How to cure the ultimate causes of migraines?

Most of the spam I get on this blog comes in as ersatz comments on The hypothalamus couples with the brainstem to cause migraines. I don’t know what it is about the post that attracts internet bots.

The unwanted attention is too bad because the post represents a good personal illustration of “changes in the neural response to painful stimuli.” Last year I experienced three three-day migraines in one month as did the study’s subject. This led to me cycling through a half-dozen medications in an effort to address the migraine causes.

None of the medications proved to be effective at treating the causes. I found one that interrupted the progress of migraines – sumatriptan, a serotonin receptor agonist. I’ve used it when symptoms start, and the medication has kept me from having a full-blown migraine episode in the past year.

1. It may be argued that migraine headache tendencies are genetically inherited. Supporting personal evidence is that both my mother and younger sister have migraine problems. My father, older sister, and younger brother didn’t have migraine problems. Familial genetic inheritance usually isn’t the whole story of diseases, though.

2. Migraine headaches may be an example of diseases that are results of how humans have evolved. From Genetic imprinting, sleep, and parent-offspring conflict:

“..evolutionary theory predicts: that which evolves is not necessarily that which is healthy.

Why should pregnancy not be more efficient and more robust than other physiological systems, rather than less? Crucial checks, balances and feedback controls are lacking in the shared physiology of the maternal–fetal unit.

Both migraine causes and effects may be traced back to natural lacks of feedback loops. These lacks demonstrate that such physiological feedback wasn’t evolutionarily necessary in order for humans to survive and reproduce.

3. Examples of other processes occurring during prenatal development that also lack feedback loops, and their subsequent diseases, are:

A. Hypoxic conditions per Lack of oxygen’s epigenetic effects are causes of the fetus later developing:

  • “age-related macular degeneration
  • cancer progression
  • chronic kidney disease
  • cardiomyopathies
  • adipose tissue fibrosis
  • inflammation
  • detrimental effects which are linked to epigenetic changes.”

B. Stressing pregnant dams per Treating prenatal stress-related disorders with an oxytocin receptor agonist caused fetuses to develop a:

  • “defect in glutamate release,
  • anxiety- and depressive-like behavior,

and abnormalities:

  • in social behavior,
  • in the HPA response to stress, and
  • in the expression of stress-related genes in the hippocampus and amygdala.”

1. What would be a treatment that could cure genetic causes for migraines?

I don’t know of any gene therapies.

2. What treatments could cure migraines caused by an evolved lack of feedback mechanisms?

We humans are who we have become, unless and until we can change original causes. Can we deal with “changes in the neural response to painful stimuli” without developing hopes for therapies or technologies per Differing approaches to a life wasted on beliefs?

3. What treatments could cure prenatal epigenetic causes for migraines?

The only effective solution I know of that’s been studied in humans is to prevent adverse conditions like hypoxia from taking place during pregnancy. The critical periods of our physical development are over once we’re adults, and we can’t unbake a cake.

Maybe science will offer other possibilities. Maybe it will be necessary for scientists to do more than their funding sponsors expect?

Advertisements

Differing approaches to a life wasted on beliefs

Let’s start by observing that people structure their lives around beliefs. As time goes on, what actions would a person have taken to ward off non-confirming evidence?

One response may be that they would engage in ever-increasing efforts to develop new beliefs that justified how they spent their precious life’s time so far.

Such was my take on the embedded beliefs in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684598/pdf/PSYCHIATRY2017-5491812.pdf “Epigenetic and Neural Circuitry Landscape of Psychotherapeutic Interventions”:

“Animal models have shown the benefits of continued environmental enrichment (EE) on psychopathological phenotypes, which carries exciting translational value.

This paper posits that psychotherapy serves as a positive environmental input (something akin to EE).”

The author conveyed his belief that wonderful interventions were going to happen in the future, although, when scrutinized, most human studies have demonstrated null effects of psychotherapy interventions on causes. Without sound evidence that treatments affect causes, this belief seemed driven by something else.

The author saw the findings of research like A problematic study of oxytocin receptor gene methylation, childhood abuse, and psychiatric symptoms as supporting external interventions to tamp down symptoms of patients’ presenting problems. Did any of the paper’s 300+ citations concern treatments where patients instead therapeutically addressed their problems’ root causes?


