Experiential feeling therapy addressing the pain of the lack of love.
This 2016 German human study with one subject found:
“The hypothalamus to be the primary generator of migraine attacks which, due to specific interactions with specific areas in the higher and lower brainstem, could alter the activity levels of the key regions of migraine pathophysiology.”
The subject underwent daily fMRI scans, and procedures to evoke brain activity. She didn’t take any medications, and suffered three migraine attacks during the 31-day experimental period.
“The dorsal pons has previously been found to be hyperactive during migraine. It’s been dubbed the brain’s ‘migraine generator.’ Schulte and May’s data suggest that this is not entirely true – rather, it looks like the hypothalamus may be the true generator of migraine, while the brainstem could be a downstream mediator of the disorder.
A hypothalamic origin of migraines would help to explain some of the symptoms of the disorder, such as changes in appetite, that often accompany the headaches.”
The above graphic looks like the result of feedback mechanisms that either didn’t exist or inadequately handled the triggering event. Other examples of the hypothalamus lacking feedback or being involved in a deviated feedback loop include:
- Lack of feedback to the HIF-1α signaling source mentioned in Lack of oxygen’s epigenetic effects
- Impaired hippocampal glucocorticoid negative feedback mentioned in Treating prenatal stress-related disorders with an oxytocin receptor agonist
There are many unanswered questions with a one-person study, of course. Addressing the cause of this painful condition would find out when, where, and how a person’s hypothalamus became modified to express migraine tendencies.
I’d guess that migraine tendencies may appear as early as the first trimester of pregnancy, given that a highly functional hypothalamus is needed for survival and development in our earliest lives. Gaining as much familial and historical information as possible from the person would be necessary steps in therapies that address migraine causes.
http://blogs.discovermagazine.com/neuroskeptic/2016/05/22/pinpointing-origins-of-migraine/ “Pinpointing the Origins of Migraine in the Brain”
This 2016 California human study found:
“A persistency of DNA methylation over time at key genomic loci associated with diabetic complications. Two sets of DNAs collected at least 16–17 years apart from the same participants are used to show the persistency of DNA-me over time.
Twelve annotated differentially methylated loci were common in both WB [whole blood] and Monos [blood monocytes], including thioredoxin-interacting protein (TXNIP), known to be associated with hyperglycemia and related complications.
The top 38 hyperacetylated promoters in cases included 15 genes associated with the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inflammatory pathway, which is strongly associated with diabetic complications.”
The researchers built on a series of studies that showed how subjects with early intensive interventions didn’t develop further complications, whereas subjects with later intensive interventions:
“Continued to develop complications, such as nephropathy, retinopathy, and macrovascular diseases, at significantly higher rates.
This persistence of benefit from early application of intensive therapy, called ‘metabolic memory,’ is an enigma.”
I’d say that the researchers needed to also consider a point of Enduring memories? Or continuous toxic stimulation? that:
“The lasting epigenomic effect would not be due to memory, but continuous stimulation by persistent pathogens or persistent components.”
Other studies that involved specific genes of this study include:
- Lack of oxygen’s epigenetic effects (NF-κB)
- A followup study of DNA methylation and age (NF-κB)
- Epigenetic memories of stress as therapeutic targets (TXNIP)
http://www.pnas.org/content/113/21/E3002.full “Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort”
“Parental behavioural traits can be transmitted by non-genetic mechanisms to the offspring.
We show that four anxiety/stress-reactive traits are transmitted via independent iterative-somatic and gametic epigenetic mechanisms across multiple generations.
As the individual traits/pathways each have their own generation-dependent penetrance and gender specificity, the resulting cumulative phenotype is pleiotropic. In the context of genetic diseases, it is typically assumed that this phenomenon arises from individual differences in vulnerability to the various effects of the causative gene. However, the work presented here reveals that pleiotropy can be produced by the variable distribution and segregated transmission of behavioural traits.”
A primary focus was how anxiety was transmitted from parents to offspring:
“The iterative propagation of the male-specific anxiety-like behaviour is most compatible with a model in which proinflammatory state is propagated from H [serotonin1A receptor heterozygote F0] to F1 [first generation] females and in which the proinflammatory state is acquired by F1 males from their H mothers, and then by F2 [second generation] males from their F1 mothers.
We propose that increased levels of gestational MIP-1β [macrophage inflammatory protein 1β] in H and F1 mothers, together with additional proinflammatory cytokines and bioactive proteins, are required to produce immune system activation in their newborn offspring, which in turn promotes the development of the anxiety-like phenotype in males.
