Ideaesthesia!

This 2018 UK review subject was colored-hearing arising on hearing music:

“Music-colour synaesthesia has a broad scope encompassing not only tone-colour synaesthesia elicited on hearing individual tones, but a complex and idiosyncratic mixture of phenomenological experiences often mediated by timbre, tempo, emotion and differing musical style.

The possession of synaesthesia or absolute pitch was shown to have very little effect on the actual colours chosen for each of the musical excerpts, but it might be reasonable to expect that music that elicits a strong emotional response may be more likely to induce synaesthesia than music that does not.

The examination of eight neuroimaging studies were found to be largely inconclusive in respect of confirming the perceptual nature of music-colour synaesthesia. Neither the hyperconnectivity nor the disinhibited feedback theory currently holds as a single categorical explanation for synaesthesia.

Theories promoting the notion of ‘ideaesthesia’ have highlighted the importance of the role of concept and meaning in the understanding of synaesthesia..and a replacement definition: Synaesthesia is a phenomenon in which a mental activation of a certain concept or idea is associated consistently with a certain perception-like experience.”

The review cited other interesting reviews, including The Merit of Synesthesia for Consciousness Research. The cited “eight neuroimaging studies were found to be largely inconclusive” and much of the review was philosophizing and casting around for clues.


One relevant element missed by the underlying research and the review was critical periods of human development. A cited reference in How brains mature during critical periods was Sensitive periods in human development: Evidence from musical training (not freely available) which illuminated some aspects of the research:

“In contrast to a critical period, where a function cannot be acquired outside the specific developmental window, a sensitive period denotes a time where sensory experience has a relatively greater influence on behavioral and cortical development. Sensitive periods may also be times when exposure to specific stimuli stimulates plasticity, enhancing changes at the neuronal and behavioral levels.

The developmental window for absolute pitch may be more similar to a critical than a sensitive period.

The auditory cortex appears to have an unusually long period of developmental plasticity compared with other sensory systems; changes in its cellular organization and connectivity continue into late childhood.

The effects of musical training have been shown to impact auditory processing in the brainstem as well.”

Let’s say that a researcher wants to examine, for example, absolute pitch, a rare trait, present in a subset of synesthetes – music-color, another rare trait. The study as designed would probably be underpowered due to an insufficient number of subjects, and it would subsequently find “very little effect.”

Let’s say another researcher focused on brain areas in the cerebrum, and like the eight cited studies, ignored the nuclei in the pons part of the brainstem which are the first brain recipients of sound and equilibrium information from the inner ear via the eighth cranial nerve. Like those studies, they were also biased against including other brain areas that would indicate “a strong emotional response.” A study design that combined leaving out important brain-area participants in the synesthesia process with a few number of synesthetes would be unlikely to find conclusive evidence.

The reviewer viewed the lack of evidence from “eight neuroimaging studies” as indicating something about the “perceptual nature of music-colour synaesthesia.” An alternative view is that the lack of evidence had more to do with study designs that:

  • Had a small number of subjects;
  • Didn’t investigate likely music-color synesthesia development periods;
  • Omitted relevant brain areas; and
  • Didn’t investigate associations of music-color synesthesia with epigenetic states.

Does an orangey twilight of fading sunflowers help you feel?

https://www.sciencedirect.com/science/article/pii/S1053810017305883 “Music-colour synaesthesia: Concept, context and qualia” (not freely available)

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in utero prevention of breast cancer by a broccoli sprouts diet

This 2018 Alabama rodent study investigated the epigenetic effects on developing breast cancer of timing a sulforaphane-based broccoli sprouts diet. Timing of the diet was as follows:

  1. Conception through weaning (postnatal day 28), named the Prenatal/maternal BSp (broccoli sprouts) treatment (what the mothers ate starting when they were adults at 12 weeks until their pups were weaned; the pups were never on a broccoli sprouts diet);
  2. Postnatal day 28 through the termination of the experiment, named the Postnatal early-life BSp treatment (what the offspring ate starting at 4 weeks; the mothers were never on a broccoli sprouts diet); and
  3. Postnatal day 56 through the termination of the experiment, named the Postnatal adult BSp treatment (what the offspring ate starting when they were adults at 8 weeks; the mothers were never on a broccoli sprouts diet).