For an analogous religious example, a person’s belief caused him to spend years of his life trying to convince men to act so that they could get their own planet after death, and trying to convince women to latch onto men who had this belief. A new and apparently newsworthy belief developed from his underlying causes:

“The founder and CEO of neuroscience company Kernel wants “to expand the bounds of human intelligence”. He is planning to do this with neuroprosthetics; brain augmentations that can improve mental function and treat disorders. Put simply, Kernel hopes to place a chip in your brain.

He was raised as a Mormon in Utah and it was while carrying out two years of missionary work in Ecuador that he was struck by what he describes as an “overwhelming desire to improve the lives of others.”

He suffered from chronic depression from the ages of 24 to 34, and has seen his father and stepfather face huge mental health struggles.”

https://www.theguardian.com/small-business-network/2017/dec/14/humans-20-meet-the-entrepreneur-who-wants-to-put-a-chip-in-your-brain “Humans 2.0: meet the entrepreneur who wants to put a chip in your brain”

The article stated that the subject had given up Mormonism. There was nothing to suggest, though, that he had therapeutically addressed any underlying causes for his misdirected thoughts, feelings, and behavior. So he developed other beliefs instead.


What can people do to keep their lives from being wasted on beliefs? As mentioned in What was not, is not, and will never be:

“The problem is that spending our time and efforts on these ideas, beliefs, and behaviors won’t ameliorate their motivating causes. Our efforts only push us further away from our truths, with real consequences: a wasted life.

The goal of the therapeutic approach advocated by Dr. Arthur Janov’s Primal Therapy is to remove the force of the presenting problems’ motivating causes. Success in reaching this goal is realized when patients become better able to live their own lives.

Experience-induced transgenerational programming of neuronal structure and functions

The second paper of Transgenerational epigenetic inheritance week was a 2017 German/Israeli review focused on:

“The inter- and transgenerational effects of stress experience prior to and during gestation..the concept of stress-induced (re-)programming in more detail by highlighting epigenetic mechanisms and particularly those affecting the development of monoaminergic transmitter systems, which constitute the brain’s reward system..we offer some perspectives on the development of protective and therapeutic interventions in cognitive and emotional disturbances resulting from preconception and prenatal stress.”

The reviewers noted that human studies have difficulties predicting adult responses to stress that are based on gene expression and early life experience. Clinical studies that experimentally manipulate the type, level and timing of the stressful exposure aren’t possible. Clinical studies are also predicated on the symptoms being recognized as disorders and/or diseases.

The researchers noted difficulties in human interventions and treatments. Before and during pregnancy, and perinatal periods are where stress effects are largest, but current human research hasn’t gathered sufficient findings to develop practical guidelines for early intervention programs.


I’m not persuaded by arguments that cite the difficulties of performing human research on transgenerational epigenetic inheritance. There are overwhelming numbers of people who have obvious stress symptoms: these didn’t develop in a vacuum.

Researchers:

  • Design human studies to test what’s known from transgenerational epigenetic inheritance animal studies that will include documenting the subjects’ detailed histories with sufficient biometric samples and data obtained from their lineage.
  • Induce the subjects to at least temporarily avoid what’s harmful for them and/or the offspring, in favor of what’s beneficial.
  • Document the subjects’ actions with history and samples.

I acknowledge that economic incentives may not be enough to get people to participate. I’m familiar with a juvenile sickle-cell study that didn’t get enough subjects despite offering free transportation and hundreds of dollars per visit. The main problem seemed to be that the additional income would be reported and threaten the caregivers’ welfare benefits.

Stop whining that your jobs are difficult, researchers. Society doesn’t owe you a job. Earn it – get yourself and the people in your organization motivated to advance science.

http://www.sciencedirect.com/science/article/pii/S014976341630731X “Experience-induced transgenerational (re-)programming of neuronal structure and functions: Impact of stress prior and during pregnancy” (not freely available)

A gaping hole in a review of nutritional psychiatry

This December 2016 Australian review published in September 2017 concerned:

“..the nutritional psychiatry field..the neurobiological mechanisms likely modulated by diet, the use of dietary and nutraceutical interventions in mental disorders, and recommendations for further research.”