In particular, increase in the number of monocytes and their transmigration to the brain parenchyma in F1 and F2 males could be central to the development of anxiety.”
Due to my quick take on the study title – “Behavioural traits propagate across generations..” – I had expectations of this study that weren’t born out. My criticisms below relate to my expectations of what the researchers could have done versus what they did.
The researchers studied parental transmission of behavioral traits and epigenetic changes. Their study design removed prenatal and postnatal parental behavioral transmission of behavioral traits and epigenetic changes as each generation’s embryos were implanted into foster wild-type (WT) mothers.
The study design substituted the foster mothers’ prenatal and postnatal parental environments for the biological parents’ parental environments. So we didn’t find out, for example:
- What effects the anxious F1 males’ behaviors may have had on their offsprings’ behaviors and epigenetic changes
- Whether the anxious, hypoactive, overly stress-reactive, hypothermic F2 males’ behaviors affected their offsprings’ behaviors and epigenetic changes
- To what extents the overly stress-reactive F1 mothers’ prenatal environments and postnatal behaviors induced behaviors and/or epigenetic changes in their children, and whether the F2 children’s parental behaviors subsequently induced behaviors and/or epigenetic changes in the F3 generation.
How did the study meet the overall goal of rodent studies: to help humans?
- Only a minority of humans experienced an early-life environment that included primary caregivers other than our biological parents.
- Very few of us experienced a prenatal environment other than our biological mothers.
- Maybe the researchers filled in some gaps in previous rodent studies, such as determining what is or isn’t a “true transgenerational mechanism.”
As an example of a rodent study that more closely approximated human conditions, the behavior of a mother whose DNA was epigenetically changed by stress induced the same epigenetic changes to her child’s DNA when her child was stressed per One way that mothers cause fear and emotional trauma in their infants:
“Our results provide clues to understanding transmission of specific fears across generations and its dependence upon maternal induction of pups’ stress response paired with the cue to induce amygdala-dependent learning plasticity.”
How did parental behavioral transmission of behavioral traits and epigenetic changes become a subject not worth investigating? These traits and effects can be seen everyday in real-life human interactions and physiology. But when investigating human correlates with behavioral epigenetic changes of rodents in the laboratory, parental behavioral transmission of behavioral traits is often treated the way this study treated it: as a confounder.
I doubt that people who have reached some degree of honesty about their early lives and concomitant empathy for others would agree with this prioritization.
http://www.nature.com/ncomms/2016/160513/ncomms11492/full/ncomms11492.html “Behavioural traits propagate across generations via segregated iterative-somatic and gametic epigenetic mechanisms”
This 2016 Finnish review’s subject was the epigenetic effects of hypoxia:
“Ever since the Cambrian period, oxygen availability has been in the center of energy metabolism. Hypoxia stabilizes the expression of hypoxia-inducible transcription factor-1α (HIF-1α), which controls the expression of hundreds of survival genes related to enhanced energy metabolism and autophagy.
There are several other signals, mostly related to stresses, which can increase the expression of HIF factors and thus improve cellular survival. However, a chronic activation of HIF factors can have detrimental effects, e.g. stimulate cellular senescence and tissue fibrosis commonly enhanced in age-related diseases.
Stabilization of HIF-1α increases the expression of histone lysine demethylases (KDM). Hypoxia-inducible KDMs support locally the gene transcription induced by HIF-1α, although they can also control genome-wide chromatin landscape, especially KDMs which demethylate H3K9 and H3K27 sites (repressive epigenetic marks).”
Gene areas where HIF-1α is involved include:
Figure 1 was instructive in that the reviewers pointed out the lack of a feedback mechanism in HIF-1α signaling. A natural lack of feedback to the HIF-1α signaling source contributed to diseases such as:
- “age-related macular degeneration
- cancer progression
- chronic kidney disease
- adipose tissue fibrosis
- detrimental effects which are linked to epigenetic changes.”
The point was similar to a study referenced in The PRice “equation” for individually evolving: Which equation describes your life? that:
“Evolution may preferentially mitigate damage to a biological system than reduce the source of this damage.”
The review was complicated primarily because the subject has many interdependencies and timings within a complex network. Contexts are important:
“The cross-talk between NF-κB [nuclear factor kappa B] and HIF-1α in inflammation might be organized in cell type and context-dependent manner.
