomnogram data show reduced slow wave sleep in subjects with PTSD (Kobayashi 2007). We know greater appetite, weight gain, and insulin resistance are all characteristic of the metabolic syndrome, and the metabolic syndrome is a risk for cardiovascular disease.

The Heart and Soul Study showed PTSD associated with worse cardiovascular health (Cohen 2009).

On the other hand, Turner et al (2013) found PTSD was an independent risk for cardiovascular disease independent of sleep problems or CRP level, so perhaps the story isn't as simple as we might think. One possible explanation is the difference between insomnia symptoms and non-restorative sleep found by Zhang et al (2013).

We are looking at BDNF levels in saliva (see link) following up from Zhang's previous work.

Also lupus markers have been associted with chronic PTSD due to the infammation from the ongoing stress response

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935252/

PS Also this is a useful bibilography: http://www.nature-nurture.org/index.php/chronic-stress/chronic-stress-human/histories-autoimmune/

I saw a study that showed the actual stem cells in the hippocampus that were permanently changed with stress in young rats, I assume.  I am spitballing here but believe the brain science is pretty well understood based on childhood trauma - the biggest cause of PTSD, by far.

My understanding is that childhood trauma, neglect being the worst, is the best predictor of all adult illnesses.  Google the ACES study and "trauma-informed care."

Elevated adrenaline or cortisol may be evidence that someone is suffering PTSD (or under chronic stress) but are probably best seen as a result of the disorder, (or of a chronically stressful environment) not as causal factors for PTSD.

In some life circumstances, (eg combat soldier, refugee from warzone, living as a victim of child abuse or domestic violence) the symptoms we call PTSD are perhaps best viewed as functional adaptions to the environment. I'd suggest that there are some life circumstances in which you want to sleep lightly, be hyper-vigilant, suspicious of the motives of others, etc. It is only a disorder if these behaviours persist when you are no longer in that environment.

As I believe has been mentioned above, there is a polymorphism in the serotonin transporter gene (locus, SLC6A4 ; variant, serotonin 5-HTTLPR) which affects vulnerability to PTSD.

People with one or two short alleles of the transporter gene are more likely to develop symptoms of PTSD after exposure to traumatic life events than people with 2 long alleles of the gene. People with one or two of the short versions are also less responsive to CBT or to pharmaceutical treatment of PTSD than people with two long versions.

 So, the short alleles of this gene are a biomarker for vulnerability to PTSD, but it is VERY important to stress that they are neither sufficient nor necessary to cause PTSD, (ie you need to be exposed to the right sort of stressors whether you possess the shorter alleles or not in order to develop PTSD; and people without the shorter variants may still develop such symptoms if they are subjected to sufficiently traumatic  life-stressors).

This is clearly a gene-environment reaction. Anyone can develop PTSD, but some of us are far more vulnerable.

Genes are potential, not destiny. We are all phenotypic expressions of our genetic potentials being unfolded within complex and fluid physical and social environments. Jared Diamond coined the phrase "nature via nurture" (as opposed to "nature versus nurture") to describe this dynamic complexity.

Serotonin transporter poly-morphisms, social supports, and liability to PTSD ;

DOI: 10.1176/appi.ajp.2007.06122007

http://ajp.psychiatryonline.org/doi/abs/10.1176/appi.ajp.2007.06122007

Serotonin transporter poly-morphism and response to CBT;

http://dx.doi.org/10.1016/j.biopsych.2010.03.016

http://www.sciencedirect.com/science/article/pii/S0006322310002453

Adding to the importance of considering the environment are studies like this one;

>

doi: 10.1093/aje/kwn397

http://aje.oxfordjournals.org/content/early/2009/02/19/aje.kwn397.full

Good concise discussion of short allele, PTSD, Panic Disorder, and response to pharmacological treatments, here;

http://www.psycheducation.org/mechanism/2OtherShortsEffects.htm#PTSD

2 x short allele, 1 x short allele, 2 x long allele and liability to depression and other problems;

http://www.psycheducation.org/mechanism/1MoralityorGenes.htm#sobo

Regards,

Paul.

My understanding is that early childhood trauma permanently over-regulates the HPA axis.  Of course, this is dependent on inherited genetic factors.

There is also evidence of hippocampus and amygdala hypergrowth - believe connections to PFC are shrunk as well.  These are all empirical questions and pretty well studied.

My understanding is also that the damage is mainly done by age 4.

Not sure why arousal threshold is increased. REM sleep is more dense with more REM and more rapid eye movements in PTSD patients. Sleep is fragmented.

As others have mentioned, there are genetic polymorphisms that can make one more vulnerable to PTSD, but you don't necessarily need to have these differences to develop PTSD.

Here's how I wrap my head around this type of genetic/environment interaction situation. Stay with me, I swear I'll connect it :). Wine. Grapes are the best fruit to make wine with; the natural properties of grapes allow the fruit to create wine without any additives during the fermentation process. However, wine can be made without grapes... it can be made with all sorts of fruit and even rice, but these materials are not as easily converted into wine and require special additives and/or processes during fermentation.

