Blood pressure and pain

A trio of papers, with the second and third citing a 2013 review:

“The relationship between pain and hypertension is potentially of great pathophysiological and clinical interest, but is poorly understood. Perception of acute pain initially plays an adaptive role, which results in prevention of tissue damage.

The consequence of ascending nociception is recruitment of segmental spinal reflexes through physiological neuronal connections:

  • In proportion to magnitude and duration of the stimulus, these spinal reflexes cause sympathetic nervous system activation, which increases peripheral resistances, heart rate, and stroke volume; and
  • The response also involves the neuroendocrine system, in particular, the hypothalamic-pituitary-adrenal axis, in addition to further activation of the sympathetic system by adrenal glands.

Persistent pain tends to become chronic and to increase BP values. After a long time, dysfunction of release of endogenous opioids results in a reduction of their analgesic effect. A vicious circle is established, where further pain leads to a reduction in pain tolerance, associated with decreased analgesia mediated by baroreceptors, in a kind of process of exhaustion.”

https://onlinelibrary.wiley.com/doi/epdf/10.1111/jch.12145 “The Relationship Between Blood Pressure and Pain”


A second paper was a 2021 human experimental pain study:

“We investigated the effectiveness of physiological signals for automatic pain intensity estimation that can either substitute for, or complement patients’ self-reported information. Results indicate that for both subject-independent and subject-dependent scenarios, electrodermal activity (EDA) – which is also referred to as skin conductance (SC) or galvanic skin response – was the best signal for pain intensity estimation.

EDA gave mean absolute error (MAE) = 0.93 using only 3 time-series features:

  1. Time intervals between successive extreme events above the mean;
  2. Time intervals between successive extreme events below the mean; and
  3. Exponential fit to successive distances in 2-dimensional embedding space.

Although we obtained good results using 22 EDA features, we further explored to see if we could reach similar or better results with fewer EDA features. This plot highlights that by considering only the top 3 features, we obtained the same level of performance given by all 22 features together.

journal.pone.0254108.g002

This is the first study that achieved less than 1-unit error for continuous pain intensity estimation using only one physiological sensor’s 3 time-series feature, and a Support Vector Regression machine learning model. Considering that this is an encouraging result, we can estimate objective pain using only the EDA sensor, which needs neither a complex setup nor a complex computationally intense machine learning algorithm.

This study paves the way for developing a smart pain measurement wearable device that can change the quality of pain management significantly.”

https://doi.org/10.1371/journal.pone.0254108 “Exploration of physiological sensors, features, and machine learning models for pain intensity estimation”


A third paper was a 2020 human rotator cuff surgery study:

“Results of our study demonstrated that:

  • Pain during the early postoperative period;
  • Time until occurrence of a retear; and
  • Existence of hypertension

were correlated with severity of pain in patients with a retorn rotator cuff.

Pain was selected as the sole outcome parameter of this study because:

  • Pain is an important factor that compels patients to seek treatment for rotator cuff tears, along with functional disability;
  • Pain and subjective functional deficits are important factors that influence a surgeon’s decision to continue with treatment in cases of retearing; and
  • Analyzing pain severity can be a good way to determine patients’ overall satisfaction after rotator cuff repair.

However, pain is not always correlated with disease severity or tear size and vice versa. A lack of pain does not necessarily depend on integrity of the repaired tendon or constitute a good prognosis. In fact, patients with partial-thickness rotator cuff tears showed more pain than did those with full-thickness tears.

Existence of hypertension had a proportional relationship with pain at 12 months postoperatively in patients with retears. This can be interpreted as a suggestion that pain in patients with retears is not acute, but rather chronic, and may be connected to pain in the early postoperative period at 3 months. However, results of this study cannot explain benefits of controlling hypertension in alleviating pain in patients with retears.”

https://journals.sagepub.com/doi/10.1177/2325967120947414 “Factors Related to Pain in Patients With Retorn Rotator Cuffs: Early Postoperative Pain Predicts Pain at 12 Months Postoperatively”


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PTSD susceptibility?

This 2021 rodent study investigated post-traumatic stress disorder (PTSD) susceptibility:

“PTSD is an incapacitating trauma-related disorder, with no reliable therapy. We show distinct DNA methylation profiles of PTSD susceptibility in the nucleus accumbens (NAc). Data analysis revealed overall hypomethylation of different genomic CpG sites in susceptible animals.

Is it possible to treat PTSD by targeting epigenetic processes? Such an approach might reverse genomic underpinning of PTSD and serve as a cure.

To test plausibility of such an approach, a reliable animal (rat) model with high construct validity is needed. Previously, we reported one such model, which uses predator-associated trauma, and cue reminders to evoke recurring trauma. This simulates clinical PTSD symptoms including re-experiencing, avoidance, and hyperarousal.

Individual PTSD-like (susceptible) behavior is analyzed, enabling identification of susceptible animals separately from those that are non-PTSD-like (resilient). This model captures salient features of this disorder in humans, in which only a fraction of trauma victims develop PTSD, while others are resilient.

experimental model

Sprague–Dawley rats were exposed to trauma and to three subsequent trauma-associated reminders. Freezing behavior was measured under conditions of:

  • Exploration;
  • Social interaction (with a companion); and
  • Hyperarousal.

Controls were exposed to identical conditions except for the traumatic event.

PTSD-like behavior of each animal was compared with baseline and with the population. Two unambiguous sub-populations were identified, resilient and susceptible.