The reviewers inexplicably omitted acetyl-L-carnitine, which I first covered in A common dietary supplement that has rapid and lasting antidepressant effects. A PubMed search on “acetyl carnitine” showed over a dozen studies from the past twelve months that were relevant to the review’s subject areas. Here’s a sample, beginning with follow-on research published in June 2016 of the study I linked above:

Reply to Arduini et al.: Acetyl-l-carnitine and the brain: Epigenetics, energetics, and stress

Dietary supplementation with acetyl-l-carnitine counteracts age-related alterations of mitochondrial biogenesis, dynamics and antioxidant defenses in brain of old rats

Neuroprotective effects of acetyl-l-carnitine on lipopolysaccharide-induced neuroinflammation in mice: Involvement of brain-derived neurotrophic factor

ALCAR promote adult hippocampal neurogenesis by regulating cell-survival and cell death-related signals in rat model of Parkinson’s disease like-phenotypes

Analgesia induced by the epigenetic drug, L-acetylcarnitine, outlasts the end of treatment in mouse models of chronic inflammatory and neuropathic pain

The cited references in these recent studies were older, of course, and in the time scope of the review. There’s no excuse for this review’s omission of acetyl-L-carnitine.

https://www.cambridge.org/core/journals/proceedings-of-the-nutrition-society/article/nutritional-psychiatry-the-present-state-of-the-evidence/88924C819D21E3139FBC48D4D9DF0C08 “Nutritional psychiatry: the present state of the evidence” (not freely available)

How one person’s paradigms regarding stress and epigenetics impedes relevant research

This 2017 review laid out the tired, old, restrictive guidelines by which current US research on the epigenetic effects of stress is funded. The reviewer rehashed paradigms circumscribed by his authoritative position in guiding funding, and called for more government funding to support and extend his reach.

The reviewer won’t change his beliefs regarding individual differences and allostatic load since he helped to start those memes. US researchers with study ideas to develop evidence beyond such memes may have difficulties finding funding.

Here’s one example of the reviewer’s restrictive views taken from the Conclusion section:

Adverse experiences and environments cause problems over the life course in which there is no such thing as “reversibility” (i.e., “rolling the clock back”) but rather a change in trajectory [10] in keeping with the original definition of epigenetics [132] as the emergence of characteristics not previously evident or even predictable from an earlier developmental stage. By the same token, we mean “redirection” instead of “reversibility”—in that changes in the social and physical environment on both a societal and a personal level can alter a negative trajectory in a more positive direction.”

What would happen if US researchers proposed tests of his “there is no such thing as reversibility” axiom? To secure funding, his sphere of influence would probably steer the prospective studies’ experiments toward altering “a negative trajectory in a more positive direction” instead.

An example of his influence may be found in the press release of Familiar stress opens up an epigenetic window of neural plasticity where the lead researcher stated a goal of:

“..not to ‘roll back the clock’ but rather to change the trajectory of such brain plasticity toward more positive directions.”

I found nothing in citation [10] (of which the reviewer is a coauthor) where the rodent study researchers even attempted to directly reverse the epigenetic changes! The researchers under his guidance simply asserted:

“..a history of stress exposure can permanently alter gene expression patterns in the hippocampus and the behavioral response to a novel stressor”

without making any therapeutic efforts to test the permanence assumption!

Never mind that researchers outside the reviewer’s sphere of influence have done exactly that, reverse both gene expression patterns and behavioral responses! In any event, citation [10] didn’t support an “there is no such thing as reversibility” axiom.

The reviewer also implied that humans respond just like lab rats and can be treated as such. Notice that the above graphic conflated rodent and human behaviors. Further examples of this inappropriate merger of behaviors are in the Conclusion section.


What may be a more promising research approach to human treatments of the epigenetic effects of stress now that it’s 2017? I pointed out in The current paradigm of child abuse limits pre-childhood causal research:

“If the current paradigm encouraged research into treatment of causes, there would probably already be plenty of evidence to demonstrate that directly reducing the source of the damage would also reverse the damaging effects. There would have been enough studies done so that the generalized question of reversibility wouldn’t be asked.

Aren’t people interested in human treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?”

http://journals.sagepub.com/doi/full/10.1177/2470547017692328 “Neurobiological and Systemic Effects of Chronic Stress”

The current paradigm of child abuse limits pre-childhood causal research

As an adult, what would be your primary concern if you suspected that your early life had something to do with current problems? Would you be interested in effective treatments of causes of your symptoms?

Such information wasn’t available in this 2016 Miami review of the effects of child abuse. The review laid out the current paradigm mentioned in Grokking an Adverse Childhood Experiences (ACE) score, one that limits research into pre-childhood causes for later-life symptoms.


The review’s goal was to describe:

“How numerous clinical and basic studies have contributed to establish the now widely accepted idea that adverse early life experiences can elicit profound effects on the development and function of the nervous system.”