It seems that ROS  affect the HIF-1α signaling in a context-dependent manner.
Hypoxia stimulated the expression of KDM3A and KDM4B genes in different cellular contexts. Given that KDM3A and KDM4B are the major histone demethylases which remove the repressive H3K9 sites, their role as transcriptional cofactors seems to be important in the activation of HIF-1α signaling..members of KDM4 subfamily have a crucial role in the DNA repair systems, although the responses seem to be enzyme-specific and appear in a context-dependent manner.
Acute hypoxia can stimulate cell-cycle arrest but does not provoke cellular senescence in all contexts.”
It wasn’t mentioned that hypoxia evokes cellular Adaptations to stress encourage mutations in a DNA area that causes diseases.
The review was tailored for the publishing journal Aging and Disease, and the subject was best summed up by:
“HIF-1α can control cellular fate in adult animals, either stimulating proliferation or triggering cellular senescence, by regulating the expression of different KDMs in a context-dependent manner.”
The review covered hypoxic conditions during human development that are clearly the origins of many immediate and later-life diseases. However, the cited remedies only addressed symptoms.
That these distant causes can no longer be addressed is a hidden assumption of research and treatment of effects of health problems. Aren’t such assumptions testable here in 2016?
http://www.aginganddisease.org/article/2016/2152-5250/147502 “Hypoxia-Inducible Histone Lysine Demethylases: Impact on the Aging Process and Age-Related Diseases”
“It was like Tom had tried to return home,” says Jacky Sweetnam. “But he didn’t quite make it.”
In memoriam to my father who died twenty years ago last week. World War II ruined his life with undiagnosed PTSD, some of the effects of which affected his children. His brother was a Navy hospital corpsman during the slaughter at Iwo Jima, and was even more afflicted. Neither of them were ever treated.
This 2016 UK review subject was the interplay of genomic imprinting and intergenerational epigenetic information transfer:
“A range of evolutionary adaptations associated with placentation transfers disproportionate control of this process to the matriline, a period unique in mammalian development in that there are three matrilineal genomes interacting in the same organism at the same time (maternal, foetal, and postmeiotic oocytes).
Genomic imprinting is absent in egg laying mammals and only around 6 imprinted genes have been detected in a range of marsupial species; this is in contrast to eutherian mammals where around 150 imprinted genes have been described.
The interactions between the maternal and developing foetal hypothalamus and placenta can provide a template by which a mother can transmit potentially adaptive information concerning potential future environmental conditions to the developing brain.
In circumstances either where the early environment provides inaccurate cues to the environmental conditions prevailing when adult due to rapid environmental change or when disruptions to normal neural development occur, the mismatch between the environmental predictions made during early development and subsequent reality may mean that an organism may have a poorly adapted phenotype to its adult environment. An appreciation of these underlying evolutionary salient processes may provide a novel perspective on the casual [causal] mechanisms of a range of health problems.
The concept of a brain that is not pathological in the classical sense but it is simply mismatched to its environment has been most extensively studied in the context of ancestral and early developmental nutrition. However, this concept can be extended to provide insights into the development of a range of alternative neural phenotypes.”
The review’s final sentence was:
“Examination of the adaptive potential of a range of neural and cognitive deficits in the context of evolutionary derived foetocentric brain and placental development, epigenetics and environmental adaptation may provide novel insights into the development and potential treatment of a range of health, neurological, and cognitive disorders.”
One of the reviewers was cited in Epigenetic DNA methylation and demethylation with the developing fetus, which the review cited along with Epigenetic changes in the developing brain change behavior.
Researchers who avoid hypotheses that can’t be proven wrong could certainly test the subject matter of this review if they investigated their subjects’ histories.
For example, let’s say a patient/subject had symptoms where the “150 imprinted genes” were implicated. What are the chances a clinician or researcher would be informed by this review’s material and investigate the mother’s and grandmother’s histories?
For clinicians or researchers who view histories as irrelevant busywork: how many tens of millions of people alive today have mothers who were fetuses when their grandmothers were adversely affected by violence? Wouldn’t it be appropriate to assess possible historical contributions of:
“The mismatch between the environmental predictions made during early development and subsequent reality”
to the patient’s/subject’s current symptoms?
http://www.hindawi.com/journals/np/2016/6827135/ “Placental, Matrilineal, and Epigenetic Mechanisms Promoting Environmentally Adaptive Development of the Mammalian Brain”