After exposure to trauma and its reminders, susceptible animals showed an increase from baseline in freezing behavior, and over time in all three behavioral tests, as opposed to resilient and control groups.

DMRs

Differentially methylated sites in susceptible and resilient animals compared to control group.

Although we focused in this study on DNA methylation changes that associate with susceptibility, we also report unique changes in DNA methylation that occur in resilient animals. Inhibition of critical genes that are downregulated in susceptible animals convert resilient animals to become susceptible.”

https://www.researchgate.net/publication/353192082_Reduction_of_DNMT3a_and_RORA_in_the_nucleus_accumbens_plays_a_causal_role_in_post-traumatic_stress_disorder-like_behavior_reversal_by_combinatorial_epigenetic_therapy “Reduction of DNMT3a and RORA in the nucleus accumbens plays a causal role in post-traumatic stress disorder-like behavior: reversal by combinatorial epigenetic therapy” (registration required)


Rodents with the same genetics and environment displayed individual differences in their responses to traumatic events. Please provide evidence for that before venturing elsewhere.

Not sure why it took 3+ years for this study received in November 2017 to finally be published in July 2021. Sites other than https://doi.org/10.1038/s41380-021-01178-y are more transparent about their peer review and publication processes.

No causes for PTSD susceptibility were investigated. PTSD effects and symptoms aren’t causes, notwithstanding this study’s finding that:

“Our results support a causal role for the NAc as a critical brain region for expression of PTSD-like behaviors, and a role for programming genes by DNA methylation in the NAc in development of PTSD-like behaviors.”

Can’t say that I understand more about causes for PTSD susceptibility now than before I read this study. Researchers attaching significance to gene functional groups seemed like hypothesis-seeking efforts to overcome limited findings.

Will this study’s combination of a methyl donor with a Vitamin A metabolite address PTSD causes in humans? If it only temporarily alleviates symptoms, what lasting value will it have?


Several brain and body areas that store traumatic memories other than the nucleus accumbens were mentioned in The role of recall neurons in traumatic memories. A wide range of epigenetic memory storage vehicles is one reason why effective human therapies need to address each individual, their whole body, and their entire history.

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Osprey breakfast

Gut and brain health

This 2021 human review subject was interactions of gut health and disease with brain health and disease:

“Actions of microbial metabolites are key for appropriate gut-brain communication in humans. Among these metabolites, short-chain fatty acids (SCFAs), tryptophan, and bile acid metabolites / pathways show strong preclinical evidence for involvement in various aspects of brain function and behaviour.

Dietary fibres, proteins, and fats ingested by the host contain components which are metabolized by microbiota. SCFAs are produced from fermentation of fibres, and tryptophan-kynurenine (TRP-KYN) metabolites from dietary proteins. Primary bile acids derived from liver metabolism aid in lipid digestion, but can be deconjugated and bio-transformed into secondary bile acids.

1-s2.0-S0149763421001032-gr1

One of the greatest challenges with human microbiota studies is making inferences about composition of colonic microbiota from faeces. There are known differences between faecal and caecal microbiota composition in humans along with spatial variation across the gastrointestinal tract.

It is difficult to interpret microbiome-host associations without identifying the driving influence in such an interaction. Large cohort studies may require thousands of participants on order to reach 20 % explanatory power for a certain host-trait with specific microbiota-associated metrics (Shannon diversity, relative microbial abundance). Collection of metadata is important to allow for a better comparison between studies, and to identify differentially abundant microbes arising from confounding variables.”

https://www.sciencedirect.com/science/article/pii/S0149763421001032 “Mining Microbes for Mental Health: Determining the Role of Microbial Metabolic Pathways in Human Brain Health and Disease”


Don’t understand why these researchers handcuffed themselves by only using PubMed searches. For example, two papers were cited for:

“Conjugated and unconjugated bile acids, as well as taurine or glycine alone, are potential neuroactive ligands in humans.”

Compare scientific coverage of PubMed with Scopus:

  • 2017 paper: PubMed citations 39; Scopus citations 69.
  • 2019 paper: PubMed citations 69; Scopus citations 102.

Large numbers of papers intentionally missing from PubMed probably influenced this review’s findings, such as:

  1. “There are too few fibromyalgia and migraine microbiome-related studies to make definitive conclusions. However, one fibromyalgia study found altered microbial species associated with SCFA and tryptophan metabolism, as well as changes in serum levels of SCFAs. Similarly, the sole migraine-microbiota study reported an increased abundance of the kynurenine synthesis GBM (gut-brain module).
  2. Due to heterogeneity of stroke and vascular disease conditions, it is difficult to make substantial comparisons between studies. There is convincing evidence for involvement of specific microbial genera / species and a neurovascular condition in humans. However, taxa were linked to LPS biosynthesis rather than SCFA production.
  3. Several studies suggest lasting microbial changes in response to prenatal or postnatal stress, though these do not provide evidence for involvement of SCFA, tryptophan, or bile-acid modifying bacteria. Similar to stress, there are very few studies assessing impact of post-traumatic stress disorder on microbiota.”

These researchers took on a difficult task. Their study design could have been better.


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Wildlife

PXL_20210710_100826663

Take acetyl-L-carnitine for early-life trauma

This 2021 rodent study traumatized female mice during their last 20% of pregnancy, with effects that included:

  • Prenatally stressed pups raised by stressed mothers had normal cognitive function, but depressive-like behavior and social impairment;
  • Prenatally stressed pups raised by control mothers did not reverse behavioral deficits; and
  • Control pups raised by stressed mothers displayed prenatally stressed pups’ behavioral phenotypes.

