Medical Gaslighting and "Somatization Disorders" (Rebranded Hysteria)

The Curse of a ‘None of the Above’ Disease
This article talks about people suffering from health conditions that are under-diagnosed or mis-diagnosed, including Chronic Fatigue Syndrome, Fibromyalgia, and IBS, but more so people whose symptoms get dissmissed or written off as fake or psychosomatic.  Many doctors are quick to jump to this conclusion about patients without doing any testing, based just on their appearance and the symptoms they present with.  It is also common for doctors to have an inflated sense of how much they know and lack of recognition of the limits of their education and the field of medicine itself.  One example cited is that of stomach ulcers, "(o)nly a few decades ago, chronic ulcers were chalked up to stress and diet rather than an infection by Helicobacter pylori, because scientists thought it unimaginable that such microorganisms could endure stomach acid."  

 When Anxiety or Depression Masks a Medical Problem

 

What Do Doctors Have to Say About It?
From Dr Courtney Snyder (In a blog post about Mold Illness)
"Symptoms of mold toxicity impact many parts of the body. Often there are many symptoms that seem unrelated, which is why many who are unknowingly dealing with this, end up seeing multiple specialists and are left feeling their doctors think it’s “all their head.” The diagnosis of anxiety or panic, depression, obsessive compulsive disorder, ADHD/ADD, pseudoseizures and conversion disorder are fairly common. I empathize with doctors who have been trained to relieve symptoms as opposed to seek deeper root causes. Still, I do think all physicians (myself included) can benefit from realizing and saying repeatedly, “There’s so much we don’t know,” or even “I don’t know why you are having your symptoms.” The lack of humility or inability to admit one doesn’t have the answer, sadly can lead to some doctors to discount symptoms as “psychiatric” or even blame their patients for feigning their symptoms."

Misdiagnoses Happen. Medical Gaslighting Should Not
Written by Dr Anne Maitland, one of the leading allergy/immunology doctors in the country, about how common it is for immunological disorders (even ones as well known as asthma, food allergies, and anaphylaxis) to be misunderstood, misdiagnosed, or missed altogether, causing an immeasurable but very large amount of unnecessary suffering.

"Missteps and misunderstandings, even by well-seasoned medical professionals, are human, but medical gaslighting is not. Medical professionals must take a step back and recognize that the interpretation of test results is only as good as the practitioner glancing at the numbers. Moreover, normal test results in patients with chronic pain, unexplained sensitivities to the world, or fatigue should provoke more investigation, rather than a weak handoff to a mental health provider. One potential remedy to avoid these misdiagnoses and medical misdemeanors may be to rebuild the patient-practitioner partnership: the medical home. We should be empowering the patient to take charge of their health care, and we should be reminding the practitioner to be a mindful partner in health, rather than a patriarchal purveyor of prescriptions and procedures."

The Martha Mitchell Effect

Martha Mitchell was married to the attorney general in the Nixon administration, John Mitchell.  She spoke up about the illegal activities that she was witnessing, but her claims were written off as delusional until the actual events of the Watergate scandal became public, when she was vindicated.  Sometimes a patient reports events to a doctor or other health care provider that the provider finds difficult to believe and considers to be delusions even when what the patient is reporting is actually true.  This is called the "Martha Mitchell effect" in reference to her experience of being wrongfully considered delusional.  This is particularly likely to happen when a patient's symptoms are the result of the malicious actions of another person, such as harm resulting from harassment or abuse.  This might include poisoning, stalking, gangstalking (group harassment), or gaslighting.  Abusers sometimes deliberately do things to their victims that make the victim sound crazy if they report it.  This is also more likely to occur if the patient reports harm from a medical procedure, treatment, or another medical provider, or from someone who is powerful or well known.

This effect was seen recently when some people presented to the hospital during the COVID 19 pandemic suffering adverse events from the COVID vaccines and were diagnosed as delusional when they were suffering actual side effects that were later acknowledged by the medical establishment and public health authorities.

Examples of medical gaslighting include:

The Incidence of Misdiagnosis in Patients with Ehlers–Danlos Syndrome
"A retrospective chart review was conducted. Among the 429 patients, 405 patients (94.4%) said yes to at least one of the questions, with only 24 patients (5.6%) not having been misdiagnosed with psychiatric illnesses. A total of 378 patients (88%) were told that they were “making it up”, 326 patients (76%) were told that they were attention-seeking, 286 patients (67%) were diagnosed with conversion disorder, 255 patients (60%) were told that “it was in their head”, and 16 patients (4%) were diagnosed with Munchausen syndrome by proxy or a factitious disorder.A retrospective chart review was conducted. Among the 429 patients, 405 patients (94.4%) said yes to at least one of the questions, with only 24 patients (5.6%) not having been misdiagnosed with psychiatric illnesses. A total of 378 patients (88%) were told that they were “making it up”, 326 patients (76%) were told that they were attention-seeking, 286 patients (67%) were diagnosed with conversion disorder, 255 patients (60%) were told that “it was in their head”, and 16 patients (4%) were diagnosed with Munchausen syndrome by proxy or a factitious disorder."

Inappropriate Sinus Tachycardia
“Like Postural Tachycardia Syndrome IST is underappreciated by many in the medical profession and many doctors mistakenly consider it to be a psychological condition. People with IST can find themselves increasingly disabled and may experience high levels of anxiety.”

The Case of CIRS (Chronic Inflammatory Response Syndrome) and Mold Illness
There are many examples of medical conditions that were first described by patients and doctors, for which no physical cause was found for many years.  They were given "placeholder" names as syndromes until such time as their biological mechanism could be figured out, which they eventually were.  There is a list of conditions including Sick Building Syndrome, Chemical Sensitivities, Environmental Illness, Chronic Inflammatory Response Syndrome (CIRS), Toxicant Induced Loss of Tolerance (TILT), Mold Illness, Biotoxin Illness, that had been identified accurately based on patient reports, and in some cases treatments were even discovered based on patient reports of benefits.  These conditions are now understood to be manifestations of Mast Cell Disease, Mitochondrial Dysfunction, and genetic variants that limit detoxification of various compounds capable of inducing excessive inflammation, among other things.  The biological understanding came in time and validated the experiences that patients reported.  

Nagging Pain
This is a Slate article about a program of "boot camps" for people, mostly children, diagnosed with chronic pain (including Fibromyalgia and Central Sensitization) that attempts to "rewire" the symptoms out of the person through brutal and painful exercise and experiences.  Many of the children sent to these "camps" with a diagnosis of AMPS (for "amplified musculoskeletal pain syndrome"), a made-up diagnosis based on an untested theory.  The treatment, which was also made-up based on a this theory, doesn't have any real scientific evidence to support it, just the theory.  The "evidence" that these boot-camp programs work are self-reported questionnaires given to participants at the end of the program.  Part of the program is aggressively drilling into the participants NOT to talk about or report pain or any pain symptoms, so then asking them to self-report is dubious at best.  Everything about this diagnosis, treatment, and these programs is exactly what a cult is and how cults function.  The "patients" are aggressively indoctrinated and brainwashed, their will is broken down, using the exact techniques that cults use- coercive control.  There are no "good" applications of coercive control.  

This is a list of some of the medical diagnoses that survivors of these "boot camp" style programs were later diagnosed with:
Ehlers-Danlos Syndrome or other Connective Tissue Disorders
MCAS
POTS
SCN9A channeloppathy (causing paroxysmal extreme pain disorder with severe dysautonomia including life threatening autonomic storming)
Yao Syndrome
Gastropareses
Adrenal Insufficiency

The following is a comment I submitted as written testimony for a legislative hearing in Oregon regarding reclassifying various pain disorders with Somatoform Disorders in the state's medical code system:

I wish to address the proposal to group Fibromyalgia and chronic pain disorders with Somatoform Disorders.  When a patient presents to the doctor with physical symptoms, including pain, there is nothing scientific about assuming that the patient has a mental health condition rather than a physical one, and that mental health treatment is appropriate.  Cursory testing does not rule out the presence of a physical condition.  Many legitimate physical conditions aren't correctly diagnosed for many years, and may be misdiagnosed many times in the process.  For example, on average a person with celiac disease is properly diagnosed 8 years after first presenting to a doctor with symptoms.  During those 8 years, it can be said that no physical cause has been found for the patient's distress, but it makes no sense to say that they have a psychiatric condition that they are miraculously cured of when they are finally correctly diagnosed with celiac. 