“The experiment was terminated when the mean tumor diameter in the control mice exceeded 1.0 cm.

Our study indicates a prenatal/maternal BSp dietary treatment exhibited maximal preventive effects in inhibiting breast cancer development compared to postnatal early-life and adult BSp treatments in two transgenic mouse models that can develop breast cancer.

Postnatal early-life BSp treatment starting prior to puberty onset showed protective effects in prevention of breast cancer but was not as effective as the prenatal/maternal BSp treatment. However, adulthood-administered BSp diet did not reduce mammary tumorigenesis.

The prenatal/maternal BSp diet may:

  • Primarily influence histone modification processes rather than DNA methylation processes that may contribute to its early breast cancer prevention effects;
  • Exert its transplacental breast cancer chemoprevention effects through enhanced histone acetylation activator markers due to reduced HDAC1 expression and enzymatic activity.

This may be also due to the importance of a dietary intervention window that occurs during a critical oncogenic transition period, which is in early life for these two tested transgenic mouse models. Determination of a critical oncogenic transition period could be complicated in humans, which may partially explain the controversial findings of the adult BSp treatment on breast cancer development in the tested mouse models as compared the previous studies. Thus long-term consumption of BSp diet is recommended to prevent cancers in humans.”


“The dietary concentration for BSp used in the mouse studies was 26% BSp in formulated diet, which is equivalent to 266 g (~4 cups) BSp/per day for human consumption. Therefore, the concentration of BSp in this diet is physiological available and represents a practical consumption level in the human diet.

Prior to the experiment, we tested the potential influences of this prenatal/maternal BSp regimen on maternal and offspring health as well as mammary gland development in the offspring. Our results showed there was no negative effect of this dietary regimen on the above mentioned factors (data not shown) suggesting this diet is safe to use during pregnancy.”


I downgraded the study’s rating because I didn’t see where the sulforaphane active content of the diet was defined. It’s one thing to state:

“SFN as the most abundant and bioactive compound in the BSp diet has been identified as a potent HDAC inhibitor that preferably influences histone acetylation processes.”

and describe how sulforaphane may do this and may do that, and include it in the study’s title.

It’s another thing to quantify an animal study into findings that can help humans. Normal people aren’t going to eat “4 cups BSp/per day” but we may take one capsule of a sulforaphane dietary supplement when the price is $.20 a day.

The study’s food manufacturer offers dietary products to the public without quantifying all of the active contents like sulforaphane. Good for them if they can stay in business by serving customers who can’t be bothered with scientific evidence.

These researchers shouldn’t have conducted a study using the same lack of details as the food manufacturer provided, though. They should have either tasked the manufacturer to specify the sulforaphane active content, or contracted the analysis.

Regarding timing of a sulforaphane-based broccoli sprouts diet for humans, the study also didn’t provide evidence for recommending:

“Thus long-term consumption of BSp diet is recommended to prevent cancers in humans.”

http://cancerpreventionresearch.aacrjournals.org/content/early/2018/05/15/1940-6207.CAPR-17-0423.full-text.pdf “Temporal efficacy of a sulforaphane-based broccoli sprout diet in prevention of breast cancer through modulation of epigenetic mechanisms”

A dietary supplement that reversed age-related hearing problems in the brainstem

This 2018 Nevada rodent study was on acetyl-L-carnitine’s action in the brainstem:

“We examined age-related changes in the efficiency of synaptic transmission at the calyx of Held, from juvenile adults (1-month old) and late middle-age (18- to 21-month old) mice. The calyx of Held synapse has been exploited as a model for understanding excitation-secretion coupling in central glutamatergic neurons, and is specialized for high-frequency transmission as part of a timing circuit for sound localization.

Our observations suggest that during aging, there is neuronal cell loss in the MNTB [Medial nucleus of the trapezoid body, a collection of brainstem nuclei in an area that’s the first recipient of sound and equilibrium information], similar to previous reports. In remaining synapses of the MNTB, we observed severe impairments in transmission timing and SV [synaptic vesicle] recycling, resulting in timing errors and increased synaptic depression in the calyx of Held synapse. These defects reduce the efficacy of this synapse to encode temporally sensitive information and are likely to result in diminished sound localization.