Acetyl-L-carnitine (ALCAR) protected against and reversed depressive-like behavior induced by prenatal trauma:

alcar regime

ALCAR was supplemented in drinking water of s → S mice either from weaning to adulthood (3–8 weeks), or for one week in adulthood (7–8 weeks). ALCAR supplementation from weaning rendered s → S mice resistant to developing depressive-like behavior.

ALCAR supplementation for 1 week during adulthood rescued depressive-like behavior. One week after ALCAR cessation, however, the anti-depressant effect of ALCAR was diminished.

Intergenerational trauma induces social deficits and depressive-like behavior through divergent and convergent mechanisms of both in utero and early-life parenting environments:

  • We establish 2-HG [2-hydroxyglutaric acid, a hypoxia and mitochondrial dysfunction marker, and an epigenetic modifier] as an early predictive biomarker for trauma-induced behavioral deficits; and
  • Demonstrate that early pharmacological correction of mitochondria metabolism dysfunction by ALCAR can permanently reverse behavioral deficits.”

https://www.nature.com/articles/s42003-021-02255-2 “Intergenerational trauma transmission is associated with brain metabotranscriptome remodeling and mitochondrial dysfunction”


Previously curated studies cited were:

This study had an effusive endorsement of acetyl-L-carnitine in its Discussion section, ending with:

“This has the potential to change lives of millions of people who suffer from major depression or have risk of developing this disabling disorder, particularly those in which depression arose from prenatal traumatic stress.”

I take a gram daily. Don’t know about prenatal trauma, but I’m certain what happened during my early childhood.

I asked both these researchers and those of Reference 70 for their estimates of a human equivalent to “0.3% ALCAR in drinking water.” Will update with their replies.


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The brainstem’s parabrachial nucleus

I often reread blog posts that you read. Yesterday, a reader clicked Treat your gut microbiota as one of your organs. On rereading, I saw that I didn’t properly reference the parabrachial nucleus as being part of the brainstem.

A “parabrachial nucleus” search led me to a discussion of two 2020 rodent studies:

“Nociceptive signals entering the brain via the spinothalamic pathway allow us to detect location and intensity of a painful sensation. But, at least as importantly, nociceptive inputs also reach other brain regions that give pain its emotional texture.

Key to that circuitry is the parabrachial nucleus (PBN), a tiny cluster of cells in the brainstem associated with homeostatic regulation of things like temperature and food intake, response to aversive stimuli, and perceptions of many kinds. Two new papers advance understanding of PBN’s role in pain:

  1. The PBN receives inhibitory inputs from GABAergic neurons in the central nucleus of the amygdala (CeA). Those inputs are diminished in chronic pain conditions, leading to PBN hyperactivity and increased pain perception. Disinhibition of the amygdalo-parabrachial pathway may be crucial to establishing chronic pain.
  2. The dorsal PBN is the first receiver of spinal nociceptive input. It transmits certain inputs to the ventral medial hypothalamus and lateral periaqueductal gray. Certain of its neurons transmit noxious inputs to the external lateral PBN, which then transmits those inputs to the CeA and bed nucleus of the stria terminalis. This is quite new, that nociceptive information the CeA receives has already been processed by the PBN. They measured many pain-related behaviors: place aversion, avoidance, and escape. That allowed them to dissect different pain-related behaviors in relation to distinct subnuclei of the PBN.

1Inline2

Chronic pain is manufactured by the brain. It’s not a one-way process driven by something coming up from the periphery. The brain is actively constructing a chronic pain state in part by this recurring circuit.

A role of the PBN is to sound an alarm when an organism is in danger, but its roles go further. It is a key homeostatic center, weighing short-term versus long-term survival. If you’re warm, fed, and comfortable, organisms can address long-term directives like procreation. When you’re unsafe, though, you need to put those things off and deal with the emergency.”

https://www.painresearchforum.org/news/147704-parabrachial-nucleus-takes-pain-limelight “The Parabrachial Nucleus Takes the Pain Limelight”

https://www.jneurosci.org/content/40/17/3424 “An Amygdalo-Parabrachial Pathway Regulates Pain Perception and Chronic Pain”

https://www.sciencedirect.com/science/article/pii/S089662732030221X “Divergent Neural Pathways Emanating from the Lateral Parabrachial Nucleus Mediate Distinct Components of the Pain Response”


Two dozen papers have since cited these two studies. One that caught my eye was a 2021 rodent study:

“Migraines cause significant disability and contribute heavily to healthcare costs. Irritation of the meninges’ outermost layer (the dura mater), and trigeminal ganglion activation contribute to migraine initiation.

Dura manipulation in humans during neurosurgery is often painful, and dura irritation is considered an initiating factor in migraine. In rodents, dura irritation models migraine-like symptoms.

Maladaptive changes in central pain-processing regions are also important in maintaining pain. The parabrachial complex (PB) receives diverse sensory information, including a direct input from the trigeminal ganglion.