The fact that there are simply so many physical conditions with a significant lag time between the time when a patient presents with complaints and accurate diagnosis should cast doubt on the usefulness and even the existence of actual somatoform disorders.  I lost count a long time ago of the number of cases I know of in which a person presented to the doctor with pain and other non-specific symptoms, was patronizingly dismissed and told to get counseling, eventually given pain meds, and then finally given testing only to be told that they have late stage cancer.  In a number of cases they were actually told "if only you'd come in sooner, we could have treated it".  Many of those people died.  It is also worth noting that new disorders are still being discovered, that medical testing is never 100% accurate, and there are over 7,000 rare diseases listed by the National Organization for Rare Diseases.

Somatoform Disorders are basically the updated name for "hysteria", an archaic concept based more on the misogynist ideas of it's time than any physical reality.  At that time, medicine was considered "scientific", but not exactly in the way we see it now- as a practice based on the sciences of biology and chemistry.  At that time, eugenics was considered science, and was deeply enmeshed in the theory and practice of medicine.  This historical reality has been swept under the rug, but the pseudoscience of eugenics still lingers in the medical practices of today- and I believe that the concept of "Somatoform Disorders" is one example.

The practice of medicine requires that patients be listened to and treated as the experts about life in their own bodies.  Treating them as misbehaving children, putting on a show for attention, has no place in a scientific practice.  I myself was subjected to this gaslighting and abuse for years while struggling to survive an illness which is life-threatening on a daily basis.  I was shamed and shunned until I myself arranged to have a tissue sample from a previous biopsy prepared by the lab that was storing it according to the instructions I got over the phone from the leading pathologist in the country for the disease that I knew I had, and then shipped to her hospital by Fed Ex.  Once she gave me the diagnosis, I was taken seriously and received more than 10 additional diagnoses. 

The delay in treating my medical condition, which I had been both laughed at and yelled at for daring to suggest I had, caused my condition to degenerate such that I have lived on life support since then.  At my lowest point, I was on oxygen, unable to eat and dependent on IV nutrition to survive, requiring continuous infusions of 2 medications, needed a central line which has resulted in 2 DVTs and 15 blood infections, was mostly bed bound, my back broken in 5 places, unable to take any pain meds and needed to undergo my surgeries without anesthesia, had skin cancer removed, had all of my teeth removed due to breakage, have had multiple heart attacks, and more.  There are many, many other people like me.  Most haven't survived.  You could say that "Somatoform Disorders" have a very high fatality rate- but not for the same reason that other deadly disorders do.  Please, it's the year 2024- isn't it time that our medical system reflected that?

This recent study shows examples of people with legitimate physical disease who were misdiagnosed with psychosomatic and psychiatric conditions, and the long-term harm it did them:
“I still can’t forget those words”: mixed methods study of the persisting impact on patients reporting psychosomatic and psychiatric misdiagnoses
"Patient-reported psychosomatic and psychiatric (mis)diagnoses are associated with persisting adverse impacts in multiple domains including mental health, medical relationships, self-worth, and some healthcare behaviours. Health services and clinicians should consider these potential adverse impacts on patients and offer support to reduce any persisting negative impacts."

Mold-Induced Illness

(work in progress)

Significant exposure to mold and related organisms, usually prolonged, can cause a wide range of symptoms and conditions.  This is a common cause or exacerbating factor for MCAS.  Common symptoms of mold illness include fatigue, headaches, digestive problems, respiratory problems (including asthma and shortness-of-breath), cough, sore throat, allergies and reactions that look like allergies (such as sneezing, hives, rashes), excessive thirst, muscle cramps, joint pain, stiffness in the morning, sleep problems, night sweats, brain fog and related cognitive issues (such as problems with memory and executive function), light sensitivity, blurred vision,  numbness, tingling, and tremors.

Mold illness can be diagnosed as many things, including- ME/CFS, Fibromyalgia, MS, Somatization disorders, anxiety, depression, PTSD, ADHD, dementia, Irritable Bowel Syndrome, and more.  That is to say that you may meet criteria for one or more of these diagnoses, but mold exposure is the reason that you have the symptoms in the first place.  For some people, treating and healing from the mold illness allows them to heal and lose the diagnosis.  Whether or not they "actually had" the illness then becomes a semantic issue rather than a scientific one.

The Basics of Mold Illness and Toxicity
Mold Toxicity - Depression, Anxiety, Fatigue, Brain Fog & Inattention 
Mold "can contribute to Pyrrole Disorder due the stress it puts on the body.  It can lead to elevated copper by overwhelming one of the antioxidants in the body that regulates copper.  Because it interferes with the immune system, it can lead to a susceptibility to candida/yeast, Lyme and its co-infections.  It also frequently worsens mast cell activation."

Mold can thrive in water damaged buildings or anywhere indoors where there is retained moisture, including AC units and ductwork.  The mold thrives because it has the ideal conditions for growth and because it doesn't have the competition that keeps it in check outdoors.  Additionally, mold spores and toxins build up inside without the natural ventilation that exists outside.  Mold can poison us with toxins and it can also colonize our bodies, such as our sinuses and GI tract.  Some people also have mold allergy.

"Seemingly 25% of people are unable to make antibodies to mold toxins. Add to that the 50% of buildings that have water damage, and you have a lot of people who are unknowingly becoming toxic while spending time in affected homes, schools, workplaces, cars, dorms, and nurseries."

"Mold toxins basically go from the body, to the liver and gallbladder where they are bound to bile and sent out into the gastrointestinal tract. The bile, however, is recycled (as a means of conservation), and thus take toxins back into the body."  

Some of the symptoms that she lists that I don't see listed often include: electric shock sensations, ice-pick pains, Atypical Parkinson's Disease, Atypical ALS, Psychogenic seizures or pseudo-seizures​​, Tics, spasms and seizure like events; Sensitivity to light touch, Suspected or Diagnosed PANS/Pediatric Acute-Onset Neuropsychiatric Syndrome, Rapid weight gain, Body temperature dysregulation, and diagnosis of fibromyalgia, or chronic fatigue.  
Detection of Mycotoxins in Patients with Chronic Fatigue Syndrome
"Urine specimens from 104 of 112 patients (93%) were positive for at least one mycotoxin (one in the equivocal range). Almost 30% of the cases had more than one mycotoxin present. OTA was the most prevalent mycotoxin detected (83%) with MT as the next most common (44%). Exposure histories indicated current and/or past exposure to WDB in over 90% of cases. Environmental testing was performed in the WDB from a subset of these patients. This testing revealed the presence of potentially mycotoxin producing mold species and mycotoxins in the environment of the WDB. Prior testing in a healthy control population with no history of exposure to a WDB or moldy environment (n = 55) by the same laboratory, utilizing the same methods, revealed no positive cases at the limits of detection."

Most doctors who specialize in mold illness use urinary mycotoxin testing to figure out which mycotoxins a patient is dealing with, as treatment consists largely of the use of binders and different ones bind different toxins  

Comprehensive Guide to Mycotoxin Binders

MCAS & Mold: Fungal Colonization of the Sinuses (video)

Mold often co-occurs with other organisms, such as bacteria, in water-damaged buildings.
Aerobic Actinomycetes of Clinical Significance

CIRS (Chronic Inflammatory Response Syndrome)
There is another condition called CIRS (Chronic Inflammatory Response Syndrome) which seems to me to be essentially another name for MCAS, but was recognized and described without as thorough an understanding of the underlying immunological mechanisms.  CIRS-WDB refers specifically to the condition when developed after prolonged exposure to the inside of water-damaged buildings.  According to this 2024 study, CIRS is "an acquired medical condition characterized by innate immune dysregulation following respiratory exposure to water-damaged buildings (WDB).", and states that ME/CFS is "a common misdiagnosis of CIRS".  MedicineNet gives a more detailed description of CIRS "a multisystem and multi-symptom illness that occurs when a person gets exposed to toxins such as mold spores or biotoxins found in tick or spider bites. These toxins get attached to the immune system to trigger an inflammatory response and induce hormonal changes. The immune system produces an excess of cytokines that can lead to the immune system attacking its tissues, causing inflammation and other associated symptoms."  This source further defines biotoxins as "fat-soluble molecules that travel from cell to cell without entering the bloodstream" and further states that "measuring biotoxins in the blood is difficult, but doctors usually identify them by the damage inflicted on various organs."

