Gaze at the sky
And picture a memory of days in your life
You knew what it meant to be happy and free
With time on your side
Remember your daddy when no one was wiser
Your ma used to say
That you would go farther than he ever could
With time on your side
Think of a boy with the stars in his eyes
Longing to reach them
But frightened to try
But day after day
The show must go on
And time slipped away
Before you could build any castles in Spain
The chance had gone by
With nothing to say
And no one to say it to
Nothing has changed
You still got it all to do
Surely you know
The chance has gone by
Think of a boy with the stars in his eyes
Longing to reach them
But frightened to try
But day after day
The show must go on
And you gaze at the sky
And picture a memory of days in your life
With time on your side
With time on your side
This 2018 Chinese study electronically modeled the brain’s circuits to evaluate memory transfer mechanisms:
“During non-rapid-eye-movement (NREM) sleep, thalamo-cortical spindles and hippocampal sharp wave-ripples have been implicated in declarative memory consolidation. Evidence suggests that long-term memory consolidation is coordinated by the generation of:
- Hierarchically nested hippocampal ripples (100-250 Hz),
- Thalamo-cortical spindles (7-15 Hz), and
- Cortical slow oscillations (<1 Hz)
enabling memory transfer from the hippocampus to the cortex.
Consolidation has also been demonstrated in other brain tasks, such as:
- In the acquisition of motor skills, where there is a shift from activity in prefrontal cortex to premotor, posterior parietal, and cerebellar structures; and
- In the transfer of conscious to unconscious tasks, where activity in initial unskilled tasks and activity in skilled performance are located in different regions, the so-called ‘scaffolding-storage’ framework.
By separating a neural circuit into a feedforward chain of gating populations and a second chain coupled to the gating chain (graded chain), graded information (i.e. information encoded in firing rate amplitudes) may be faithfully propagated and processed as it flows through the circuit. The neural populations in the gating chain generate pulses, which push populations in the graded chain above threshold, thus allowing information to flow in the graded chain.
In this paper, we will describe how a set of previously learned synapses may in turn be copied to another module with a pulse-gated transmission paradigm that operates internally to the circuit and is independent of the learning process.”
The study had neither been peer-reviewed, nor were the mechanisms tested in living beings.
https://www.biorxiv.org/content/early/2018/07/27/351114 “A Mechanism for Synaptic Copy between Neural Circuits”
Here are the most popular of the 65 posts I’ve made so far in 2018, starting from the earliest:
“Although there is an increasing line of evidence from preclinical models of addiction, there are only a few human studies that systematically assessed DNA methylation in addiction. Most of the studies were done on small cohorts and focused on one or a few candidate genes, except in the case of alcohol use where larger studies have been carried out.
A long line of evidence suggests that abnormal patterns of gene expression occur in brain regions related to drug addiction such as the nucleus accumbens, prefrontal cortex, amygdala, and the ventral tegmental area.
Using the “incubation of craving” model in rats trained to self-administer cocaine, and treated with either SAM or RG108, the genome-wide DNA methylation and gene expression landscape in the nucleus accumbens after short (1 day) and long (30 days) abstinence periods and the effects of epigenetic treatments were delineated. The main findings are:
- A long incubation period results in robust changes in methylation;
- Direct accumbal infusion of SAM that is paired with a “cue” after long incubation times increases drug-seeking behavior,
- Whereas a single treatment with RG108 decreases this behavior.
Importantly, the effects of these single administrations of a DNA methylation inhibitor remain stable for 30 more days. These data suggest that DNA methylation might be mediating the impact of “incubation” on the craving phenotype and that this phenotype could be reprogrammed by a DNA demethylation agent.”
The subject has a large scope, and a narrow aspect was presented in this paper. Rodent research by one of the coauthors that was cited, Chronic pain causes epigenetic changes in the brain and immune system, provided some relevant details.