PB-projecting trigeminal ganglion neurons project also to the dura. These neurons represent a direct pathway between the dura, a structure implicated in migraine, and PB, a key node in chronic pain and aversion.”

https://www.sciencedirect.com/science/article/pii/S2452073X21000015 “Parabrachial complex processes dura inputs through a direct trigeminal ganglion-to-parabrachial connection”


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The amino acid ergothioneine

A trio of papers on ergothioneine starts with a 2019 human study. 3,236 people without cardiovascular disease and diabetes mellitus ages 57.4±6.0 were measured for 112 metabolites, then followed-up after 20+ years:

“We identified that higher ergothioneine was an independent marker of lower risk of cardiometabolic disease and mortality, which potentially can be induced by a specific healthy dietary intake.

overall mortality and ergothioneine

Ergothioneine exists in many dietary sources and has especially high levels in mushrooms, tempeh, and garlic. Ergothioneine has previously been associated with a higher intake of vegetables, seafood and with a lower intake of solid fats and added sugar as well as associated with healthy food patterns.”

https://heart.bmj.com/content/106/9/691 “Ergothioneine is associated with reduced mortality and decreased risk of cardiovascular disease”


I came across this study by its citation in a 2021 review:

“The body has evolved to rely on highly abundant low molecular weight thiols such as glutathione to maintain redox homeostasis but also play other important roles including xenobiotic detoxification and signalling. Some of these thiols may also be derived from diet, such as the trimethyl-betaine derivative of histidine, ergothioneine (ET).

image description

ET can be found in most (if not all) tissues, with differential rates of accumulation, owing to differing expression of the transporter. High expression of the transporter, and hence high levels of ET, is observed in certain cells (e.g. blood cells, bone marrow, ocular tissues, brain) that are likely predisposed to oxidative stress, although other tissues can accumulate high levels of ET with sustained administration. This has been suggested to be an adaptive physiological response to elevate ET in the damaged tissue and thereby limit further injury.”

https://www.sciencedirect.com/science/article/pii/S2213231721000161 “Ergothioneine, recent developments”


The coauthors of this review were also coauthors of a 2018 review:

“Ergothioneine is avidly taken up from the diet by humans and other animals through a transporter, OCTN1. Ergothioneine is not rapidly metabolised, or excreted in urine, and has powerful antioxidant and cytoprotective properties.

ergothioneine in foods

Effects of dietary ET supplementation on oxidative damage in young healthy adults found a trend to a decrease in oxidative damage, as detected in plasma and urine using several established biomarkers of oxidative damage, but no major decreases. This could arguably be a useful property of ET: not interfering with important roles of ROS/RNS in healthy tissues, but coming into play when oxidative damage becomes excessive due to tissue injury, toxin exposure or disease, and ET is then accumulated.”

https://febs.onlinelibrary.wiley.com/doi/full/10.1002/1873-3468.13123 “Ergothioneine – a diet-derived antioxidant with therapeutic potential”


I’m upping a half-pound of mushrooms every day to 3/4 lb. (340 g). Don’t think I could eat more garlic than the current six cloves.

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I came across this subject in today’s video:

How will you feel?

Consider this a partial repost of Moral Fiber:

“We are all self-reproducing bioreactors. We provide an environment for trillions of microbes, most of which cannot survive for long without the food, shelter and a place to breed that we provide.

They inhabit us so thoroughly that not a single tissue in our body is sterile. Our microbiome affects our development, character, mood and health, and we affect it via our diet, medications and mood states.

The microbiome:

  • Affects our thinking and our mood;
  • Influences how we develop;
  • Molds our personalities;
  • Our sociability;
  • Our responses to fear and pain;
  • Our proneness to brain disease; and
  • May be as or more important in these respects than our genetic makeup.

Dysbiosis has become prevalent due to removal of prebiotic fibers from today’s ultra-processed foods. I believe that dietary shift has created a generation of humans less able to sustain or receive love.

They suffer from reduced motivation and lower impulse control. They are more anxious, more depressed, more selfish, more polarized, and therefore more susceptible to the corrosive politics of identity.


Other recent blog posts by Dr. Paul Clayton and team include Skin in The Game and Kenosha Kids.

Image from Thomas Cole : The Consummation, The Course of the Empire (1836) Canvas Gallery Wrapped Giclee Wall Art Print (D4060)

Treating psychopathological symptoms will somehow resolve causes?

This 2020 Swiss review subject was potential glutathione therapies for stress:

“We examine available data supporting a role for GSH levels and antioxidant function in the brain in relation to anxiety and stress-related psychopathologies. Several promising compounds could raise GSH levels in the brain by either increasing availability of its precursors or expression of GSH-regulating enzymes through activation of Nrf2.

GSH is the main cellular antioxidant found in all mammalian tissues. In the brain, GSH homeostasis has an additional level of complexity in that expression of GSH and GSH-related enzymes are not evenly distributed across all cell types, requiring coordination between neurons and astrocytes to neutralize oxidative insults.

Increased energy demand in situations of chronic stress leads to mitochondrial ROS overproduction, oxidative damage and exhaustion of GSH pools in the brain.

Several compounds can function as precursors of GSH by acting as cysteine (Cys) donors such as taurine or glutamate (Glu) donors such as glutamine (Gln). Other compounds stimulate synthesis and recycling of GSH through activation of the Nrf2 pathway including sulforaphane and melatonin. Compounds such as acetyl-L-carnitine can increase GSH levels.”

https://www.sciencedirect.com/science/article/abs/pii/S0149763419311133 “Therapeutic potential of glutathione-enhancers in stress-related psychopathologies” (not freely available)


Many animal studies of “stress-related psychopathologies” were cited without noting applicability to humans. These reviewers instead had curious none-of-this-means-anything disclaimers like:

“Comparisons between studies investigating brain disorders of such different nature such as psychiatric disorders or neurodegenerative diseases, or even between brain or non-brain related disorders should be made with caution.”