We orally administered ALCAR for 1 month and found that it reversed transmission defects at the calyx of Held synapse in the older mice.

These results support the concept that facilitators of mitochondrial metabolism and antioxidants may be an extremely effective therapy to increase synaptic function and restore short-term plasticity in aged brains, and provide for the first time a clear mechanism of action for ALCAR on activity-dependent synaptic transmission.


Human brainstem research is neglected, as noted by Advance science by including emotion in research. Evidence from such research doesn’t play well with beliefs in the popular models and memes of human cerebral dominance.

Do you know any “late middle-age” people who have obvious auditory and synaptic deficits? What if some of the neurobiological causes of what’s wrong in their brains could be “reversed by ALCAR?”

Before using this study as a guide, however, I’ve asked the study’s researchers to calculate the human-equivalent dosage. When I translated the “daily dose of ~2.9 g/kg/d” it worked out to several hundred times the 500 mg-1 g dietary supplement dosage of acetyl-L-carnitine.

The study’s corresponding coauthor replied:

“This is indeed much larger than that normally consumed by humans via dietary supplementation. We are currently working to determine the effective ‘minimal’ dose of ALCAR and alpha lipoic acid, to better assist guidelines for human application of this supplement.”

https://www.researchgate.net/publication/323941877_Age-related_defects_in_short-term_plasticity_are_reversed_by_acetyl-L-carnitine_at_the_mouse_calyx_of_Held “Age-related defects in short-term plasticity are reversed by acetyl-L-carnitine at the mouse calyx of Held”

Immune memory of pregnancies

This 2018 Israeli human study subject was natural killer cell epigenetic memory of pregnancies:

“Natural killer (NK) cells were first discovered for their ability to kill tumor cells, and later found to also kill pathogen-infected cells.

Different tissue-resident subpopulations of human NK cells exist throughout the body, displaying unique phenotypic and functional properties. One of the most fascinating tissue-resident subsets of NK cells, termed decidual NK cells, is found at the maternal fetal interface (decidua) in direct contact with the placenta.

We discovered a population found in repeated pregnancies, which has a unique transcriptome and epigenetic signature..have open chromatin around the enhancers of [growth factor genes] IFNG [essential for angiogenesis] and VEGFA [supporting vascular formation].

The pregnancy-related NK memory cells identified here might represent the first example of improved function of NK cells that occurs under healthy physiological conditions.”

One source for the experiments was:

“Decidual samples from healthy women who underwent elective first trimester terminations of normal pregnancies.”

https://www.sciencedirect.com/science/article/pii/S1074761318301286 “Trained Memory of Human Uterine NK Cells Enhances Their Function in Subsequent Pregnancies” (not freely available)

A trio of epigenetic clock studies

The first 2018 epigenetic clock human study was from Finland:

“We evaluated the association between maternal antenatal depression and a novel biomarker of aging at birth, namely epigenetic gestational age (GA) based on fetal cord blood methylation data. We also examined whether this biomarker prospectively predicts and mediates maternal effects on early childhood psychiatric problems.

Maternal history of depression diagnosed before pregnancy and greater antenatal depressive symptoms were associated with child’s lower epigenetic GA. Child’s lower epigenetic GA, in turn, prospectively predicted total and internalizing problems and partially mediated the effects of maternal antenatal depression on internalizing problems in boys.”


Listening to a podcast by one of the coauthors, although the researchers’ stated intent was to determine the etiology of the findings, I didn’t hear any efforts to study the parents in sufficient detail to be able to detect possible intergenerational and transgenerational epigenetic inheritance causes and effects. There were the usual “associated with” and “it could be this, it could be that” hedges, which were also indicators of the limited methods employed toward the study’s limited design.

Why was an opportunity missed to advance human research in this area? Are researchers satisfied with non-causal individual differences non-explanations instead of making efforts in areas that may produce etiological findings?

https://www.jaacap.org/article/S0890-8567(18)30107-2/pdf “The Epigenetic Clock at Birth: Associations With Maternal Antenatal Depression and Child Psychiatric Problems” (not freely available)


The second 2018 epigenetic clock human study was from Alabama:

“We estimated measures of epigenetic age acceleration in 830 Caucasian participants from the Genetics Of Lipid Lowering Drugs and diet Network (GOLDN) considering two epigenetic age calculations.