The hidden assumption of almost all of the cited references was that these distant causes can no longer be addressed. Aren’t such assumptions testable here in 2016?

As an example, the Discussion section posed the top nine “most pressing unanswered questions related to the neurobiological effects of early life trauma.” In line with the current paradigm, the reviewer assigned “Are the biological consequences of ELS [early life stress] reversible?” into the sixth position.

If the current paradigm encouraged research into treatment of causes, there would probably already be plenty of evidence to demonstrate that directly reducing the source of the damage would also reverse the damaging effects. There would have been enough studies done so that the generalized question of reversibility wouldn’t be asked.

Aren’t people interested in human treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?


The review also demonstrated how the current paradigm of child abuse misrepresents items like telomere length and oxytocin. Researchers on the bandwagon tend to forget about the principle Einstein expressed as:

“No amount of experimentation can ever prove me right; a single experiment can prove me wrong.”

That single experiment for telomere length arrived in 2016 with Using an epigenetic clock to distinguish cellular aging from senescence. The seven references the review cited for telomere length that had “is associated with” or “is linked to” child abuse findings should now be viewed in a different light.

The same light shone on oxytocin with Testing the null hypothesis of oxytocin’s effects in humans and Oxytocin research null findings come out of the file drawer. See their references, and decide for yourself whether or not:

“Claimed research findings may often be simply accurate measures of the prevailing bias.”

http://www.cell.com/neuron/fulltext/S0896-6273%2816%2900020-9 “Paradise Lost: The Neurobiological and Clinical Consequences of Child Abuse and Neglect”

Epigenetic consequences of early-life trauma: What are we waiting for?

This 2015 UK human review discussed:

“The progress that has been made by studies that have investigated the relationship between depression, early trauma, the HPA axis and the NR3C1 [glucocorticoid receptor] (GR) gene.

Gene linkage studies for depression, as well as for other common complex disorders, have been perceived by some to be of only limited success; hence the focus on GWAS [genome-wide association studies]. However, even for simple traits, genetic variants identified by GWAS are rarely shown to account for more than 20% of the heritability.

Epigenetic changes are potentially reversible and therefore amenable to intervention, as has been seen in cancer, cardiovascular disease and neurological disorders.”


Five of the review’s references included FKBP5 (a gene that produces a protein that dampens glucocorticoid receptor sensitivity) in their titles, but it wasn’t mentioned in the review itself. A search on FKBP5 also showed human studies such as the 2014 Placental FKBP5 Genetic and Epigenetic Variation Is Associated with Infant Neurobehavioral Outcomes in the RICHS Cohort that found:

“Adverse maternal environments can lead to increased fetal exposure to maternal cortisol, which can cause infant neurobehavioral deficits. The placenta regulates fetal cortisol exposure and response, and placental DNA methylation can influence this function.

Placental FKBP5 methylation reduces expression in a genotype specific fashion, and genetic variation supersedes this effect. These genetic and epigenetic differences in expression may alter the placenta’s ability to modulate cortisol response and exposure, leading to altered neurobehavioral outcomes.”


The authors listed seven human studies conducted 2008-2015 “investigating interactions between methylation of NR3C1, depression and early adversity”:

“Newborn offspring exposed to maternal depression in utero had increased methylation at [a GR CpG site] as well as adverse neurobehavioural outcomes.

Unlike the majority of animal studies examining NR3C1 methylation, many types of potential stressors, sometimes at different developmental stages, have been used to represent early human adversity.

Substantial differences can be expected in the nature of stresses prenatally compared with postnatally, as well as their developmental consequences.”

Seven human studies over the past eight years was a very small number considering both the topic’s importance and the number of relevant animal studies during the period.

Is the topic too offensive for human studies? What makes people pretend that adverse prenatal and perinatal environments have no lasting consequences to the child?

“Many more studies will be needed before effects directly attributable to early life trauma can be separated from those relating to tissue type.

Although investigators have amassed a considerable amount of evidence for an association between differential methylation and HPA axis function in humans, a causal relationship still needs to be fully established.”

Factors that disrupt neurodevelopment may be the largest originators of epigenetic changes that are sustained throughout an individual’s entire lifespan.

Are the multitude of agendas that have resources thrown at them more important than ensuring the well-being of a human before and after they are born?

https://www.researchgate.net/publication/282048312_Early_life_trauma_depression_and_the_glucocorticoid_receptor_gene_-_an_epigenetic_perspective “Early life trauma, depression and the glucocorticoid receptor gene–an epigenetic perspective”