Regardless, this paper had informative sections for my 27th week of eating broccoli sprouts every day.

1. I forgot to mention in Broccoli sprout synergies that I’ve taken 500 mg of trimethyl glycine (aka betaine) twice a day for over 15 years. Section 3.1.2 highlighted amino acid glycine:

“Endogenous synthesis is insufficient to meet metabolic demands for most mammals (including humans) and additional glycine must be obtained from diet. While most research has focused on increasing cysteine levels in the brain in order to drive GSH synthesis, glycine supplementation alone or in combination with cysteine-enhancing compounds are gaining attention for their ability to enhance GSH.”

2. Amino acid taurine dropped off my supplement regimen last year after taking 500 mg twice a day for years. It’s back on now after reading Section 3.1.3:

“Most studies that reported enhanced GSH in the brain following taurine treatment were performed under a chronic regimen and used in age-related disease models.

Such positive effects of taurine on GSH levels may be explained by the fact that cysteine is the essential precursor to both metabolites, whereby taurine supplementation may drive metabolism of cysteine towards GSH synthesis.”

3. A study in Upgrade your brain’s switchboard with broccoli sprouts was cited for its potential:

“Thalamic GSH values significantly correlated with blood GSH levels, suggesting that peripheral GSH levels may be a marker of brain GSH content. Studies point to the capacity of sulforaphane to function both as a prophylactic against stress-induced behavioral changes and as a positive modulator in healthy animals.”


Sunrise minus 5 minutes

Unraveling oxytocin – is it nature’s medicine?

This 2020 review attempted to consolidate thousands of research papers on oxytocin:

“Chemical properties of oxytocin make this molecule difficult to work with and to measure. Effects of oxytocin are context-dependent, sexually dimorphic, and altered by experience. Its relationship to a related hormone, vasopressin, have created challenges for its use as a therapeutic drug.

Widely used medical interventions i.e.:

  • Exogenous oxytocin, such as Pitocin given to facilitate labor;
  • Opioid medications that block the oxytocin system; or
  • Cesarean sections that alter exposure to endogenous oxytocin

have lasting consequences for the offspring and/or mother.

Such exposures hold the potential to have epigenetic effects on the oxytocin systems, including changes in DNA methylation. These changes in turn would have lasting effects on the expression of receptors for oxytocin, leaving individuals differentially able to respond to oxytocin and also possibly to the effects of vasopressin.

Regions with especially high levels of OXTR [oxytocin receptor gene] are:

  • Various parts of the amygdala;
  • Bed nucleus of the stria terminalis;
  • Nucleus accumbens;
  • Brainstem source nuclei for the autonomic nervous system;
  • Systems that regulate the HPA axis; as well as
  • Brainstem tissues involved in pain and social attention.

Oxytocin protects neural cells against hypoxic-ischemic conditions by:

  • Preserving mitochondrial function;
  • Reducing oxidative stress; and
  • Decreasing a chromatin protein that is released during inflammation

which can activate microglia through the receptor for advanced glycation end products (RAGE). RAGE acts as an oxytocin-binding protein facilitating the transport of oxytocin across the blood-brain barrier and through other tissues.

Directionality of this transport is 5–10 times higher from the blood to the brain, in comparison with brain to blood transport. Individual differences in RAGE could help to predict cellular access to oxytocin and might also facilitate access to oxytocin under conditions of stress or illness.

Oxytocin and vasopressin and their receptors are genetically variable, epigenetically regulated, and sensitive to stressors and diet across the lifespan. As one example, salt releases vasopressin and also oxytocin.

Nicotine is a potent regulator of vasopressin. Smoking, including prenatal exposure of a fetus, holds the potential to adjust this system with effects that likely differ between males and females and that may be transgenerational.

Relative concentrations of endogenous oxytocin and vasopressin in plasma were associated with:

These studies support the usefulness of measurements of both oxytocin and vasopressin but leave many empirical questions unresolved.

The vast majority of oxytocin in biosamples evades detection using conventional approaches to measurement.”

https://pharmrev.aspetjournals.org/content/pharmrev/72/4/829.full.pdf “Is Oxytocin Nature’s Medicine?”


I appreciated efforts to extract worthwhile oxytocin research from countless poorly performed studies, research that wasted resources, and research that actually detracted from science.

I was disappointed that at least one of the reviewers didn’t take this review as an opportunity to confess their previous wastes like three flimsy studies discussed in Using oxytocin receptor gene methylation to pursue an agenda.

Frank interpretations of one’s own study findings to acknowledge limitations is one way researchers can address items upfront that will be questioned anyway. Such analyses also indicate a goal to advance science.

Although these reviewers didn’t provide concrete answers to many questions, they highlighted promising research areas, such as:

  • Improved approaches to oxytocin measurements;
  • Prenatal epigenetic experience associations with oxytocin and OXTR; and
  • Possible transgenerational transmission of these prenatal epigenetic experiences.

Sleep

If you can stand the woo of two Californians trying to outwoo each other, listen to these five podcasts with a sleep scientist.

https://peterattiamd.com/matthewwalker1/

“Ambien, sedation, hypnotives, are not sleep.

Sleep is a life support system. It’s the Swiss army knife of health.

Lack of sleep is like a broken water pipe in your home that leaks down into every nook and cranny of your physiology.

Sleep research is not being transmitted to clinical practice.”


I live on the US East Coast. Hyperbole in normal conversations outside of urban centers is an exception.