In this illustration, wine is PTSD; grapes are the serotonin transporter genes with one or two shorter alleles. The other types of fruit and the rice are the genes with the long alleles, they can make wine (develop PTSD) but it's easier with the grapes (shorter alleles). That being said, just because you have grapes (short alleles) doesn't necessarily mean you are going to make wine (develop PTSD), you could always have a nice fruit salad. :)

Candace

I very much appreciate the analogy.  I may use that when trying to explain these things to my students, thank you!

I saw a study of Danish soldiers who got PTSD behavioral symptoms from war also having had childhood trauma.  The correlation was very high.

I have frequently found the arguments for nurture thinly disguised arguments against the medical, deterministic facts of inherited genetic disorders.  This seems a cultural belief and not medically fact based.

Regardless of the model, the cellular mechanisms need to be specified and all cellular mechanisms are caused by genes.

Barry,

That would be so cool!  If you use it, please let me know how it goes :).  Creating analogies and metaphors to explain (in a simple way) complex ideas is a random thing I like doing and I'm glad it might prove useful!  

After going through all the responses, I wonder if there exists ONE unique "PTSD-specific" biomarker. It appears like PTSD is a result of various mechanisms and expressions of  various genes, wherein each PTSD case is probably due to a different combination of these mechanisms/gene expressions. If this is indeed the case, identifying ALL the key mechanisms/genes (and associated biomarkers) would just be the first step. What is going to be more important is to identify which combinations of these result in PTSD symptoms. It is a challenging, yet interesting, problem. 

I like where Sridhar is coming from in more senses than one. It has seemed to me, for a long time, that we will need some very sophisticated computer programmes to understand the chemical relationships involved in PTSD and the other stressor-related disorders. The response to stress, like infection, is one of the two oldest responses to the challenges of living. Since the lead players, catecholamines and corticosteroids, are not markers and a yet to be determined number of other chemicals are involved, the relationships between them is what has to be demonstrated. The possibility of a single marker becomes daily more remote.

 While the response in vertebrates is remarkably conserved it is the essence rather than the detail and great variability is to be expected. Feed back loops are a start but we should expect wheels within wheels within wheels. It is certainly an interesting and challenging problem - inviting the concern of a range of disciplines.

It's a bit of a leap but, if i were funding the work, I would look at problems with the g-protein neuronal receptors.   Someone mentioned this happening in childhood.

You all know that childhood abuse/trauma is the cause of like 80% of PTSD, right?

I recommend that an article published to the Web on Thursday in Lancet Neurology by a team led by Daniel Perl and Sharon Baughman Shively. It is a post-mortem study that links TBI and (by implication) PTSD to scarring of astrocytes in various brain sites (e.g., gray matter-white matter boundaries, hypothalamus, etc.).

Not sure TBI and PTSD are related.  Any research on that model?

Elmer, the Shively-Perl study is relevant. Another study found considerable co-morbidity involving TBI and PTSD (Tanielian, T., & Jaycox, L. H. (2008). A comprehensive study of the post-deployment health-related needs associated with post-traumatic stress disorder, major depression, and traumatic brain injury among service members returning from Operations Enduring Freedom and Iraqi Freedom. Santa Monica, CA: Rand.).

Ok,but most PTSD comes from childhood trauma and car accidents, by far.  Where is there evidence of TBI from say childhood trauma, most of which is from neglect.  

Nice paper, but am I missing evidence of TBI and say, childhood trauma?  There was also a recent paper, forget the cite, suggesting non-deployed soilders suffered more PTSD, questioning the relationship between TBI and PTSD, even in soldiers..

Couple of interesting ints of new ideas:  

"Cognitive impairments associated with posttraumatic stress disorder (PTSD)

J. J. Vasterling · J. A. Alvarez"

"Heart rate variability in patients with post-traumatic stress disorder or borderline personality disorder: relationship to early life maltreatment

Traumatic experiences have severe impact on the autonomous nervous system. Heart rate variability (HRV) is a reliable psychophysiological marker for the autonomous nervous system functioning. Reduced vagally mediated HRV has been found in patients with post-traumatic stress disorder (PTSD) and, in some studies, in patients with borderline personality disorder (BPD). In this study, we compared HRV parameters of patients with PTSD, current BPD, and BPD in remission with healthy volunteers in a 5 min resting-state electrocardiogram recording. 91 unmedicated female participants took part in the study (18 with PTSD, 27 with the current BPD, 23 with BPD in remission, and 23 healthy volunteers). We found significant group differences in both time-domain and frequency-domain (total power, low-frequency and high-frequency power) HRV parameters. Root mean square of the successive differences (RMSSD) was lowest in patients with PTSD (M = 48.6 ms, SD = 23.5 ms) followed by patients with BPD in remission (M = 57.7 ms, SD = 31.5 ms) and patients with the current BPD (M = 71.1 ms, SD = 44.5 ms), while the highest RMSSD was found in healthy volunteers (M = 84.1 ms, SD = 41.7 ms). Variance of HRV was higher in patients with BPD than in patients with PTSD. In addition, RMSSD was significantly negatively correlated with self-reported early life maltreatment assessed with the Childhood Trauma Questionnaire. Our findings point out a complex interaction between traumatic experiences, the functioning of the autonomic nervous system, and psychopathology. Alterations in HRV might be related to early life maltreatment or associated psychological factors rather than diagnostic entities"

I am hearing that the HRV is a robust measure...but bit obscure currently, also very easy to measure.