According to Dr Shoemaker, there are some HLA-DR/DQ haplotypes (combinations of genes that are inherited together) that make a person less able to clear biotoxins, such as mold toxins, from their bodies, making them more likely to develop CIRS when exposed to mold, which then cause the innate immune system to overreact and lead to chronic inflammation.  These include:
HLA-DR4-3-53
HLA-DR7-2/3-53
HLA-DR11-3-52B
HLA-DR13-6-52A/B/C
HLA-DR17-2-52B
HLA-DR18-4-52A

Diagnostic Process for Chronic Inflammatory Response Syndrome (CIRS): A Consensus Statement
Report of the Consensus Committee of Surviving Mold
"Clinical management of patients with a complex, multisystem, multi-symptom illness identified as a chronic inflammatory response syndrome (CIRS) has expanded. Often associated with illness due to exposure to low molecular weight biotoxins and inflammagens found (i) inside water-damaged buildings (WDB); (ii) following exposure to blooms of cyanobacteria; (iii) following consumption of ciguatoxic fish; and (iv) following confirmed acute Lyme disease, persistent despite reasonable use of antibiotics, CIRS is increasingly recognized. A need for a formal case definition and case management protocol has arisen. Patients with CIRS will have abnormalities in innate responses, reduced levels of
regulatory neuropeptides MSH and VIP, elevated inflammatory markers of C4a, MMP9 and TGF beta-1.  Systemic illness, based on abnormal gene activation and suppression, as shown by RNA Seq and transcriptomics, requires a multi-factorial, rigorous diagnostic assessment to assist in both differential diagnosis and monitoring response to therapy. A consensus statement is herein provided to assist practitioners in case identification and management."

Chronic inflammatory response syndrome: a review of the evidence of clinical efficacy of treatment

Dr. Scott McMahon, a board-certified pediatrician and CIRS specialist (Podcast)

Treatment for Mold Illness
The Shoemaker Protocol is widely recognized as the best treatment for mold-induced illness, whether or not you call it CIRS.  

Doctors who specialize in treating people with mold-induced illness tend to use urinary mycotoxin testing to identify which mycotoxins a person is dealing with, and prescribe substances that bind and remove those specific toxins as part of the treatment protocol.  Examples of binders include bentonite clay, activated charcoal, chlorella, cholestyramine, and colesevelam HCI. 

Finding and Remediating Mold in Your Environment
Consensus Statement for Microbial Remediation 2020
(Indoor Environmental Professional Panel of Surviving Mold)

Dr Jill Carnahan is considered by many to be an authority on cleaning mold and mold remediation.  This page from her website has the basics:
How to Get Rid of Mold – Definitive Mold Removal Guide

"Michael Rubino provides valuable resources and professional guidance on safely addressing mold issues in your home. His website offers detailed information on proper mold cleaning techniques, prevention, and the importance of air quality in maintaining a healthy living environment."

This is information given to me by someone with specialized knowledge of building materials:
"MDF is Medium-Density Fiberboard. There is also OSB, or Oriented Strand Board, and there are number of other building products like particle board made with the tailings or trash from milling lumber, held together by resins. The wood millings are damp from cutting, lay around in damp piles, and develop mold. The mold in this wood is fed by the resins used to make it into building materials. The paper backing on drywall has the same issue. I understand that there is now third-party certified mold-free OSB and MDF made differently."

ImmunoLytics swab tests

Resources Regarding Mold and Mold Illness:
Dr Ritchie Shoemaker's "Surviving Mold" website

International Society For Environmentally Acquired Illnesses / ISEAI website

American Academy for Environmental Medicine 
(database of practitioners who treat environmentally acquired illnesses including mold)

Dr Neil Nathan, MD is an expert in mold illness.  This book from him is highly regarded:
Toxic: Heal Your Body from Mold Toxicity, Lyme Disease, Multiple Chemical Sensitivities, and Chronic Environmental Illness

Dr Jill Crista, ND is a highly respected mold doctor.  "Dr. Jill focuses on conditions that cause injury to the brain and nervous system, including mold, PANS/PANDAS, Lyme disease, and concussion."
Dr Jill Crista online courses about mold 

Dr. Efrat Lamandre focuses on integrative and functional medicine, offering solutions for mold toxicity, chronic illnesses, and environmental health issues. Her practice emphasizes a holistic approach to diagnosing and treating mold-related conditions. Her website provides information and support for those navigating mold toxicity and other environmental health concerns.
Toxic Overload and Chronic Illness: How Mold, Plastics and Pesticides Make You Sick

#moldfinders: RADIO (Podcast)
Mold expert Brian Karr shares his secrets on how to find and remove mold and mycotoxins from your home,

The Virginia Center for Health and Wellness (has video series from Dr Andrew Heyman 

National Institute of Environmental Health Sciences Mold Information

CDC Information About Mold 

EPA Information About Mold

RealTime Laboratories, Inc. (RTL)
"RealTime Laboratories, Inc. (RTL) is a CAP and CLIA accredited clinical and environmental diagnostic laboratory that specializes in testing for and identifying hazardous mold, toxins, and infectious diseases."  They have a free e-book called:
Mycotoxins 101: An Introduction to Crucial Facts

MyMycoLab provides mycotoxin testing

Mold prevention strategies and possible health effects in the aftermath of hurricanes and major floods

The Hidden Connection: COVID, Mold Exposure, and Viral Reactivation 

A comprehensive review of mold research literature from 2011 - 2018

Legal Resources
Well.Law is a legal practice that understands the complexities of mold-related and environmental illness cases. They support clients navigating housing issues, disability rights, and toxic exposure with compassion and legal expertise. She started the personal injury firm she couldn't find.

How to get the most insurance money for mold remediation
"Learn the secrets insurance companies don’t want you to know that will maximize your insurance coverage amount."

Mold Insurance Playbook with Corey Levy (Podcast)
"It can be really expensive... But what if you didn’t have to pay full price for remediation? That’d be awesome! Today we share our entire playbook on how to maximize your coverage! Here is the quick overview... and we go in depth on each one of these in the episode: 1) DON’T CALL YOUR INSURANCE COMPANY! 2) STOP the water 3) Mold Inspection 4) Get Remediation Bids 5) Hire a public adjuster 6) Now you can contact your insurance company... If you go out of order you can literally cost yourselves tens of 1,000s of dollars!"

Mast Cell Activation Syndrome and the Vagus Nerve

These are my notes from the article "Mast cell activation syndrome and the vagus nerve"
written by Ross Hauser, MD of Caring Medical on February 4, 2023 

Many patients diagnosed with MCAS (Mast Cell Activation Syndrome) also have neck pain that is diagnosed as (or can be described as) upper cervical instability or cervical spine instability.  It is generally assumed that this pain is part of the existing illness, but in this article Dr Hauser explains that the causality could be going the other way.  Many of these patients are also diagnosed with  Chronic Fatigue Syndrome, Myalgic Encephalomyelitis (ME/CFS), POTS, or some other form of Dysautonomia.  When these patients see specialists to see if the neck pain and problems could be causing some of their symptoms, some are then diagnosed with "degenerative disc disease in their cervical spine and a loss of the cervical curve contributing to kyphosis".Dr Hauser explains that:

"Which brings us to an important question, which came first? Autonomic nervous dysfunction or immune-mediated allergy?  At a minimum, we know they are interconnected. A lot of antigen-antibody immune complexes and a host of histamine releases are going to excite the autonomic nervous system throughout and likewise, autonomic nervous system dysfunction makes antigen-antibody reactions more likely. The patient has the symptoms, is it the neck causing them? Is it the allergies?"

He explains that the way cervical instability could lead to symptoms of MCAS, etc, is because it may be causing the vagus nerve to be pinched or compressed in the neck or: "damaged cervical ligaments’ inability to hold the “wandering” vertebrae in place."  The vagus nerve is how signals from the brain reach the viscera (the organs in your torso) in order to control them, so anything that impedes its function can have major consequences:

"When the vagal nerve sensory afferents are dysfunctional, the important body sensors for homeostasis are switched off. Cervicovagopthy or vagus nerve disorder brought on by cervical spine instability, has wide-ranging negative effects on mucosal barriers in the intestines and lungs, producing a large number of inflammatory mediators, including histamine."

Dr Hauser explains that many patients who fit this profile- having MCAS along with many of the following additional diagnoses- EDS (Ehlers-Danlos Syndrome, POTS (Postural Orthostatic Tachycardia Syndrome), Gastroparesis, Fibromyalgia, sleep disturbances, low blood pressure, serious gastrointestinal pain and dysfunction, "When someone has a myriad of symptoms like this, it is of course difficult to believe they all start spontaneously without a common thread linking them together. In a person like this, when all is a mystery, we follow the neurology, we look for short-circuiting messages between brain and body being caused by compression of the arteries, veins, and the nerves that travel through the cervical spine."