It’s different on the West Coast. For example:

  • Interviewer assertions regarding heart rate variability should be compared and contrasted with Dead physiological science zombified by psychological research evidence that:

    “A broad base of further evidence was amassed within human cardiac, circulatory, and autonomic physiology such that the hypotheses do not work as described.”

  • Interviewer favorable comments for MDMA (Ecstasy) “to deal with issues of underlying trauma, anxiety, and depression.”

Flatten the Panic Curve April 13-17, 2020

To better understand our internal origins of panic, here’s Dr. Arthur Janov’s interpretation of a 2013 Iowa study Fear and panic in humans with bilateral amygdala damage (not freely available):

“Justin Feinstein did a study with those who had a damaged amygdala, the hub of the emotional system. They did not have normal fear responses. But if oxygen supplies were lowered and carbon dioxide supplies were increased, mimicking suffocation (increasing acidity of the blood) there were panic attacks.

Where in the world did those attacks come from? Certainly not from the usual emotional structures.

They believe it includes the brainstem! Because the lowering of oxygen supplies and adding carbon dioxide provoked the lower structures to sense the danger and reacted appropriately.

Very much like what happens to a fetus when the mother smokes during pregnancy and produces those same effects.”


Since those of us who chronically experience panic aren’t going into therapy over this weekend, what else can we do?

1. Stop looking at the John Hopkins Panic map.

2. Search out realistic news such as: “Change in [New York state] ICU admissions is actually a negative number for the first time since we started this intense journey.”

3. Stop clicking sensational headline links.

4. Question your information, and investigate multiple views. Trust has been lost:

  • Dr. Scott Jensen, a Minnesota physician for 35 years and state senator, on the inappropriate CDC / WHO guidelines for reporting COVID-19 deaths:

    “It’s ridiculous. The determination of cause of death is a big deal. The idea that we’re going to allow people to massage and game the numbers is a real issue because we’re going to undermine trust.

    I would never put down influenza as the cause of death. Yet that’s what we’re being asked to do here.”

  • The same day, Dr. Fauci arrogantly grouped physicians in with conspiracy theorists if they didn’t conform to these bordering-on-fraudulent CDC / WHO guidelines:

    “Every time we have a crisis of any sort, there’s always this popping-up of conspiracy theories. I think the deaths that we’re seeing are coronavirus deaths, and the other deaths are not being counted as coronavirus deaths.”

    Telling people to trust him – a bureaucrat who hasn’t been in active practice for over three decades – because he had far superior medical judgment than did practicing doctors who for years continuously see patients?

  • Consider the evidence.
  • Don’t accept lies you feel uneasy about. Trust your internal BS detector.

Which herd will you choose to belong to?

https://nypost.com/video/bison-stampede-terrorizes-family-trapped-in-car/

or

Clearing out the 2019 queue of interesting papers

I’m clearing out the below queue of 27 studies and reviews I’ve partially read this year but haven’t taken the time to curate. I have a pesky full-time job that demands my presence elsewhere during the day. :-\

Should I add any of these back in? Let’s be ready for the next decade!


Early life

https://link.springer.com/article/10.1007/s12035-018-1328-x “Early Behavioral Alterations and Increased Expression of Endogenous Retroviruses Are Inherited Across Generations in Mice Prenatally Exposed to Valproic Acid” (not freely available)

https://www.sciencedirect.com/science/article/pii/S0166432818309392 “Consolidation of an aversive taste memory requires two rounds of transcriptional and epigenetic regulation in the insular cortex” (not freely available)

https://www.nature.com/articles/s41380-018-0265-4 “Intergenerational transmission of depression: clinical observations and molecular mechanisms” (not freely available)

mother

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454089/ “Epigenomics and Transcriptomics in the Prediction and Diagnosis of Childhood Asthma: Are We There Yet?”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628997/Placental epigenetic clocks: estimating gestational age using placental DNA methylation levels”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770436/ “Mismatched Prenatal and Postnatal Maternal Depressive Symptoms and Child Behaviours: A Sex-Dependent Role for NR3C1 DNA Methylation in the Wirral Child Health and Development Study”

https://www.sciencedirect.com/science/article/pii/S0889159119306440 “Environmental influences on placental programming and offspring outcomes following maternal immune activation”

https://academic.oup.com/mutage/article-abstract/34/4/315/5581970 “5-Hydroxymethylcytosine in cord blood and associations of DNA methylation with sex in newborns” (not freely available)

https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/JP278270 “Paternal diet impairs F1 and F2 offspring vascular function through sperm and seminal plasma specific mechanisms in mice”

https://onlinelibrary.wiley.com/doi/full/10.1111/nmo.13751 “Sex differences in the epigenetic regulation of chronic visceral pain following unpredictable early life stress” (not freely available)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811979/ “Genome-wide DNA methylation data from adult brain following prenatal immune activation and dietary intervention”

https://link.springer.com/article/10.1007/s00702-019-02048-2miRNAs in depression vulnerability and resilience: novel targets for preventive strategies”


