Be Afraid - Be Very Afraid ...

A World of Hurt Hyper-reactivity and the toxin of fear

Dr. Greg Nigh Scottsdale, AZ May 2022

“Fog of war” Definition

● “The unavoidable aspect of war wherein the intelligence gathered is always incomplete to a degree, thereby making any decisions concerning said war a bit... foggy. -- Urban Dictionary

● A new presentation in my practice

The hyperreactive patient

● Rising tide over the past 5 years ● Every day these patients are walking through a minefield ● Eating shockingly limited diet ● Life dictated by potential exposures

● Standard therapies are less/not effective

● Most have been tested for Lyme/co-infections ● Some test positive

The Standard Lens: infections and toxins

● Most have been tested for mycotoxins ● Some test positive ● Most have had various GI panels run ● Essentially all have some degree of dysbiosis ● Most have had toxic metal testing ● Most have a few, some have a lot ● Most tell me that treating these things brought them little sustained relief

● Most have been tested for viral infections ● Most have EBV, HHV-6, HHV-7, mycoplasma, and/or any number of others

The Standard Lens: con’t

● Most have done food allergy testing ● Everyone has a few, some have a lot

● Most know of specific food intolerances, and many have multiple intolerances ● Sulfur, histamine, salicylates, phenols, oxalates, etc.

● How do infections and metals and toxins wreak their havoc?

Relevant underlying mechanisms

● ● ● ● ● ●

Cytokine imbalances and dysregulation Microglial activation and inflammation Immune suppression (innate and acquired) Mitochondrial damage and impaired energy production Increased intestinal and BBB leak Direct negative effects on microbiome composition

● What are the physiological effects of fear, stress, and feelings of insecurity

Fear: the new universal toxin

● ● ● ● ● ●

Cytokine imbalances and dysregulation Microglial activation and inflammation Immune suppression (innate and acquired) Mitochondrial damage and impaired energy production Increased intestinal and BBB leak Direct negative effects on microbiome composition

Cytokines

● “These finding suggest that, in humans, changes in the production of the pro-inflammatory cytokines, TNF-α, IL-6 and IFN-γ, and negative immunoregulatory cytokines, IL-10 and IL-4, take part in the homeostatic response to psychological stress and that stress-induced anxiety is related to a T-helper-1-like response.” ● Maes, Michael, et al. "The effects of psychological stress on humans: increased production of pro-inflammatory cytokines and Th1-like response in stress-induced anxiety." Cytokine 10.4 (1998): 313-318. https://doi.org/10.1006/cyto.1997.0290

Cytokines

● “[w]e report on the percentage of studies in the literature that observed increases in either IL-1β, TNF-α, or IL-6 within the hypothalamus, hippocampus, or prefrontal cortex after either acute or chronic stress exposure. The key takeaway is that catecholamines and glucocorticoids play critical roles in the regulation of brain cytokines after psychological stress exposure. ● Johnson, John D., et al. "Neuroendocrine regulation of brain cytokines after psychological stress." Journal of the Endocrine Society 3.7 (2019): 1302-1320. https://doi.org/10.1210/js.2019-00053

Microglia

● “Repeated social defeat (RSD) is a mouse model of psychosocial stress that activates microglia, increases neuroinflammatory signaling, and augments pain and anxiety-like behaviors. We hypothesized that activated microglia within the spinal cord facilitate increased pain sensitivity following RSD. ● Sawicki, Caroline M., et al. "Microglia promote increased pain behavior through enhanced inflammation in the spinal cord during repeated social defeat stress." Journal of Neuroscience 39.7 (2019): 1139-1149. https://doi.org/10.1523/JNEUROSCI.2785-18.2018

Microglia

● “…our results showed that RSD in adolescence produced inflammatory reactivity in microglia that is prolonged into adulthood, affecting astrocytes and neurons of two reward-processing areas of the brain (the prelimbic cortex, and the nucleus accumbens core). ● Rodríguez-Arias, Marta, et al. "Social stress during adolescence activates long-term microglia inflammation insult in reward processing nuclei." PLoS One 13.10 (2018): e0206421. https://doi.org/10.1371/journal.pone.0206421

Microglia

● “Microglia, the brain’s resident myeloid cell, produce “silent” immune machinery in response to stress and aging that does not cause immediate immune activation; rather, these changes prime the cell for a subsequent immune insult.