Dr Hauser notes that many of the different disorders and symptoms experienced by these patients Do have established connections and that these connections are further evidence of vagus nerve involvement.  A key example of this is the interconnection between the immune system and the gut, mediated by the vagus nerve, in which modulating signals are sent both ways.  Also, regulating signals and neurotransmitters in this system are part of the mechanism that the body uses to turn inflammation on and off.  To explain this he quotes a may 2021 study in the journal Frontiers in Pharmacology:

“Inflammatory bowel disease, irritable bowel syndrome, and severe central nervous system injury (of which the vagus nerve plays a dominant role) can lead to intestinal mucosal barrier damage, which can cause endotoxin/enterobacteria translocation (movement, or better thought of as escaping to other parts of the body) to induce infection and is closely related to the progression of metabolic diseases, cardiovascular and cerebrovascular diseases, tumors and other diseases.”

"The researchers add that repairing the intestinal barrier represents a potential therapeutic target for many diseases. Repair means addressing the dysfunction of enteral afferent nerves, efferent nerves, and the intrinsic enteric nervous system that play key roles in regulating intestinal physiological homeostasis and coping with acute stress. Furthermore, innervation actively regulates immunity and induces inherent and adaptive immune responses through complex processes, such as secreting neurotransmitters or hormones and regulating their corresponding receptors."

"Histamine is synthesized by mast cells, basophils, platelets, histaminergic neurons, and enterochromaffin cells, where it is stored intracellularly and released upon stimulation. It can be found basically everywhere in the body, including the spinal cord and brain. Histamine causes smooth muscle cell contraction, vasodilation, increased vascular permeability and mucus secretion, tachycardia, alterations of blood pressure, and arrhythmias, while it stimulates gastric secretion and nociceptive nerve fibers. Histamine increases secretions such as hydrochloric acid in the stomach and is vital to protecting the lungs and gastrointestinal tract from infections. When histamine levels are high, increased secretions in the lungs, therefore, cause coughing, phlegm production, sneezing, and diarrhea occur in the digestive tract in an attempt by the body to rid itself of an infectious agent or toxin."

When the transmission of nerve impulses along the vagus nerve from the brain are interrupted or stopped, this can limit the body's ability to regulate and maintain homeostasis (balance of systems), which can keep the body from appropriately limiting the inflammatory response.  It also results in higher histamine content of mast cells, mast cells being more responsive to nerve signals to react, which ultimately means a higher level of histamine in the organs systems.  

"The GI tract harbors the largest population of mast cells in the body and is thus the main reservoir of the body’s histamine. The mast cells’ job is to maintain intestinal permeability and make sure that no microorganisms or antigens enter the body. (A dysfunction of this system can lead to Leaky Gut Syndrome and inflammation of the intestines.) The neurological control over mast cells and their various digestive functions is via the vagal influences on the enteric nervous system.  Elevated histamine levels in the body occur when there is an increase in intestinal permeability (regardless of the cause), including that from synthetic foods (industrial food additives, chemicals in food, genetically modified foods), Ehlers-Danlos syndrome (EDS), and cervical spine instability induced cervicovagopathy."

The effects of histamine on gut function, and how this impacts other disease processes especially autoimmune, has been well-studied.  Some common industrial food additives are known to trigger mast cells to make the gut more permeable (increase the amount of space between cells that line the gut and regulate what gets into the bloodstream and what doesn't), allowing larger proteins than usual into the bloodstream.  Once there, these proteins can trigger allergic and other inflammatory responses and are especially associated with autoimmune disease.  

"Histamine intolerance results from excessive histamine and a decreased ability to absorb or neutralize it.  Elevated levels of histamine give symptoms that mimic allergic reactions, and these include diarrhea, headache, rhinoconjunctival symptoms, asthma, hypotension, arrhythmia, urticaria, pruritis, flushing, and skin lesions. A true allergy is tied to IgE-mediated histamine release, which is to be differentiated from histamine intolerance. The latter is associated with some forms of urticaria, eczema, asthma, food sensitivity, migraines, and chronic GI and neurological ailments, including inflammatory and irritable bowel syndromes."

"The reservoir of histamine in the body originates in the gut and comes from the breakdown of food that is ingested or the microbiota-generated histamine. Histamine intolerance is akin to lactose intolerance in that the body is missing a key enzyme to digest a food substance. In histamine intolerance, it is DAO in the digestive tract, a deficiency of which leads to elevated histamine levels in the body. DAO is synthesized by the intestinal villi (enterocytes) and is constantly released from the intestinal mucosa into the gut, as well as the blood circulation, during eating and digestion."

Mast cell dysfunction is also being increasingly recognized as a major part of many neurological and psychiatric disorders, especially neurodegenerative disease.  "What is being suggested is that the Mast cells are causing runaway neurological inflammation by excerpting a disruptive influence (bad messages) on the central nervous system and brain and this is leading to neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease for example." 

"vagal activity, partially driven by gastric mast cells, induces long-lasting changes in corticotrophin-releasing factor signaling in the amygdala that may be responsible for enhanced pain and enhanced anxiety- and depression-like behaviors."

"What they found was vagus nerve stimulation resulted in a significant reduction of the different inflammatory parameters assessed. They said their results underscore the anti-inflammatory properties of the vagus nerve and the potential of neuro-immune interactions in the intestine.  In other words, if the vagus nerve is working correctly, anti-inflammatory and mast cell activation could be suppressed."

Further Information from Dr Hauser:
Can Chronic fatigue syndrome and Myalgic encephalomyelitis be caused by cervical stenosis and cervical spine instability? 

Postural Orthostatic Tachycardia Syndrome (POTS), the Vagus Nerve and Cervical Spine instability

Treatments for Neck Pain and Cervical Instability: A review of upper cervical instability and symptom treatment with Ross Hauser, MD

Cervical Curve Correction – Caring Cervical Realignment Therapy

Research Articles Cited in this Article (not all):
How to evaluate the patient with a suspected mast cell disorder and how/when to manage symptoms

Diagnosis of mast cell activation syndrome: a global "consensus-2"

Global Classification of Mast Cell Activation Disorders: An ICD-10-CM-Adjusted Proposal of the ECNM-AIM Consortium

Evaluation and Classification of Mast Cell Disorders: A Difficult to Manage Pathology in Clinical Practice

Intestinal Mucosal Barrier Is Regulated by Intestinal Tract Neuro-Immune Interplay

The Gut's Little Brain in Control of Intestinal Immunity

Vagal gut-brain signaling mediates amygdaloid plasticity, affect, and pain in a functional dyspepsia model

Vagus nerve stimulation dampens intestinal inflammation in a murine model of experimental food allergy

Low-Dose Naltrexone (LDN)

Low-Dose Naltrexone, usually abbreviated LDN, is used fairly often in treating some of the diseases that co-occur with MCAS and even MCAS itself.  It is considered to be quite safe.  In this capacity it is usually used to treat chronic pain, particularly in cases of Fibromylagia and Ehlers-Danlos Syndrome.  The drug was originally used to treat heroin addiction (and sometimes alcohol addiction) by reducing the symptoms of withdrawl.  Later it was discovered that very low doses could stop an HIV infection from becoming AIDS.  LDN has been found to have anti-inflammatory properties, anti-depressive properties, and anti-anxiety properties.  Doctors began using it in this low dose form to treat other things including Crohn's Disease, Fibromyalgia, MS, some skin disorders, and lately even in treating some cancers.  While the ways that LDN helps in many diseases is not well understood, it is clear that it is very safe and able to help many people suffering a wide range of diseases/disorders.

LDN is an immune-modulator rather than an immune-suppressant.  Drugs that are immune-suppressors treat the symptoms of some diseases by suppressing the body's production of inflammatory molecules, suppressing the body's ability to fight infection.  This may put a disease into a less active state but it does not actually treat the disease by addressing the underlying cause, and it can leave the person dangerously susceptible to infection.  By up-regulating the expression of certain cellular receptors, LDN actually changes the immune system itself, making it more able to respond appropriately to a challenge.  It can be said to "modulate" the immune system because it reduces inflammation while supporting a person to be more healthy in an overall sense.  

LDN works by blocking the opiate receptors on cells for about 3 hours at a time, which tricks the body into thinking that there aren't enough receptors, causing it to produce more.  The body also responds by producing more endorphins, which are the body's own chemicals to reduce pain and cause a state of well-being.  It reduces inflammation in the brain and CNS by acting on the TLR-4 receptors on immune cells called glial cells, causing them to reduce their production of pro-inflammatory molecules including IL-6.  This provides an anti-inflammatory effect on the brain but this benefit can include other parts of the body because the brain controls so much of the body.