Later life

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543991/ “Effect of Flywheel Resistance Training on Balance Performance in Older Adults. A Randomized Controlled Trial”

https://www.mdpi.com/2411-5142/4/3/61/htm “Eccentric Overload Flywheel Training in Older Adults”

https://www.nature.com/articles/s41577-019-0151-6 “Epigenetic regulation of the innate immune response to infection” (not freely available)

https://link.springer.com/chapter/10.1007/978-981-13-6123-4_1 “Hair Cell Regeneration” (not freely available)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422915/Histone Modifications as an Intersection Between Diet and Longevity”

https://www.sciencedirect.com/science/article/abs/pii/S0306453019300733 “Serotonin transporter gene methylation predicts long-term cortisol concentrations in hair” (not freely available)

https://www.sciencedirect.com/science/article/abs/pii/S0047637419300338 “Frailty biomarkers in humans and rodents: Current approaches and future advances” (not freely available)

https://onlinelibrary.wiley.com/doi/full/10.1111/pcn.12901 “Neural mechanisms underlying adaptive and maladaptive consequences of stress: Roles of dopaminergic and inflammatory responses

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627480/ “In Search of Panacea—Review of Recent Studies Concerning Nature-Derived Anticancer Agents”

https://www.sciencedirect.com/science/article/abs/pii/S0028390819303363 “Reversal of oxycodone conditioned place preference by oxytocin: Promoting global DNA methylation in the hippocampus” (not freely available)

https://www.futuremedicine.com/doi/10.2217/epi-2019-0102 “Different epigenetic clocks reflect distinct pathophysiological features of multiple sclerosis”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834159/ “The Beige Adipocyte as a Therapy for Metabolic Diseases”

https://www.sciencedirect.com/science/article/abs/pii/S8756328219304077 “Bone adaptation: safety factors and load predictability in shaping skeletal form” (not freely available)

https://www.nature.com/articles/s41380-019-0549-3 “Successful treatment of post-traumatic stress disorder reverses DNA methylation marks” (not freely available)

https://www.sciencedirect.com/science/article/abs/pii/S0166223619301821 “Editing the Epigenome to Tackle Brain Disorders” (not freely available)

Using oxytocin receptor gene methylation to pursue an agenda

A pair of 2019 Virginia studies involved human mother/infant subjects:

“We show that OXTRm [oxytocin receptor gene DNA methylation] in infancy and its change is predicted by maternal engagement and reflective of behavioral temperament.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795517 “Epigenetic dynamics in infancy and the impact of maternal engagement”

“Infants with higher OXTRm show enhanced responses to anger and fear and attenuated responses to happiness in right inferior frontal cortex, a region implicated in emotion processing through action-perception coupling.

Infant fNIRS [functional near-infrared spectroscopy] is limited to measuring responses from cerebral cortex. It is unknown whether OXTR is expressed in the cerebral cortex during prenatal and early postnatal human brain development.”

https://www.sciencedirect.com/science/article/pii/S187892931830207X “Epigenetic modification of the oxytocin receptor gene is associated with emotion processing in the infant brain”


Both studies had weak disclosures of limitations on their findings’ relevance and significance. The largest non-disclosed contrary finding was from the 2015 Early-life epigenetic regulation of the oxytocin receptor gene:

These results suggest that:

  • Blood Oxtr DNA methylation may reflect early experience of maternal care, and
  • Oxtr methylation across tissues is highly concordant for specific CpGs, but
  • Inferences across tissues are not supported for individual variation in Oxtr methylation.

That rat study found that blood OXTR methylation of 25 CpG sites couldn’t accurately predict the same 25 CpG sites’ OXTR methylation in each subject’s hippocampus, hypothalamus, and striatum (which includes the nucleus accumbens) brain areas. Without significant effects in these limbic system structures, there couldn’t be any associated behavioral effects.

But CpG site associations and correlations were deemed good in the two current studies because they cited:

“Recent work in prairie voles has found that both brain- and blood-derived OXTRm levels at these sites are negatively associated with gene expression in the brain and highly correlated with each other.”

https://www.sciencedirect.com/science/article/pii/S0306453018306103 “Early nurture epigenetically tunes the oxytocin receptor”

The 2018 prairie vole study – which included several of the same researchers as the two current studies – found four nucleus accumbens CpG sites that had high correlations to humans. Discarding one of these CpG sites allowed their statistics package to make a four-decimal place finding:

“The methylation state of the blood was also associated with the level of transcription in the brain at three of the four CpG sites..whole blood was capable of explaining 94.92% of the variance in Oxtr DNA methylation and 18.20% of the variance in Oxtr expression.”

Few limitations on the prairie vole study findings were disclosed. Like the two current studies, there wasn’t a limitation section that placed research findings into suitable contexts. So readers didn’t know researcher viewpoints on items such as:

  • What additional information showed that 3 of the 30+ million human CpGs accurately predicted specific brain OXTR methylation and expression from saliva OXTR methylation?
  • What additional information demonstrated how “measuring responses from cerebral cortex” although “it is unknown whether OXTR is expressed in the cerebral cortex” provided detailed and dependable estimates of limbic system CpG site OXTR methylation and expression?
  • Was the above 25-CpG study evidence considered?

Further contrast these three studies with a typical, four-point, 285-word limitation section of a study like Prenatal stress heightened adult chronic pain. The word “limit” appeared 6 times in that pain study, 3 times in the current fNIRS study, and 0 times in the current maternal engagement and cited prairie vole studies.

Frank interpretations of one’s own study findings to acknowledge limitations is one way researchers can address items upfront that will be questioned anyway. Such analyses also indicate a goal to advance science.

Prenatal stress heightened adult chronic pain

This 2019 McGill rodent study found:

Prenatal stress exacerbates pain after injury. Analysis of mRNA expression of genes related to epigenetic regulation and stress responses in the frontal cortex and hippocampus, brain structures implicated in chronic pain, showed distinct sex and region-specific patterns of dysregulation.