Primed microglia exhibit a hyperinflammatory response upon immune activation that can exacerbate pathology.” ● Fonken, Laura K., et al. "Stress and aging act through common mechanisms to elicit neuroinflammatory priming." Brain, behavior, and immunity 73 (2018): 133-148. https://doi.org/10.1016/j.bbi.2018.07.012

Immune suppression

● “Primarily, chronic stress activates the classic neuroendocrine system [the hypothalamic-pituitary-adrenal (HPA) axis] and the sympathetic nervous system (SNS) and leads to a decline and dysfunction of the prefrontal cortex and the hippocampus under stress… Chronic stress can also cause corresponding changes in the body's immune function and inflammatory response, which is significant because a long-term inflammatory response and the decline of the body's immune surveillance capabilities are implicated in tumorigenesis. ● Dai, Shirui, et al. "Chronic stress promotes cancer development." Frontiers in oncology 10 (2020): 1492. https://doi.org/10.3389/fonc.2020.01492

Immune suppression

● “We show that [psychological stress] induces remodeling of the chromatin landscape and transcriptomic reprogramming of monocytes, skewing them to a primed hyperinflammatory phenotype. Monocytes from stressed mice and humans exhibit a characteristic inflammatory transcriptomic signature and are hyperresponsive upon stimulation with Toll-like receptor ligands. ● Barrett, Tessa J., et al. "Chronic stress primes innate immune responses in mice and humans." Cell reports 36.10 (2021): 109595. https://doi.org/10.1016/j.celrep.2021.109595

Mitochondria

● “[C]hronic stress induced through a form of psychosocial stressor decreases mitochondrial energy production capacity and alters mitochondrial morphology. This manifested at multiple levels, in respiratory chain enzymatic activity of various complexes, in the rate or oxygen consumption (i.e., respiration) measured directly from fresh tissues or isolated mitochondria, in mitochondrial membrane potential, or in mitochondrial content.” ● Picard, Martin, and Bruce S. McEwen. "Psychological stress and mitochondria: a systematic review." Psychosomatic medicine 80.2 (2018): 141. https://dx.doi.org/10.1097%2FPSY.0000000000000545

Mitochondria

● “Here, we discuss how chronic stress may induce depressive behavior by potentiating mitochondrial allostatic load, which ultimately decreases energy production, elevates the generation of harmful reactive oxygen species, damages mitochondrial DNA and increases membrane permeability and pro-apoptotic factor release.

We also discuss how mitochondrial insults can exacerbate the immune response, contributing to depressive symptomology.” ● Allen, Josh, Hector J. Caruncho, and Lisa E. Kalynchuk.

"Severe life stress, mitochondrial dysfunction, and depressive behavior: a pathophysiological and therapeutic perspective." Mitochondrion 56 (2021): 111-117. https://doi.org/10.1016/j.mito.2020.11.010

Leaky guts

● “These data support that Ocln [Occludin, an epithelial tight-junction protein] plays a potentially significant role in the development of stress-induced increased colon permeability. We believe this is the first demonstration that the level of chronic stress-associated visceral hyperalgesia directly correlates with the magnitude of altered colon epithelial paracellular permeability.” ● Creekmore, Amy L., et al. "Chronic stress-associated visceral hyperalgesia correlates with severity of intestinal barrier dysfunction." Pain 159.9 (2018): 1777. https://dx.doi.org/10.1097%2Fj.pain.0000000000001271