The review covered neither human dimensions of the impacts of unfulfilled needs nor investigations of exactly what pain may impel human drug-seeking behavior. The “Implications for Diagnostic and Therapeutics” were largely at the molecular level.
https://www.sciencedirect.com/science/article/pii/S1877117318300164 “The Role of DNA Methylation in Drug Addiction: Implications for Diagnostic and Therapeutics” (not freely available)
This 2018 UK review subject was colored-hearing experiences from 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.”
Much of the review was philosophizing and casting around for clues. The review cited interesting studies and reviews, including The Merit of Synesthesia for Consciousness Research.
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 wanted – as one cited study did – to examine 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, the researcher was also biased against including limbic 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 “inconclusive” evidence had more to do with study designs that:
- Had a small number of subjects;
- Omitted brain areas relevant to the music-color synesthesia process;
- Didn’t investigate likely music-color synesthesia development periods; and
- Didn’t investigate associations of music-color synesthesia with epigenetic states.
Consider the magnitude of omitting the thalamus from synesthesia studies as one “perceptual nature” example. Just the background information of Thalamus gating and control of the limbic system and cerebrum is a form of memory indicated its relevance to synesthesia:
“Despite the fundamental differences between visual, auditory and somatosensory signals, the basic layouts of the thalamocortical systems for each modality are quite similar.
For a given stimulus, the output neural response will not be static, but will depend on recent stimulus and response history.
Sensory signals en route to the cortex undergo profound signal transformations in the thalamus. A key thalamic transformation is sensory adaptation in which neural output adjusts to the statistics and dynamics of past stimuli.”
One of this study’s researchers described ways that an individual’s “stimulus and response history” became unconscious memories with the thalamus. Including the thalamus in synesthesia studies may also have findings that involve reliving or re-experiencing a memory, possibly an emotional memory.
In such future research, it could be a design element to ask synesthetes before and after the experiment to identify feelings and memories accompanying synesthesia experiences.
It shouldn’t be a requirement, however, to insist that memories and emotions be consciously identified in order to be included in the findings. Human studies, for example, Unconscious stimuli have a pervasive effect on our brain function and behavior have found:
“Pain responses can be shaped by learning that takes place outside conscious awareness.
Our results support the notion that nonconscious stimuli have a pervasive effect on human brain function and behavior and may affect learning of complex cognitive processes such as psychologically mediated analgesic and hyperalgesic responses.”
Does an orangy twilight of aging sunflowers help you feel?
https://www.sciencedirect.com/science/article/pii/S1053810017305883 “Music-colour synaesthesia: Concept, context and qualia” (not freely available)
This 2018 US Veterans Administration review subject was resiliency and stress responses:
“Neurobiological and behavioral responses to stress are highly variable. Exposure to a similar stressor can lead to heterogeneous outcomes — manifesting psychopathology in one individual, but having minimal effect, or even enhancing resilience, in another.
We highlight aspects of stress response modulation related to early life development and epigenetics, selected neurobiological and neurochemical systems, and a number of emotional, cognitive, psychosocial, and behavioral factors important in resilience.”
The review cited studies I’ve previously curated:
- The truth about complex traits and GWAS that I curated yesterday;
- Conscious mental states should not be the first-choice explanation of behavior on the first day of this blog, February 1, 2015; and
- Manufacturing PTSD evidence with machine learning, but I had a different view of the study than the reviewers’ favorable one.
There were two things I didn’t understand about this review. The first was why the paper isn’t freely available. It’s completely paid for by the US taxpayer, and no copyright is claimed. I recommend contacting the authors for a copy.
The second was why the VA hasn’t participated in either animal or human follow-on studies to the 2015 Northwestern University GABAergic mechanisms regulated by miR-33 encode state-dependent fear. That study’s relevance to PTSD, this review’s subject, and the VA’s mission is too important to ignore. For example:
“Fear-inducing memories can be state dependent, meaning that they can best be retrieved if the brain states at encoding and retrieval are similar.
“It’s difficult for therapists to help these patients,” Radulovic said, “because the patients themselves can’t remember their traumatic experiences that are the root cause of their symptoms.”
The findings imply that in response to traumatic stress, some individuals, instead of activating the glutamate system to store memories, activate the extra-synaptic GABA system and form inaccessible traumatic memories.”