In general, mRNA expression was most frequently altered in the male hippocampus and effects of prenatal stress were more prevalent than effects of nerve injury. Recent studies investigating chronic pain-related pathology in the hippocampus in humans and in rodent models demonstrate functional abnormalities in the hippocampus, changes in associated behavior, and decreases in adult hippocampal neurogenesis.

The change in expression of epigenetic- and stress-related genes is not a consequence of nerve injury but rather precedes nerve injury, consistent with the hypothesis that it might play a causal role in modulating the phenotypic response to nerve injury. These findings demonstrate the impact of prenatal stress on behavioral sensitivity to a painful injury.

Decreased frontal mRNA expression of BDNF and BDNF IV in male offspring following neuropathic pain or prenatal stress respectively. Relative mRNA expression of other stress-related genes (GR17, FKBP5) and epigenetic-related genes (DNMTs, TETs, HDACs, MBDs, MeCP2) in male offspring.

A drastic decrease in expression of HDAC1 was observed in all groups compared to sham-control animals. CCI: chronic constriction injury.”


The study’s design was similar to the PRS (prenatal restraint stress) model, except that the PRS procedure covered gestational days 11 to 21 (birth):

“Prenatal stress was induced on Embryonic days 13 to 17 by restraining the pregnant dams in transparent cylinder with 5 mm water, under bright light exposure, 3 times per day for 45 min.”

None of the French, Italian, and Swiss PRS studies were cited.

The limitation section included:

  1. “Although our study shows significant changes in expression of epigenetic enzymes, it didn’t examine the impact of these changes on genes that are epigenetically regulated by this machinery or their involvement in intensifying pain responses.
  2. The current study is limited by the focus on changes in gene expression which do not necessarily correlate with changes in protein expression.
  3. Another limitation of this study is the inability to distinguish the direct effects of stress in utero vs. changes in the dam’s maternal behavior due to stress during pregnancy; cross-fostering studies are needed to address this issue.
  4. Functional experiments that involve up and down regulation of epigenetic enzymes in specific brain regions are required to establish a causal role for these processes in chronic pain.”

What do you think about possible human applicability of this study’s “effects of prenatal stress were more prevalent than effects of nerve injury” finding?

Are there any professional therapeutic frameworks that instruct trainees to recognize that if a person’s mother was stressed while pregnant, their prenatal experiences could cause more prevalent biological and behavioral effects than a recent injury?

https://www.sciencedirect.com/science/article/pii/S0166432819315219 “Prenatal maternal stress is associated with increased sensitivity to neuropathic pain and sex-specific changes in supraspinal mRNA expression of epigenetic- and stress-related genes in adulthood” (not freely available)

A review of fetal adverse events

This 2019 Australian review subject was fetal adversities:

“Adversity during the perinatal period is a significant risk factor for the development of neurodevelopmental disorders long after the causative event. Despite stemming from a variety of causes, perinatal compromise appears to have similar effects on the developing brain, thereby resulting in behavioural disorders of a similar nature.

These behavioural disorders occur in a sex‐dependent manner, with males affected more by externalizing behaviours such as attention deficit hyperactivity disorder (ADHD) and females by internalizing behaviours such as anxiety. The term ‘perinatal compromise’ serves as an umbrella term for intrauterine growth restriction, maternal immune activation, prenatal stress, early life stress, premature birth, placental dysfunction, and perinatal hypoxia.

The above conditions are associated with imbalanced excitatory-inhibitory pathways resulting from reduced GABAergic signalling. Methylation of the GAD1/GAD67 gene, which encodes the key glutamate‐to‐GABA synthesizing enzyme Glutamate Decarboxylase 1, resulting in increased levels of glutamate is one epigenetic mechanism that may account for a tendency towards excitation in disorders such as ADHD.

The posterior cerebellum’s role in higher executive functioning is becoming well established due to its connections with the prefrontal cortex, association cortices, and limbic system. It is now suggested that disruptions to cerebellar development, which can occur due to late gestation compromises such as preterm birth, can have a major impact on the region of the brain to which it projects.

Activation of the maternal hypothalamic-pituitary adrenal (HPA) axis and placental protection. Psychological stress is perceived by the maternal HPA axis, which stimulates cortisol release from the maternal adrenal gland.

High levels of maternal cortisol are normally prevented from reaching the fetus by the 11β-hydroxysteroid dehydrogenase 2 (HSD11B2) enzyme, which converts cortisol to the much less active cortisone. Under conditions of high maternal stress, this protective mechanism can be overwhelmed, with the gene encoding the enzyme becoming methylated, which reduces its expression allowing cortisol to cross the placenta and reach the fetus.”


The reviewers extrapolated many animal study findings to humans, although most of their own work was with guinea pigs. The “suggest” and “may” qualifiers were used often – 22 and 37 times, respectively. More frequent use of the “appears,” “hypothesize,” “propose,” and “possible” terms was justified.

As a result, many reviewed items such as the above graphic and caption should be viewed as hypothetical for humans rather than reflecting solid evidence from quality human studies.

The reviewers focused on the prenatal (before birth) period more than the perinatal (last trimester of pregnancy to one month after birth) period. There were fewer mentions of birth and early infancy adversities.

https://onlinelibrary.wiley.com/doi/abs/10.1111/jne.12814 “Perinatal compromise contributes to programming of GABAergic and Glutamatergic systems leading to long-term effects on offspring behaviour” (not freely available)