The only two side effects that seem to be reported much are that it can cause people to have vivid dreams,and that when a person begins taking it, during the first few weeks it can cause insomnia.  However, there are also some people who report that it causes there sleep to improve.  Some patients experience benefits from LDN very soon after starting it, while it can take longer in others.  It should be tried for at least 2 to 3 months before deciding that it isn't working for a patient.  

Low dose Naltrexone for induction of remission in inflammatory bowel disease patients

Low-dose naltrexone for the treatment of fibromyalgia: Findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels

The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial

Naltrexone a potential therapeutic candidate for COVID-19

Low-dose naltrexone in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
"The high frequency of treatment response and good safety profile observed in this retrospective open label study could prompt prospective controlled studies to confirm the feasibility of LDN in alleviating ME/CFS symptoms."

Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone
"The Transient receptor potential melastatin 3 (TRPM3) channel, involved in pain transduction, thermosensation, transmitter and neuropeptide release, mechanoregulation, vasorelaxation, and immune defense, shows altered function in ME/CFS. Dysfunction of TRPM3 in natural killer (NK) cells, characterized by reduced calcium flux, has been observed in ME/CFS and PCS patients, suggesting a role in ineffective pathogen clearance and potential virus persistence and autoimmunity development. TRPM3 dysfunction in NK cells can be improved by naltrexone in vitro and ex vivo, which may explain the moderate clinical efficacy of low-dose naltrexone (LDN) treatment."

Naltrexone at low doses (LDN) and its relevance to cancer therapy
"Considering the increase in the number of anecdotal reports of activity, there will likely be a bigger drive toward using LDN in the oncological setting. These reports support clinical trials of LDN in cancer, especially when given in combination with certain chemotherapy."

"We review three mechanisms through which LDN can influence cancer progression; namely, (a) antagonism of receptors to which LDN binds, which include toll-like receptors 7–9 that lead to IL-6 suppression b) modulation of immune function in patients; and c) direct inhibition of signaling pathways involved in cancer cell control, including the priming of pro-apoptotic pathways."

Mitochondria Are Involved in Many Diseases and Disorders

Mitochondrial Functioning:

The Neuro-Ophthalmology of Mitochondrial Disease
"Mitochondrial diseases frequently manifest neuro-ophthalmologic symptoms and signs. Because of the predilection of mitochondrial disorders to involve the optic nerves, extraocular muscles, retina, and even the retrochiasmal visual pathways, the ophthalmologist is often the first physician to be consulted. Disorders caused by mitochondrial dysfunction can result from abnormalities in either the mitochondrial DNA or in nuclear genes which encode mitochondrial proteins."

Regulation of skeletal muscle mitochondrial fatty acid metabolism in lean and obese individuals.
"A reduction in fatty acid (FA) oxidation has been associated with lipid accumulation and insulin resistance in skeletal muscle of obese individuals. Whole-muscle mitochondrial content and FA oxidation was reduced in the obese, but there was no decrease in the ability of isolated mitochondria to oxidize FA. The mitochondrial content of the transport protein, FA translocase (FAT/CD36), did not differ between lean and obese women but was correlated with mitochondrial FA oxidation. It was concluded that the reduced FA oxidation in obesity is attributable to decreased muscle mitochondrial content and not intrinsic defects in mitochondrial FA oxidation, and that mitochondrial FAT/CD36 is involved in regulating FA oxidation in human skeletal muscle. The reduced skeletal muscle mitochondrial content with obesity may result from impaired mitochondrial biogenesis."

Autophagy, organelles and ageing.

"As a result of insufficient digestion of oxidatively damaged macromolecules and organelles by autophagy and other degradative systems, long-lived postmitotic cells, such as cardiac myocytes, neurons and retinal pigment epithelial cells, progressively accumulate biological 'garbage' ('waste' materials). The latter include lipofuscin (a non-degradable intralysosomal polymeric substance), defective mitochondria and other organelles, and aberrant proteins, often forming aggregates (aggresomes). An interaction between senescent lipofuscin-loaded lysosomes and mitochondria seems to play a pivotal role in the progress of cellular ageing. Lipofuscin deposition hampers autophagic mitochondrial turnover, promoting the accumulation of senescent mitochondria, which are deficient in ATP production but produce increased amounts of reactive oxygen species. Increased oxidative stress, in turn, further enhances damage to both mitochondria and lysosomes, thus diminishing adaptability, triggering mitochondrial and lysosomal pro-apoptotic pathways, and culminating in cell death."

Fibromyalgia is caused by mitochondrial dysfunction
People with Fibromyalgia experience a wide range of symptoms occurring in most of their body systems, including muscles, brain and nervous system, digestive system, urinary problems, joints and skin, and more.  This range of symptoms indicates a systemic disease not isolated to one organ or type of tissue.  Mitochondrial Dysfunction typically involves many different body systems as well, as nearly all cells (with the exception of red blood cells) have mitochondria in them to make their own energy.  If the mitochondria are not able to make adequate energy for the cell than it's function will be diminished.  When muscle cells don't have enough energy, they hurt.  When the brain doesn't have enough energy you get brain fog, depression, memory and cognitive problems.  Your digestive system won't break down and absorb nutrients from your food as well.

There are 3 basic approaches to improving mitochondrial function featured in this video.  The first is to heal the gut because in many ways the gut's ability to absorb and produce the needed nutrients is the foundation for other approaches.  This includes eating a variety of nutritious foods including taking probiotics, eating fresh fruits and vegetables in a variety of colors, low sugar intake, and high levels of healthy fats.  Reduce inflammation which includes not eating gluten and dairy, taking anti-inflammatory supplements such as quercetin and fish oil, and a myriad of other supplements and changes in behavior.  The third important thing is to heal the cell walls of the mitochondria so that they can better function and produce energy, which they do by creating a charge gradient between their two cell walls.  This doctor advocates lipid therapy in which appropriate fats are administered intravenously in order to restore the fats of the mitochondrial walls which have been damaged by oxidative stress, something that occurs when mitochondria burn oxygen to make energy. 

In Alzheimer's Disease (and Diabetes)

Alzheimer's disease: a lesson from mitochondrial dysfunction.

"Extensive literature exists supporting a role for mitochondrial dysfunction and oxidative damage in the pathogenesis of Alzheimer's disease. Mitochondria are a major source of intracellular reactive oxygen species and are particularly vulnerable to oxidative stress. This review discusses evidence supporting the notion that mitochondrial dysfunction is intimately associated with Alzheimer's disease pathogenesis. Furthermore, the potential connection between mitochondrial dysfunction/oxidative stress and autophagy in Alzheimer's disease is also discussed. As a result of insufficient digestion of oxidatively damaged macromolecules and organelles by autophagy, neurons progressively accumulate lipofuscin (biological garbage) that could exacerbate neuronal dysfunction. The knowledge that mitochondrial dysfunction has a preponderant role in several pathological conditions instigated the development of mitochondrial antioxidant therapies. Mitochondria-targeted antioxidant treatments are briefly discussed in this review."

Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology.

"Mitochondria are uniquely poised to play a pivotal role in neuronal cell survival or death because they are regulators of both energy metabolism and cell death pathways. Extensive literature exists supporting a role for mitochondrial dysfunction and oxidative damage in the pathogenesis of Alzheimer's disease. This review discusses evidence indicating that mitochondrial dysfunction has an early and preponderant role in Alzheimer's disease. Furthermore, the link between mitochondrial dysfunction and autophagy in Alzheimer's disease is also discussed. As a result of insufficient digestion of oxidatively damaged macromolecules and organelles by autophagy, neurons progressively accumulate lipofuscin that could exacerbate neuronal dysfunction. Since autophagy is the major pathway involved in the degradation of protein aggregates and defective organelles, an intense interest in developing autophagy-related therapies is growing among the scientific community. The final part of this review is devoted to discuss autophagy as a potential target of therapeutic interventions in Alzheimer's disease pathophysiology."

The key role of mitochondria in Alzheimer's disease.

"This review is mainly focused in the discussion of evidence suggesting a clear association between amyloid-beta toxicity, mitochondrial dysfunction, oxidative stress and neuronal damage/death in Alzheimer's disease pathophysiology. The knowledge that mitochondrial dysfunction has a preponderant role in Alzheimer's disease opened a window for new therapeutic strategies aimed to preserve/ameliorate mitochondrial function. Based on recent developments in mitochondrial research, increased pharmacological and pharmaceutical efforts have lead to the emergence of 'Mitochondrial Medicine' as a whole new field of biomedical research being this topic discussed in the last section of this review."