I curated the research in A study that provided evidence for basic principles of Primal Therapy. These researchers have published several papers since then. Here are the abstracts from three of them:
“Pharmacological treatments for psychiatric illnesses are often unsuccessful. This is largely due to the poor understanding of the molecular mechanisms underlying these disorders. We are particularly interested in elucidating the mechanism of affective disorders rooted in traumatic experiences.
To date, the research of mental disorders in general has focused on the causal role of individual genes and proteins, an approach that is inconsistent with the proposed polygenetic nature of these disorders. We recently took an alternative direction, by establishing the role of miRNAs in the coding of stress-related, fear-provoking memories.
Here we describe in detail our work on the role of miR-33 in state-dependent learning, a process implicated in dissociative amnesia, wherein memories formed in a certain brain state can best be retrieved if the brain is in the same state. We present the specific experimental approaches we apply to study the role of miRNAs in this model and demonstrate that miR-33 regulates the susceptibility to state-dependent learning induced by inhibitory neurotransmission.”
“State-dependent learning (SDL) is a phenomenon relating to information storage and retrieval restricted to discrete states. While extensively studied using psychopharmacological approaches, SDL has not been subjected to rigorous neuroscientific study.
Here we present an overview of approaches historically used to induce SDL, and highlight some of the known neurobiological mechanisms, in particular those related to inhibitory neurotransmission and its regulation by microRNAs (miR).
We also propose novel cellular and circuit mechanisms as contributing factors. Lastly, we discuss the implications of advancing our knowledge on SDL, both for most fundamental processes of learning and memory as well as for development and maintenance of psychopathology.”
“Retrieval of fear memories can be state-dependent, meaning that they are best retrieved if the brain states at encoding and retrieval are similar. Such states can be induced by activating extrasynaptic γ-aminobutyric acid type A receptors (GABAAR) with the broad α-subunit activator gaboxadol. However, the circuit mechanisms and specific subunits underlying gaboxadol’s effects are not well understood.
Here we show that gaboxadol induces profound changes of local and network oscillatory activity, indicative of discoordinated hippocampal-cortical activity, that were accompanied by robust and long-lasting state-dependent conditioned fear. Episodic memories typically are hippocampus-dependent for a limited period after learning, but become cortex-dependent with the passage of time.
In contrast, state-dependent memories continued to rely on hippocampal GABAergic mechanisms for memory retrieval. Pharmacological approaches with α- subunit-specific agonists targeting the hippocampus implicated the prototypic extrasynaptic subunits (α4) as the mediator of state-dependent conditioned fear.
Together, our findings suggest that continued dependence on hippocampal rather than cortical mechanisms could be an important feature of state-dependent memories that contributes to their conditional retrieval.”
Here’s an independent 2017 Netherlands/UC San Diego review that should bring these researchers’ efforts to the VA’s attention:
“Post-traumatic stress disorder (PTSD) is a psychiatric disorder that can develop following exposure to or witnessing of a (potentially) threatening event. A critical issue is to pinpoint the (neuro)biological mechanisms underlying the susceptibility to stress-related disorder such as PTSD, which develops in the minority of ~15% of individuals exposed to trauma.
Over the last few years, a first wave of epigenetic studies has been performed in an attempt to identify the molecular underpinnings of the long-lasting behavioral and mental effects of trauma exposure. The potential roles of non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) in moderating or mediating the impact of severe stress and trauma are increasingly gaining attention. To date, most studies focusing on the roles of miRNAs in PTSD have, however, been completed in animals, using cross-sectional study designs and focusing almost exclusively on subjects with susceptible phenotypes.
Therefore, there is a strong need for new research comprising translational and cross-species approaches that use longitudinal designs for studying trajectories of change contrasting susceptible and resilient subjects. The present review offers a comprehensive overview of available studies of miRNAs in PTSD and discusses the current challenges, pitfalls, and future perspectives of this field.”