Leaky guts

● “These bacterial LPS translocation data illustrate how a distressed marriage and a mood disorder history can promote a proinflammatory milieu through increased gut permeability, thus fueling inflammation-related disorders.” ● Kiecolt-Glaser, Janice K., et al. "Marital distress, depression, and a leaky gut: translocation of bacterial endotoxin as a pathway to inflammation." Psychoneuroendocrinology 98 (2018): 52-60. https://doi.org/10.1016/j.psyneuen.2018.08.007

Leaky guts

● “Rapidly developing evidence suggests that intestinal epithelial barrier dysfunction and microbial dysbiosis play a potentially significant role in chronic stress-associated visceral hyperalgesia in nociceptive neurons innervating the lower intestine via downregulation in intestinal epithelial cell tight junction protein expression and increase in paracellular permeability.” ● Higgins, Gerald A., Shaungsong Hong, and John W. Wiley.

"The role of epigenomic regulatory pathways in the gut-brain axis and visceral hyperalgesia." Cellular and Molecular Neurobiology (2021): 1-16. https://doi.org/10.1007/s10571-021-01108-0

Leaky brains

● “In summary, chronic stress decreases the size of cerebral vessels and increases BBB permeability. These results may suggest that the sustained decrease in cerebro-vascular volume due to chronic stress leads to a hypoxic condition that causes molecular changes such as VEGF and claudin-5, which eventually impairs the function of BBB.” ● Lee, Sohee, et al. "Real-time in vivo two-photon imaging study reveals decreased cerebro-vascular volume and increased blood-brain barrier permeability in chronically stressed mice." Scientific reports 8.1 (2018): 1-14. https://doi.org/10.1038/s41598-018-30875-y

Leaky brains

● “Our results demonstrated that the stress model… reduced spatial learning and memory… these effects coincided with a significant increase in hippocampal BBB permeability. In sum, the stress model can be used in future studies focusing on the relationship between stress and BBB permeability of the hippocampus.” ● Taghadosi, Zohreh, et al. "Effect of chronically electric foot shock stress on spatial memory and hippocampal blood brain barrier permeability." Behavioural Brain Research 410 (2021): 113364. https://doi.org/10.1016/j.bbr.2021.113364

Gut bugs

● “This study points to persistent stress as a potential source of the destabilization of microbial diversity seen after trauma. This lack of microbiota stability could be associated with worse long-term outcomes in critically ill trauma patients.” ● Kelly, Lauren S., et al. "Stress-related changes in the gut microbiome after trauma." Journal of Trauma and Acute Care Surgery 91.1 (2021): 192-199. doi: 10.1097/TA.0000000000003209

Gut bugs

● “The increased concentration of the Clostridiales family and decrease in the abundance of Bacteroides has been observed in different chronic stress paradigms, which also correlated with the levels of proinflammatory cytokines [114]. Collectively, these data support the influence of stressful events on microbiota density… the physiologically sterile epithelium is altered in exposure to stress. There is a significant decrease in fecal bacteria, especially Lactobacilli, and this alteration produces the same changes as the inhibition of gastric acid release, alterations in gastrointestinal motility, or increased duodenal bicarbonate production. Overall stress may lead to conditions less favorable for the growth and proliferation of beneficial bacteria such as Lactobacilli, as well as reducing survival and adherence [119].” ● Sharma, Vivek Kumar, et al. "Dysbiosis and Alzheimer’s disease: a role for chronic stress?." Biomolecules 11.5 (2021): 678. https://doi.org/10.3390/biom11050678

Glutathione

● “Blood reduced glutathione concentration is significantly diminished 5 to 10 hours after such psychological stresses as jumping from a 34-foot tower while in harness, parachute jumping, and participation in night-infiltration exercises, but not after extremely severe, purely physical activity. The exact nature of the psychological stress capable of evoking this metabolic response is unknown. It is postulated that severe psychological stress operating over long periods may produce irreversible depression of the blood glutathione level and its associated metabolic dysfunctions.” ● PERSKY, HAROLD Ph.D. Glutathione Metabolism in Men under Psychological Stress, Psychosomatic Medicine: November 1954 Volume 16 - Issue 6 - p 489-495

Autonomic Nervous System Dysregulation: The common denomenator

● “The historical development of the inflammatory reflex concept is reviewed, along with evidence that the endogenous reflex response to systemic inflammation is mediated by the splanchnic sympathetic nerves rather than by the vagi. We describe the coordinated nature of this reflex anti-inflammatory action: suppression of pro-inflammatory cytokines coupled with enhanced levels of the anti-inflammatory cytokine, interleukin 10.