Alzheimer's disease and diabetes: an integrative view of the role of mitochondria, oxidative stress, and insulin.

"An increasing number of studies have demonstrated a connection between Alzheimer's disease (AD) and diabetes, particularly type 2 diabetes (T2D). The risk for developing T2D and AD increases exponentially with age and having T2D increases the risk of developing AD. This has propelled researchers to investigate the mechanism(s) underlying this connection. This review critically discusses the involvement of mitochondrial abnormalities and oxidative stress in AD and diabetes highlighting the similarities between both pathologies. The impact of insulin resistance/insulin signaling impairment in AD pathogenesis will be also debated. A better understanding of the key mechanisms underlying the interaction between AD and diabetes is needed for the design of effective preventive and therapeutic strategies."

An integrative view of the role of oxidative stress, mitochondria and insulin in Alzheimer's disease.

"The processes underlying the pathogenesis of Alzheimer's disease involve several factors including impaired glucose/energy metabolism, mitochondrial dysfunction, oxidative stress and altered insulin-signaling pathways. This review is mainly devoted to discuss evidence supporting the notion that mitochondrial dysfunction and oxidative stress are interconnected and intimately associated with the development and progression of Alzheimer's disease."

Insulin signaling, glucose metabolism and mitochondria: major players in Alzheimer's disease and diabetes interrelation.

"Many epidemiological studies have shown that diabetes, particularly type 2 diabetes, significantly increases the risk to develop Alzheimer's disease. Both diseases share several common abnormalities including impaired glucose metabolism, increased oxidative stress, insulin resistance and deposition of amyloidogenic proteins. It has been suggested that these two diseases disrupt common cellular and molecular pathways and each disease potentiates the progression of the other. This review discusses clinical and biochemical features shared by Alzheimer's disease and diabetes, giving special attention to the involvement of insulin signaling, glucose metabolism and mitochondria."

Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer's disease.

"The results demonstrate that AD is associated with early and striking increases in the molecular indices of oxidative stress, including up-regulation of NOS and NOX genes, which could impair the function of Complexes IV and V within the electron transport chain. The simultaneous reductions in cyto-protective mechanisms (UCP and PPAR), could allow oxidative injury to go unchecked and persist or increase over time. Adopting strategies to reduce the effects of NOS and NOX activities, and improve the actions of UCPs and PPARs may help in the treatment of AD."

Oxidative stress, mitochondrial dysfunction, and stress signaling in Alzheimer's disease.

"In this review, we examine current evidence supporting the involvement of mitochondria and mitochondrially generated stress signaling in AD and discuss potential implications for the mechanism of pathogenesis of this disease. Mitochondria are pivotal in controlling cell life and death not only by producing ATP, and sequestering calcium, but by also generating free radicals and serving as repositories for proteins which regulate the intrinsic apoptotic pathway. Perturbations in the physiological function of mitochondria inevitably disturb cell function, sensitize cells to neurotoxic insults and may initiate cell death, all significant phenomena in the pathogenesis of a number of neurodegenerative disorders including AD."

Molecular insights into mechanisms of the cell death program: role in the progression of neurodegenerative disorders.

"Synaptic degeneration and death of neurons in limbic and cortical brain regions are the fundamental processes responsible for the manifestation of cognitive dysfunction and behavioural abnormalities in Alzheimer's disease (AD). Despite the various genetic and environmental factors, and the aging process itself that may lead to the manifestation of AD, multiple evidence from studies in experimental models and in AD brain tissue demonstrate that the underlying neurodegeneration is associated with morphological and biochemical features of apoptosis. At the cellular level, neuronal apoptosis in AD may be initiated by oxidative stress and related DNA damage, disruption of cellular calcium homeostasis, or endoplasmic reticulum (ER) stress. The molecular mechanisms of the biochemical cascades of apoptosis are beginning to be understood and involve upstream effectors such as Par-4, p53, and pro-apoptotic Bcl-2 family members, which mediate mitochondrial dysfunction and subsequent release of pro-apoptotic proteins, such as cytochrome c or apoptosis inducing factor (AIF), and subsequent caspase-dependent and -independent pathways which finally result in degradation of proteins and nuclear DNA."

Brain mitochondrial dysfunction as a link between Alzheimer's disease and diabetes.

"It has been argued that in late-onset Alzheimer's disease a disturbance in the control of neuronal glucose metabolism consequent to impaired insulin signalling strongly resembles the pathophysiology of type 2 diabetes in non-neural tissue. The fact that mitochondria are the major generators and direct targets of reactive oxygen species led several investigators to foster the idea that oxidative stress and damage in mitochondria are contributory factors to several disorders including Alzheimer's disease and diabetes. Since brain possesses high energetic requirements, any decline in brain mitochondria electron chain could have a severe impact on brain function and particularly on the etiology of neurodegenerative diseases. This review is primarily focused in the discussion of brain mitochondrial dysfunction as a link between diabetes and Alzheimer's disease."

Mitochondrial control of autophagic lysosomal pathway in Alzheimer's disease.

"While the etiology of AD remains largely unclear, there is accumulating evidence suggesting that mitochondrial dysfunction occurs prior to the onset of symptoms in AD. Mitochondria are exceptionally poised to play a crucial role in neuronal cell survival or death because they are regulators of both energy metabolism and apoptotic pathways. This review is mainly focused in the discussion of evidence suggesting a clear association between mitochondrial dysfunction, autophagy impairment and amyloid-beta accumulation in Alzheimer's disease pathophysiology. The knowledge that autophagic insufficiency may compromise the cellular degradation mechanisms that may culminate in the progressive accumulation of dysfunctional mitochondria, aberrant protein aggregates buildup and lysossomal burden shield new insights to the way we address Alzheimer's disease."

Diabetes

Mitochondria as potential targets in antidiabetic therapy.

"A growing body of evidence suggests that mitochondrial abnormalities are involved in diabetes and associated complications. This chapter gives an overview about the effects of diabetes in mitochondrial function of several tissues including the pancreas, skeletal and cardiac muscle, liver, and brain. The realization that mitochondria are at the intersection of cells' life and death has made them a promising target for drug discovery and therapeutic interventions. Here, we also discuss literature that examined the potential protective effect of insulin, insulin-sensitizing drugs, and mitochondrial-targeted antioxidants."

Mitochondria as a therapeutic target in Alzheimer's disease and diabetes.

"Due to the increasing number of data demonstrating a connection between diabetes and Alzheimer's disease (AD), efforts have been developed to elucidate the exact mechanism(s) underlying this connection. Although both disorders possess several overlapping features, mitochondrial dysfunction is one of the most relevant rendering mitochondria an important target of scientific research. This review discusses clinical and biochemical features shared by AD and diabetes, giving special attention to the involvement of mitochondria. The realization that mitochondria are at the intersection of cells' life and death has made them a promising target for drug discovery and therapeutic interventions. Here we also discuss in vitro, in vivo and clinical studies that examined the effect of mitochondria-directed therapeutics particularly mitochondrial target antioxidants and Szeto-Schiller peptides."

Alzheimer's disease and diabetes: an integrative view of the role of mitochondria, oxidative stress, and insulin.

"An increasing number of studies have demonstrated a connection between Alzheimer's disease (AD) and diabetes, particularly type 2 diabetes (T2D). The risk for developing T2D and AD increases exponentially with age and having T2D increases the risk of developing AD. This has propelled researchers to investigate the mechanism(s) underlying this connection. This review critically discusses the involvement of mitochondrial abnormalities and oxidative stress in AD and diabetes highlighting the similarities between both pathologies. The impact of insulin resistance/insulin signaling impairment in AD pathogenesis will be also debated. A better understanding of the key mechanisms underlying the interaction between AD and diabetes is needed for the design of effective preventive and therapeutic strategies."

Mitochondrial dysfunction and oxidative stress in insulin resistance.

"Evidence is mounting of the involvement of mitochondrial dysfunction in insulin resistance, diabetes and associated complications. This review aims to provide an overview of the effects of insulin resistance on mitochondrial function in several tissues. We consider the pathogenesis of insulin resistance from a mitochondrial perspective and contemplate potential beneficial effects of strategies aimed at modulating mitochondrial function in insulin resistance, including insulin and insulin-sensitizing drugs, antioxidants, and selectively targeting antioxidants to mitochondria."