Both DNA methylation age estimates were highly correlated with chronological age. We found that the Horvath and Hannum measures of epigenetic age acceleration were moderately correlated.

The Horvath age acceleration measure exhibited marginal associations with increased postprandial [after eating a meal] HDL [high-density lipoprotein], increased postprandial total cholesterol, and decreased soluble interleukin 2 receptor subunit alpha (IL2sRα). The Hannum measure of epigenetic age acceleration was inversely associated with fasting HDL and positively associated with postprandial TG [triglyceride], interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor alpha (TNFα).

Overall, the observed effect sizes were small.


https://clinicalepigeneticsjournal.biomedcentral.com/track/pdf/10.1186/s13148-018-0481-4 “Metabolic and inflammatory biomarkers are associated with epigenetic aging acceleration estimates in the GOLDN study”


The third 2018 epigenetic clock human study was a meta-analysis of cohorts from the UK, Italy, Sweden, and Scotland:

“The trajectories of Δage showed a declining trend in almost all of the cohorts with adult sample collections. This indicates that epigenetic age increases at a slower rate than chronological age, especially in the oldest population.

Some of the effect is likely driven by survival bias, where healthy individuals are those maintained within a longitudinal study, although other factors like underlying training population for the respective clocks may also have influenced this trend. It may also be possible that there is a ceiling effect for Δage whereby epigenetic clock estimates plateau.”

https://academic.oup.com/biomedgerontology/advance-article/doi/10.1093/gerona/gly060/4944478 “Tracking the Epigenetic Clock Across the Human Life Course: A Meta-analysis of Longitudinal Cohort Data”

How to hijack science: Ignore its intent and focus on the 0.0001%

This 2018 Belgian review hijacked science to further an agenda:

“We addressed this issue at the LATSIS Symposium ‘Transgenerational Epigenetic Inheritance: Impact for Biology and Society’, in Zürich, 28–30 August 2017, and here provide important arguments why environmental and lifestyle-related exposures in young men should be studied.”

The reviewer DETRACTED from science in the studied area – transgenerational epigenetic inheritance – by ignoring its intent. As shown by A self-referencing study of transgenerational epigenetic inheritance which I also curated today, the purpose of such animal studies is to find the mechanisms in order to help humans.


Putting that study’s graphic into human terms, F3 men may be adversely affected by their F0 great-grandmothers being poisoned while pregnant with their F1 grandfathers, who – with their F2 fathers – may have also been adversely affected.

What the reviewer asserted without proof:

“The importance of maternal lifestyle, diet and other environmental exposures before and during gestation period is well recognized.”

is NOT TRUE for the studied area.

The evidence disproving this assertion is that NO scientifically adequate HUMAN studies of transgenerational epigenetic inheritance have been published!

Ever!!

There’s a huge gap between “The importance..is well recognized” of anything regarding transgenerational epigenetic inheritance and ZERO human studies.

Why has no one published scientifically adequate human evidence to demonstrate “Transgenerational Epigenetic Inheritance: Impact for Biology and Society” on ALL of the F1, F2, and F3 human generations as consequences “of maternal lifestyle, diet and other environmental exposures before and during gestation period?” What are we waiting for?

The reviewer said “young men should be studied” but said nothing about resolving bottlenecks in funding human research of the studied area. Do researchers have opportunities to make a NON-AGENDA-DRIVEN difference in this field?

With ZERO published human studies, can transgenerational epigenetic inheritance research be recharacterized into a female vs. male agenda? The reviewer’s attempt diminished the importance of research into human critical development periods.

The agenda’s viewpoint ignored human correlates of evidence from animal studies like The lifelong impact of maternal postpartum behavior:

“The defect in maternal care induced by gestational stress programs the development of the offspring.”

Will the reviewer’s suggested interventions – such as changing an adult’s lifestyle a long time after their development was altered – somehow make up for what went wrong early in their life, even before they were born?