The limited information on the afferent and central pathways of the reflex is noted. We describe that the efferent anti-inflammatory action of the reflex is distributed among the abdominal viscera: several organs, including the spleen, can be removed without disabling the reflex… Finally we speculate on the biological and clinical significance of the reflex, citing evidence of its power to influence the resolution of experimental bacteraemia.” ● McAllen, Robin M., Michael J. McKinley, and Davide Martelli. "Reflex regulation of systemic inflammation by the autonomic nervous system." Autonomic Neuroscience 237 (2022): 102926. https://doi.org/10.1016/j.autneu.2021.102926

ANS

● “Pollutants perturb the autonomic nervous system, whose function is critical to cardiopulmonary homeostasis. Recent studies suggest that pollutants can stimulate defensive sensory nerves within the cardiopulmonary system, thus providing a possible mechanism for pollutant-induced autonomic dysfunction.” ● “Autonomic responses to irritant and pollutant inhalation are modified by preexisting CVD, from sympathoinhibition toward sympathoexcitation, a major risk for CVD. Currently, the mechanism underlying the switch of pollutant-sensitive pulmonary-cardiac reflexes toward sympathoexcitation is unknown. ● Taylor-Clark, Thomas E. "Air pollution-induced autonomic modulation." Physiology 35.6 (2020): 363-374. https://doi.org/10.1152/physiol.00017.2020

ANS

● “These data suggest that mucin secretion [in saliva] is predominantly regulated by the sympathetic nervous system via β adrenoceptors, both β1 and β2.”

● Kinjo, K., T. Nishikawa, and A. Tsujimoto. "Role of the autonomic nervous system in regulating salivary mucin secretion by the canine submandibular gland in vivo." Archives of Oral Biology 28.1 (1983): 97-98. https://doi.org/10.1016/0003-9969(83)90031-6

● “Exposure to heavy metals in airborne particulate matter was associated with ANS dysfunction.”

ANS

● Liao, Yi-Hsueh, et al. "Associations between personal exposure to metals in fine particulate matter and autonomic nervous system dysfunction among healthy adults." Aerosol and Air Quality Research 20.8 (2020): 1842-1849. https://doi.org/10.4209/aaqr.2020.04.0156

Vaccination: a brief aside

● “ A 42-year-old male, with no prior symptoms of sinus tachycardia and presyncope episodes, is diagnosed with POTS secondary to the first dose of the mRNA COVID-19 vaccine. Symptoms to this date include sinus tachycardia, dizziness, headaches, and fatigue that are often triggered after a large meal or standing for a longer duration.” ● Reddy, Sujana, Satvik Reddy, and Manish Arora. "A case of postural orthostatic tachycardia syndrome secondary to the messenger RNA COVID-19 vaccine." Cureus 13.5 (2021).

10.7759/cureus.14837

Vaccination, continued

● “Tracer studies have shown that, following injection into the arm muscle, the mRNA in mRNA vaccines is carried into the lymph system by immune cells and ultimately accumulates in the spleen in high concentrations (Bahl et al., 2017). Other studies have shown that stressed immune cells in germinal centers in the spleen release large quantities of exosomes that travel to the brain stem nuclei along the vagus nerve (as reviewed in Seneff and Nigh (2021)). ● Seneff, S., Nigh, G., Kyriakopoulos, A. M., & McCullough, P. A. (2022). Innate Immune Suppression by SARS-CoV-2 mRNA Vaccinations: The role of G-quadruplexes, exosomes and microRNAs. https://doi.org/10.1016/j.fct.2022.113008 ● Seneff, S., & Nigh, G. (2021). Worse than the disease? Reviewing some possible unintended consequences of the mRNA vaccines against COVID-19. International Journal of Vaccine Theory, Practice, and Research, 2(1), 38-79. https://ijvtpr.com/index.php/IJVTPR/article/view/23