Fibromyalgia is caused by mitochondrial dysfunction
People with Fibromyalgia experience a wide range of symptoms occurring in most of their body systems, including muscles, brain and nervous system, digestive system, urinary problems, joints and skin, and more.  This range of symptoms indicates a systemic disease not isolated to one organ or type of tissue.  Mitochondrial Dysfunction typically involves many different body systems as well, as nearly all cells (with the exception of red blood cells) have mitochondria in them to make their own energy.  If the mitochondria are not able to make adequate energy for the cell than it's function will be diminished.  When muscle cells don't have enough energy, they hurt.  When the brain doesn't have enough energy you get brain fog, depression, memory and cognitive problems.  Your digestive system won't break down and absorb nutrients from your food as well.

There are 3 basic approaches to improving mitochondrial function featured in this video.  The first is to heal the gut because in many ways the gut's ability to absorb and produce the needed nutrients is the foundation for other approaches.  This includes eating a variety of nutritious foods including taking probiotics, eating fresh fruits and vegetables in a variety of colors, low sugar intake, and high levels of healthy fats.  Reduce inflammation which includes not eating gluten and dairy, taking anti-inflammatory supplements such as quercetin and fish oil, and a myriad of other supplements and changes in behavior.  The third important thing is to heal the cell walls of the mitochondria so that they can better function and produce energy, which they do by creating a charge gradient between their two cell walls.  This doctor advocates lipid therapy in which appropriate fats are administered intravenously in order to restore the fats of the mitochondrial walls which have been damaged by oxidative stress, something that occurs when mitochondria burn oxygen to make energy. 

Neurodegenerative Disease

Mitochondrial diseases of the brain.

"Neurodegenerative disorders are debilitating diseases of the brain, characterized by behavioral, motor and cognitive impairments. Ample evidence underpins mitochondrial dysfunction as a central causal factor in the pathogenesis of neurodegenerative disorders including Parkinson's disease, Huntington's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Friedreich's ataxia and Charcot-Marie-Tooth disease. In this review, we discuss the role of mitochondrial dysfunction such as bioenergetics defects, mitochondrial DNA mutations, gene mutations, altered mitochondrial dynamics (mitochondrial fusion/fission, morphology, size, transport/trafficking, and movement), impaired transcription and the association of mutated proteins with mitochondria in these diseases. We highlight the therapeutic role of mitochondrial bioenergetic agents in toxin and in cellular and genetic animal models of neurodegenerative disorders. We also discuss clinical trials of bioenergetics agents in neurodegenerative disorders. Lastly, we shed light on PGC-1α, TORC-1, AMP kinase, Nrf2-ARE, and Sirtuins as novel therapeutic targets for neurodegenerative disorders."

Mitochondria and neurodegeneration.

"Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. However, despite the evidence of morphological, biochemical and molecular abnormalities in mitochondria in various tissues of patients with neurodegenerative disorders, the question "is mitochondrial dysfunction a necessary step in neurodegeneration?" is still unanswered. In this review, we highlight some of the major neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis and Huntington's disease) and discuss the role of the mitochondria in the pathogenetic cascade leading to neurodegeneration."

Oxidative stress and neurotoxicity.

"There is increasing awareness of the ubiquitous role of oxidative stress in neurodegenerative disease states. A continuing challenge is to be able to distinguish between oxidative changes that occur early in the disease from those that are secondary manifestations of neuronal degeneration. This perspective highlights the role of oxidative stress in Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis, and multiple sclerosis, neurodegenerative and neuroinflammatory disorders where there is evidence for a primary contribution of oxidative stress in neuronal death, as opposed to other diseases where oxidative stress more likely plays a secondary or by-stander role. We begin with a brief review of the biochemistry of oxidative stress as it relates to mechanisms that lead to cell death, and why the central nervous system is particularly susceptible to such mechanisms. Following a review of oxidative stress involvement in individual disease states, some conclusions are provided as to what further research should hope to accomplish in the field."

Mitochondrial complex I deficiency in Parkinson's disease.

"The structure and function of mitochondrial respiratory-chain enzyme proteins were studied postmortem in the substantia nigra of nine patients with Parkinson's disease and nine matched controls. Total protein and mitochondrial mass were similar in the two groups. NADH-ubiquinone reductase (Complex I) and NADH cytochrome c reductase activities were significantly reduced, whereas succinate cytochrome c reductase activity was normal. These results indicated a specific defect of Complex I activity in the substantia nigra of patients with Parkinson's disease. This biochemical defect is the same as that produced in animal models of parkinsonism by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and adds further support to the proposition that Parkinson's disease may be due to an environmental toxin with action(s) similar to those of MPTP."

Mitochondria: a therapeutic target in neurodegeneration.

"Mitochondrial dysfunction has long been associated with neurodegenerative disease. Therefore, mitochondrial protective agents represent a unique direction for the development of drug candidates that can modify the pathogenesis of neurodegeneration. This review discusses evidence showing that mitochondrial dysfunction has a central role in the pathogenesis of Alzheimer's, Parkinson's and Huntington's diseases and amyotrophic lateral sclerosis. We also debate the potential therapeutic efficacy of metabolic antioxidants, mitochondria-directed antioxidants and Szeto-Schiller (SS) peptides. Since these compounds preferentially target mitochondria, a major source of oxidative damage, they are promising therapeutic candidates for neurodegenerative diseases. Furthermore, we will briefly discuss the novel action of the antihistamine drug Dimebon on mitochondria."

Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia.

"There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia (FRDA), multiple sclerosis and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) associated with mitochondrial dysfunction. The mitochondrial genome may play an essential role in the pathogenesis of these diseases, and evidence for mitochondria being a site of damage in neurodegenerative disorders is based in part on observed decreases in the respiratory chain complex activities in Parkinson's, Alzheimer's, and Huntington's disease. Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant imbalance, are thought to underlie defects in energy metabolism and induce cellular degeneration."

Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with focus on neurodegenerative disorders.

"The mitochondria have several important functions in the cell. A mitochondrial dysfunction causes an abatement in ATP production, oxidative damage and the induction of apoptosis, all of which are involved in the pathogenesis of numerous disorders. This review focuses on mitochondrial dysfunctions and discusses their consequences and potential roles in the pathomechanism of neurodegenerative disorders. There are a number of neurodegenerative disorders whose pathogenesis has been demonstrated to involve multiple imbalances of the kynurenine pathway metabolism. These changes may disturb normal brain function and can add to the pathomechanisms of the diseases. In certain disorders, there is a quinolinic acid overproduction, while in others the alterations in brain kynurenic acid levels are more pronounced. A more precise knowledge of these alterations yields a basis for getting better therapeutic possibilities. The last part of the review discusses metabolic disturbances and changes in the kynurenine metabolic pathway in Parkinson's, Alzheimer's and Huntington's diseases."

Cellular and molecular mechanisms underlying perturbed energy metabolism and neuronal degeneration in Alzheimer's and Parkinson's diseases.

"Synaptic degeneration and death of nerve cells are defining features of Alzheimer's disease (AD) and Parkinson's disease (PD), the two most prevalent age-related neurodegenerative disorders. In AD, neurons in the hippocampus and basal forebrain (brain regions that subserve learning and memory functions) are selectively vulnerable. In PD dopamine-producing neurons in the substantia nigra-striatum (brain regions that control body movements) selectively degenerate. Studies of postmortem brain tissue from AD and PD patients have provided evidence for increased levels of oxidative stress, mitochondrial dysfunction and impaired glucose uptake in vulnerable neuronal populations. Studies of animal and cell culture models of AD and PD suggest that increased levels of oxidative stress (membrane lipid peroxidation, in particular) may disrupt neuronal energy metabolism and ion homeostasis, by impairing the function of membrane ion-motive ATPases and glucose and glutamate transporters. Such oxidative and metabolic compromise may there-by render neurons vulnerable to excitotoxicity and apoptosis. Studies of the pathogenic mechanisms of AD-linked mutations in amyloid precursor protein (APP) and presenilins strongly support central roles for perturbed cellular calcium homeostasis and aberrant proteolytic processing of APP as pivotal events that lead to metabolic compromise in neurons. Interestingly, while studies continue to elucidate cellular and molecular events occurring in the brain in AD and PD, recent data suggest that both AD and PD can manifest systemic alterations in energy metabolism (e.g., increased insulin resistance and dysregulation of glucose metabolism). Emerging evidence that dietary restriction can forestall the development of AD and PD is consistent with a major "metabolic" component to these disorders, and provides optimism that these devastating brain disorders of aging may be largely preventable."