With the evidence from animal studies such as:

is there any doubt that similar mechanisms may be involved in humans, and that human phenotypes may likewise be intergenerationally and/or transgenerationally transmitted?

The reviewer asserted:

“Studying humans is challenging, because of ethical reasons”

But do “ethical reasons” prohibit non-instigating human studies of stress, the intergenerationally and transgenerationally transmitted effects of which seem to be ubiquitous among humans?

In The Not-Invented-Here syndrome I pointed out another problem that the reviewer’s agenda is less than helpful in resolving:

“How can animal studies like the current study help humans when their models don’t replicate common human conditions? This failure to use more relevant models has follow-on effects such as human intergenerational and transgenerational epigenetic inheritance being denigrated due to insufficient evidence.”

I’ll repeat What is a father’s role in epigenetic inheritance? in closing:

“The review focused on 0.0001% of the prenatal period for what matters with the human male – who he was at the time of a Saturday night drunken copulation – regarding intergenerational and transgenerational epigenetic inheritance of metabolic diseases.

The human female’s role – who she was at conception AND THEN what she does or doesn’t do during the remaining 99.9999% of the prenatal period to accommodate the fetus and prevent further adverse epigenetic effects from being intergenerationally and transgenerationally transmitted – wasn’t discussed.

Who benefits from this agenda’s narrow focus?”

https://academic.oup.com/eep/article/4/2/dvy007/4987171 “POHaD: why we should study future fathers”

A self-referencing study of transgenerational epigenetic inheritance

This 2018 Washington rodent study subject was transgenerational epigenetic inheritance caused by a fungicide that’s been phased out or banned for over a decade:

“This study was designed to help understand how three different epigenetic processes in sperm are correlated with vinclozolin-induced epigenetic transgenerational inheritance of disease.

  1. Most DMRs [differential DNA-methylated regions] identified in this study are unique between the F1, F2, and F3 generations.
  2. The number of lncRNA was much higher than the number of sncRNA [small noncoding RNA, including microRNA]. The overlap between each generation was very low or nonexistent.
  3. The F1 and the F2 generation control versus vinclozolin lineage sperm had negligible DHRs [differential histone retention sites]. This observation suggests that the direct vinclozolin exposure does not alter histone retention or trigger any changes. However, the F3 generation control versus vinclozolin lineage sperm DHRs increased considerably.

It appears that the phenomenon is more complex than just a direct exposure triggering the formation of epimutations that are then simply maintained in the subsequent generations.”


There’s something odd about a study where a third of the 87 cited references list one of the study’s coauthors, who also coauthored A review of epigenetic transgenerational inheritance of reproductive disease. I couldn’t find a satisfactory explanation for the study’s over-the-top self-referencing.

What do you think?

I asked the coauthors why a third of the cited references were self-referencing. The lead author replied:

“The field in epigenetic transgenerational inheritance is expanding, however it is still hard for us to find relevant studies in rodents or human that we can cite. Most of the time DNA methylation, ncRNA and histone modifications are investigated from a direct exposure and/or from a purely mechanistic angle (e.g. DNA methylation of specific genes).

In contrast, transgenerational phenotypes and toxicology by definition excludes direct exposure and must be transmitted through multiple generations (the F3 generation is the first transgenerational one). We are not looking at specific genes but using whole genome sequencing technologies which is a broader approach.

Besides, if you do a pubmed search with the keywords “epigenetics” and “transgenerational”, you will probably find that more than 50% of the studies have been done by Dr Michael K. Skinner. He is also one of the first researcher who started to work on the epigenetic transgenerational inheritance phenomenon 15 years ago. Not citing his previous work is challenging.

We hope to see other labs contributing to this particular field and we will be delighted to cite them. In the meantime, our only option is to reference our previous work.”

I replied:

“Thank you for your reply! It must be exasperating to see other researchers stop their studies short of the F3 generation for no apparent or disclosed reason.

Have you seen even one scientifically adequate human study of transgenerational epigenetic inheritance?”

https://academic.oup.com/eep/article/4/2/dvy010/4987173 “Alterations in sperm DNA methylation, non-coding RNA expression, and histone retention mediate vinclozolin-induced epigenetic transgenerational inheritance of disease”