Barry,

I have other recommendations for you. 

Admon, R., Lubin, G., Stern, O., Rosenberg, K., Sela, L., Ben-Ami, H., & Hendler, T. (2009). Human vulnerability to stress depends on amygdala’s predisposition and hippocampal plasticity. Proceedings of the National Academy of Sciences of the United States of America, 106, 14120-14125. doi:10.1073/pnas.0903183106

Admon, R., Lubin, G., Rosenblatt, J. D., Stern, O., Kahn, I., Assaf, M., & Hendler, T. (2013). Imbalanced neural responsivity to risk and reward indicates stress vulnerability in humans. Cerebral Cortex, 23, 28-35. doi:10.1093/cercor/bhr369

Admon, R., Milad, M., & Hendler, T. (2013). A causal model of post-traumatic stress disorder: disentangling predisposed from acquired neural abnormalities. Trends in Cognitive Sciences, 17, 337-347. doi:10.1016/j.tics.2013.05.005

Irvin

Been scanning some papers, Google the quotes to find the papers 

"Research Group Leader Elisabeth Binder of the Max Planck Institute of Psychiatry examined the DNA of almost 2000 Afro-Americans who had been repeatedly and severely traumatised as adults or in childhood. One-third of trauma victims had become ill and was now suffering from post-traumatic stress disorder. The risk of developing post-traumatic stress disorder rose with increasing severity of abuse only in the carriers of a specific genetic variant in the FKBP5 gene. FKPB5 determines how effectively the organism can react to stress, and by this regulates the entire stress hormone system....In individuals with a genetic predisposition, trauma causes long-term changes in DNA methylation leading to a lasting dysregulation of the stress hormone system. As a result, those affected find themselves less able to cope with stressful situations throughout their lives, frequently leading to depression, post-traumatic stress disorder or anxiety disorders in adulthood."

Blog post on bunch of findings...

https://brainmoleculermarketing.com/2016/06/25/recent-findings-on-trauma/

Just found this - "...FKBP5 polymorphisms, directly and interactively with childhood abuse, predict severity of lifetime PTSD symptoms, most notably hyperarousal symptoms, in two nationally representative samples of EA veterans. They further indicate that FKBP5 polymorphisms and childhood abuse may contribute to vulnerability for PTSD symptoms and may be most strongly associated with trauma-related hyperarousal symptoms that comprise this phenotype."

I'll shortly be publishing a paper on the BDNF gene and trauma processing following a 4 year research programme on hippocampal integrity and PTSD. For a summary (abstract) do email me directly. Work in progress. 

[email protected]

Barry, 

A paper was recently published that may be interest to you. 

Shively, S.B., Horkayne-Szakaly, I., Jones, R.V., Kelly, J.P., Armstrong, R.C., & Perl, D.P. (in press). Characterisation of interface astroglial scarring in the human brain after blast exposure: a post-mortem case series. Lancet Neurology.

It has been published online.

Irvin

I thought we were discussing PTSD and not TBI.

This is a thought in connection to Elmer Rich's above comment. There is likely to be neurological involved in PTSD. Often PTSD and TBI are comorbid. This was the case in the Rand study of U.S. military veterans (Tanielian, T., & Jaycox, L. H. (2008). A comprehensive study of the post-deployment health-related needs associated with post-traumatic stress disorder, major depression, and traumatic brain injury among service members returning from Operations Enduring Freedom and Iraqi Freedom. Santa Monica, CA: Rand). The study by Shively et al. (in press) that I mentioned above is also relevant. 

Not, to be a pain, but my understanding is that most PTSd comes from childhood trauma and accidents, and not from warfare.  Thus, TBI seems a distraction and whole separate subject related to concussive injuries.  Maybe concussive, warfare brain injuries is the topic here and not PTSD.  Of course, inflammation in the brain may be a common symptom.

My interest is in trauma that occurred during military service. I needed to review that literature for a book I wrote and that will be published in the fall.

Ah, OK.  There was a Danish study showing military trauma/PTSd was more likely in men who reported childhood trauma....so....perhaps there is some priming of the limbic system.....?

really interested in biological markers of PTSD just like Barry Turner's question. Would be interested to find out nay study that has clearly indicated any real directly linked markers. I appreciate the wine/grape metaphor with PTSD but interested in more.