Mitochondrial dysfunction and oxidative damage in Alzheimer's and Parkinson's diseases and coenzyme Q10 as a potential treatment.

"There is substantial evidence that mitochondrial dysfunction and oxidative damage may play a key role in the pathogenesis of neurodegenerative disease. Evidence supporting this in both Alzheimer's and Parkinson's diseases is continuing to accumulate. This review discusses the increasing evidence for a role of both mitochondrial dysfunction and oxidative damage in contributing to beta-amyloid deposition in Alzheimer's disease. I also discuss the increasing evidence that Parkinson's disease is associated with abnormalities in the electron transport gene as well as oxidative damage. Lastly, I reviewed the potential efficacy of coenzyme Q as well as a number of other antioxidants in the treatment of both Parkinson's and Alzheimer's diseases."

Mitochondrial abnormalities and oxidative imbalance in neurodegenerative disease.

"An increasing body of evidence now suggests the involvement of mitochondrial abnormalities in the etiology of neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer disease. In this Perspective, we describe a recent study that shows that treatment of human patients with the antioxidant coenzyme Q(10'), which functions in concert with certain mitochondrial enzymes, reduced the worsening of symptoms associated with PD. These findings are consistent with the hypothesis that mitochondrial dysfunction plays a role in the pathogenesis of PD and that treatments that target mitochondrial biochemistry might ameliorate the functional decline observed in patients suffering from PD."

Metals, oxidative stress and neurodegenerative disorders.

"The neurodegenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD), are age-related disorders characterized by the deposition of abnormal forms of specific proteins in the brain. AD is characterized by the presence of extracellular amyloid plaques and intraneuronal neurofibrillary tangles in the brain. Biochemical analysis of amyloid plaques revealed that the main constituent is fibrillar aggregates of a 39-42 residue peptide referred to as the amyloid-β protein (Aβ). PD is associated with the degeneration of dopaminergic neurons in the substantia nigra pars compacta. One of the pathological hallmarks of PD is the presence of intracellular inclusions called Lewy bodies that consist of aggregates of the presynaptic soluble protein called α-synuclein. There are various factors influencing the pathological depositions, and in general, the cause of neuronal death in neurological disorders appears to be multifactorial. However, it is clear, that the underlying factor in the neurological disorders is increased oxidative stress substantiated by the findings that the protein side-chains are modified either directly by reactive oxygen species (ROS) or reactive nitrogen species (RNS), or indirectly, by the products of lipid peroxidation."

Mitochondria, oxidative damage, and inflammation in Parkinson's disease.

"The pathogenesis of Parkinson's disease (PD) remains obscure, but there is increasing evidence that impairment of mitochondrial function, oxidative damage, and inflammation are contributing factors. The present paper reviews the experimental and clinical evidence implicating these processes in PD. There is substantial evidence that there is a deficiency of complex I activity of the mitochondrial electron transport chain in PD. There is also evidence for increased numbers of activated microglia in both PD postmortem tissue as well as in animal models of PD. Impaired mitochondrial function and activated microglia may both contribute to oxidative damage in PD. A number of therapies targeting inflammation and mitochondrial dysfunction are efficacious in the MPTP model of PD. Of these, coenzyme Q(10) appears to be particularly promising based on the results of a recent phase 2 clinical trial in which it significantly slowed the progression of PD."

Ubiquinone (coenzyme q10) and mitochondria in oxidative stress of Parkinson's disease.

"A definitive neuropathological diagnosis of Parkinson's disease requires loss of dopaminergic neurons in the substantia nigra and related brain stem nuclei, and the presence of Lewy bodies in remaining nerve cells. The contribution of genetic factors to the pathogenesis of Parkinson's disease is increasingly being recognized. A point mutation which is sufficient to cause a rare autosomal dominant form of the disorder has been recently identified in the alpha-synuclein gene on chromosome 4 in the much more common sporadic, or 'idiopathic' form of Parkinson's disease, and a defect of complex I of the mitochondrial respiratory chain was confirmed at the biochemical level. Disease specificity of this defect has been demonstrated for the parkinsonian substantia nigra. These findings and the observation that the neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), which causes a Parkinson-like syndrome in humans, acts via inhibition of complex I have triggered research interest in the mitochondrial genetics of Parkinson's disease.

A defect in mitochondrial oxidative phosphorylation, in terms of a reduction in the activity of NADH CoQ reductase (complex I) has been reported in the striatum of patients with Parkinson's disease. The reduction in the activity of complex I is found in the substantia nigra, but not in other areas of the brain, such as globus pallidus or cerebral cortex. Therefore, the specificity of mitochondrial impairment may play a role in the degeneration of nigrostriatal dopaminergic neurons. This view is supported by the fact that MPTP generating 1-methyl-4-phenylpyridine (MPP(+)) destroys dopaminergic neurons in the substantia nigra. Although the serum levels of CoQ10 is normal in patients with Parkinson's disease, CoQ10 is able to attenuate the MPTP-induced loss of striatal dopaminergic neurons."

Mitochondrial Dysfunction: The Road to Alpha-Synuclein Oligomerization in PD.

" In this paper, we focus on mitochondrial dysfunction-mediated alpha-synuclein aggregation. We highlight some of the findings that provide proof of evidence for a mitochondrial metabolism control in Parkinson's disease, namely, mitochondrial regulation of microtubule-dependent cellular traffic and autophagic lysosomal pathway. The knowledge that microtubule alterations may lead to autophagic deficiency and may compromise the cellular degradation mechanisms that culminate in the progressive accumulation of aberrant protein aggregates shields new insights to the way we address Parkinson's disease."

The rescue of microtubule-dependent traffic recovers mitochondrial function in Parkinson's disease.

"In Parkinson's disease mitochondrial dysfunction can lead to a deficient ATP supply to microtubule protein motors leading to mitochondrial axonal transport disruption. Compromised axonal transport will then lead to a disorganized distribution of mitochondria and other organelles in the cell, as well as, the accumulation of aggregated proteins like alpha-synuclein. Moreover, axonal transport disruption can trigger synaptic accumulation of autophagosomes packed with damaged mitochondria and protein aggregates promoting synaptic failure. We previously observed that neuronal-like cells with an inherent mitochondrial impairment derived from PD patients contain a disorganized microtubule network, as well as, alpha-synuclein oligomer accumulation. In this work we provide new evidence that an agent that promotes microtubule network assembly, NAP (davunetide), improves microtubule-dependent traffic, restores the autophagic flux and potentiates autophagosome-lysosome fusion leading to autophagic vacuole clearance in Parkinson's disease cells. Moreover, NAP is capable of efficiently reducing alpha-synuclein oligomer content and its sequestration by the mitochondria. Most interestingly, NAP decreases mitochondrial ubiquitination levels, as well as, increases mitochondrial membrane potential indicating a rescue in mitochondrial function. Overall, we demonstrate that by improving microtubule-mediated traffic, we can avoid mitochondrial-induced damage and thus recover cell homeostasis. These results prove that NAP may be a promising therapeutic lead candidate for neurodegenerative diseases that involve axonal transport failure and mitochondrial impairment as hallmarks, like Parkinson's disease and related disorders."

 

Cardiac and Vascular Disease

Mitochondria and heart failure.

"Energetic abnormalities in cardiac and skeletal muscle occur in heart failure and correlate with clinical symptoms and mortality. It is likely that the cellular mechanism leading to energetic failure involves mitochondrial dysfunction. Therefore, it is crucial to elucidate the causes of mitochondrial myopathy, in order to improve cardiac and skeletal muscle function, and hence quality of life, in heart failure patients."

Nitric oxide and oxidative stress in vascular disease.

"Endothelium-derived nitric oxide (NO) is a paracrine factor that controls vascular tone, inhibits platelet function, prevents adhesion of leukocytes, and reduces proliferation of the intima. An enhanced inactivation and/or reduced synthesis of NO is seen in conjunction with risk factors for cardiovascular disease. This condition, referred to as endothelial dysfunction, can promote vasospasm, thrombosis, vascular inflammation, and proliferation of vascular smooth muscle cells. Vascular oxidative stress with an increased production of reactive oxygen species (ROS) contributes to mechanisms of vascular dysfunction. Oxidative stress is mainly caused by an imbalance between the activity of endogenous pro-oxidative enzymes (such as NADPH oxidase, xanthine oxidase, or the mitochondrial respiratory chain) and anti-oxidative enzymes (such as superoxide dismutase, glutathione peroxidase, heme oxygenase, thioredoxin peroxidase/peroxiredoxin, catalase, and paraoxonase) in favor of the former."