Here’s a 2017 Netherlands human study that similarly merits the US Veterans Administration’s attention:
“Posttraumatic stress disorder (PTSD) affects many returning combat veterans, but underlying biological mechanisms remain unclear. In order to compare circulating micro RNA (miRNA) of combat veterans with and without PTSD, peripheral blood from 24 subjects was collected following deployment, and isolated miRNA was sequenced.
PTSD was associated with 8 differentially expressed miRNA. Pathway analysis shows that PTSD is related to the axon guidance and Wnt signaling pathways, which work together to support neuronal development through regulation of growth cones. PTSD is associated with miRNAs that regulate biological functions including neuronal activities, suggesting that they play a role in PTSD symptomatology.”
See the below comments for reasons why I downgraded this review’s rating.
https://link.springer.com/article/10.1007/s11920-018-0887-x “Stress Response Modulation Underlying the Psychobiology of Resilience” (not freely available)
This 2018 Chinese rodent study found:
“Elevated Dnmt3a [a DNA methyltransferase] level in the dorsal dentate gyrus (dDG) of hippocampus was associated with the absence of fear renewal in an altered context after extinction training. Overexpression and knockdown of Dnmt3a in the dDG regulated the occurrence of fear renewal in a bi-directional manner.
We found that renewal of remote fear memory can be prevented, and the absence of renewal was concurrent with an elevated Dnmt3a level.
Our results indicate that Dnmt3a in the dDG is a key regulator of fear renewal after extinction, and Dnmt3a may play a critical role in controlling fear memory return and thus has therapeutic values.”
The study was a collection of five experiments investigating causes and effects of biology and behavior. The researchers used different techniques to achieve their goals. I’ve quoted extensively below to show some background and results.
“Alterations in histone acetylation and DNA methylation are involved in the formation and extinction of long-term memory. DNMTs catalyze the cytosine methylation and are required to establish and maintain genomic methylation.
Dnmt3a and Dnmt3b are de novo DNA methyltransferases. Dnmt1 is the maintenance DNA methyltransferase.
- Dnmt3a expression was elevated in the dDG after extinction training followed by a brief memory retrieval (Rec+Ext), which was associated with the absence of fear renewal when tested in an altered context.
- Increasing Dnmt3a expression in the dDG using AAV [recombinant adeno-associated virus] expression led to the prevention of fear renewal following a standard extinction training protocol.
- Knockdown of Dnmt3a in the dDG using CRISPR/Cas9 resulted in fear renewal following Rec+Ext protocol.
- Renewal of remote fear memory can be prevented using the Rec+Ext protocol.
- The absence of renewal was concurrent with an elevated Dnmt3a level.
Current exposure therapy, although effective in many patients, suffers from the inability to generalize its efficacy over time, or is limited by the potential return of adverse memory in the new/novel contexts. These limitations are caused by the context-dependent nature of extinction which is widely viewed as the biological basis of exposure therapy.
Thus, achieving a context-independent extinction may significantly reduce fear renewal to improve the efficacy of exposure therapy. Our current study suggests that the effectiveness of these approaches, and ultimately the occurrence of fear renewal, is determined by the level of Dnmt3a after extinction training, especially in the dDG.
There are two potential mechanisms underlying extinction, one is erasure or updating of the formed memory, and the other is the formation of a new extinction memory which suppresses or competes with the existing memory in a context-dependent manner. While most studies favor the suppression mechanism in the adult, limited studies do suggest that erasure occurs in the immature animals.
We propose that if Dnmt3a level is elevated with extinction training (such as with Rec+Ext protocol), modification to the existing memory occurs and as a consequence extinction does not act as a separate mechanism or form a new memory; but if Dnmt3a level is unaltered with extinction training, a separate extinction memory is formed which acts to suppress or compete with the existing memory.”
The relevant difference between humans and lab rats is that we can ourselves individually change our responses to experiential causes of ongoing adverse effects. Standard methodologies can only apply external treatments such as exposure therapy and manipulating Dnmt3a levels.
https://www.nature.com/articles/s41598-018-23533-w “Dnmt3a in the dorsal dentate gyrus is a key regulator of fear renewal”