Environmental Toxicants

Inflammatory cytokines

Microglia activation

Immune suppression

Mitochondria dysfunction

Chronic fear/stress

Gut & brain permeability

Microbiome imbalances

Environmental Toxicants Autonomic Dysregulation

Inflammatory cytokines

Microglia activation

Immune suppression

Mitochondria dysfunction

Autonomic Dysregulation

Chronic fear/stress

Gut & brain permeability

Microbiome imbalances

Environmental Toxicants Autonomic Dysregulation

Inflammatory cytokines

Microglia activation

Mitochondria dysfunction

Immune suppression

Gut & brain permeability

Autonomic Dysregulation

Chronic fear/stress

Hyperreactivity

Impaired decision-making capacity Emotional Lability Hyperalgia

Hypersensitivity

Wired but crushingly tired

Microbiome imbalances

ANS Dysregulation

Systemic Hyperreactivity

Steps to treating environmental toxins

● Stop the exposure ● Remove the toxin ● Mitigate/repair the damage caused ● Create conditions for sustained health

There is nothing good or bad but thinking makes it so.

If you can change it, why worry about it?

If you can’t change it, why worry about it?

Stop the exposure

● Identify the sources of anxiety and remediate. ● Ask: “Do you know what you are anxious about?” ● Inventory news sources. ● Support groups can be a double-edged sword.

● https://www.positive.news/ ● https://gretchenrubin.com/the-happiness-project

● DNRS ● Safe & Sound Protocol ● Polyvagal theory

● EFT/TFT

Remove toxin/mitigate damage

● Infoceuticals ● Bach Flowers/homeopathics ● Rhythmic breathing/muscle contraction ● Chin, M. S., & Kales, S. N. (2019). Understanding mind–body disciplines: A pilot study of paced breathing and dynamic muscle contraction on autonomic nervous system reactivity. Stress and Health, 35(4), 542-548. https://doi.org/10.1002/smi.2887

Remove toxin/mitigate damage

● “These results suggest that hearing laughter might produce a relaxing effect by increasing parasympathetic nervous activity. This would make it an easily accessible method for improving the recovery process of the autonomic nervous system after a stress-loading task that does not require specialized skills or tools.” https://doi.org/10.1186/s13030-018-0141-0

Remove toxin/mitigate damage

● “Compared to the control condition, combined stimulation significantly decreased oxyhemoglobin (oxy-Hb) concentrations in both prefrontal cortices and increased parasympathetic nervous activity, reflecting a relaxed state; visual and auditory stimulation significantly decreased the oxy-Hb concentration in the right prefrontal cortex; and “comfortable,” “relaxed,” “natural,” and “realistic” feelings increased significantly for all stimulations. In conclusion, forest-derived visual, auditory, and combined stimuli induced physiologically and psychologically relaxing effects, and physiological relaxation was more pronounced under combined stimulus.” Song, Chorong, Harumi Ikei, and Yoshifumi Miyazaki. "Effects of forest-derived visual, auditory, and combined stimuli." Urban Forestry & Urban Greening 64 (2021): 127253.

https://doi.org/10.1016/j.ufug.2021.127253

Mitigate/repai r the damage caused

● Enemas (chlorine dioxide, coffee, etc.) ● Castor oil packs ● Hydrotherapy/contrast showers

● Make sure what is needed is present.

Conditions for sustained health

● Make sure what isn’t needed is removed. ● ANS dysregulation is the proverbial elephant in the living room.

Thank You! Greg Nigh, ND, LAc drnigh@immersionhealthpdx.com http://immersionhealthpdx.com