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.”

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, they were 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 orangey twilight of fading sunflowers help you feel? “Music-colour synaesthesia: Concept, context and qualia” (not freely available)


Resiliency in stress responses

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:

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:

Experimental Methods for Functional Studies of microRNAs in Animal Models of Psychiatric Disorders

“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.”

Neurobiological mechanisms of state-dependent learning

“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.”

Neurobiological correlates of state-dependent context fear

“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:

MicroRNAs in Post-traumatic Stress Disorder

“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:

Circulating miRNA associated with posttraumatic stress disorder in a cohort of military combat veterans

“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. “Stress Response Modulation Underlying the Psychobiology of Resilience” (not freely available)

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 “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 psychotherapeutic 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.” “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.

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An update on brain zapping

This 2017 general-audience article entitled Ultrasound for the brain provided a hyped update on brain zapping:

“Ultrasound could potentially treat other movement disorders, as well as depression, anxiety and a host of intract­able neuropsychiatric disorders..

This could be a breakthrough..

Researchers hope one day to help people with neuropsychiatric conditions by repairing or resetting the relevant neural pathways..

The potential advantages, especially for deep brain areas, are huge..”

Though not the main thrust of the article, another potential use of ultrasound would be to activate drugs delivered to a specific area, as this image portrays:

Vanderbilt University was again at the forefront of brain zapping, as noted in What’s an appropriate control group for a schizophrenia study? for example. I hope the disclaimers for subjects participating in Vanderbilt’s brain-zapping studies made it clear that:

“At high intensities, such as those used to relieve essential tremor, ultrasound’s effects are largely thermal: the tissue heats up and cells die.”

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Epigenetic effects of early life stress exposure

This 2017 Netherlands review subject was the lasting epigenetic effects of early-life stress:

“Exposure to stress during critical periods in development can have severe long-term consequences.

One of the key stress response systems mediating these long-term effects of stress is the hypothalamic-pituitary-adrenal (HPA) axis.

Early life stress (ELS) exposure has been reported to have numerous consequences on HPA-axis function in adulthood.

ELS is able to “imprint” or “program” an organism’s neuroendocrine, neural and behavioral responses to stress. Research focuses along two complementary lines.

Firstly, ELS during critical stages in brain maturation may disrupt specific developmental processes (by altered neurotransmitter exposure, gene transcription, or neuronal differentiation), leading to aberrant neural circuit function throughout life.

Secondly, ELS may induce modifications of the epigenome which lastingly affect brain function.

These epigenetic modifications are inducible, stable, and yet reversible, constituting an important emerging mechanism by which transient environmental stimuli can induce persistent changes in gene expression and ultimately behavior.”

In early life, the lower brain and limbic system brain structures are more developed and dominant, whereas the cerebrum and other brain structures are less developed (use the above rodent graphic as a rough guide).

Stress and pain generally have a greater impact on the fetus than the infant, and on the infant than the adult.

The reviewers cited 50+ studies from years 2000-2015 in the “Early Life Stress Effects in a “Matching” Stressful Adult Environment” section to argue for the match/mismatch theory:

“Encountering ELS prepares an organism for similar (“matching”) adversities during adulthood, while a mismatching environment results in an increased susceptibility to psychopathology, indicating that ELS can exert either beneficial or disadvantageous effects depending on the environmental context.

Initial evidence for HPA-axis hypo-reactivity is observed for early social deprivation, potentially reflecting the abnormal HPA-axis function as observed in post-traumatic stress disorder.

Interestingly, experiencing additional (chronic) stress in adulthood seems to normalize these alterations in HPA-axis function, supporting the match/mismatch theory.”

Evidence for this theory was contrasted with the allostatic load theory presented in, for example, How one person’s paradigms regarding stress and epigenetics impedes relevant research.

The review mainly cited evidence from rodent studies that mismatched reactions in adulthood may be consequences of early-life events. These events:

“Imprint or program an organism’s neuroendocrine, neural and behavioral responses..

Leading to aberrant neural circuit function throughout life..

Which lastingly affect brain function.”

Taking this research to a personal level:

  • Have you had feelings that you were unsafe, although your environment was objectively safe?
  • Have you felt uneasy when people are nice to you?
  • Have you felt anxious when someone pays attention to you, even after you’ve acted to gain their attention?

Mismatched human feelings are one form of mismatched reactions. These may be consequences of early-life experiences, and indicators of personal truths.

If researchers can let go of their biases and Advance science by including emotion in research, they may find that human subjects’ feelings produce better evidence for what actually happened during the subjects’ early lives than do standard scientific methods of:

Incorporating this evidence may bring researchers closer to backwardly predicting the major insults to an individual that knocked their development processes out of normally robust pathways and/or induced “persistent changes in gene expression and ultimately behavior.” “Modulation of the Hypothalamic-Pituitary-Adrenal Axis by Early Life Stress Exposure”

I discovered this review as a result of it being cited in “Long-term effects of early environment on the brain: Lesson from rodent models” (not freely available)

A human study of pain avoidance

This 2016 UK human study found:

“People differ in how they learn to avoid pain, with some individuals refraining from actions that resulted in painful outcomes, whereas others favor actions that helped prevent pain.

Learning in our task was best explained as driven by an outcome prediction error that reflects the difference between expected and actual outcomes. Consistent with the expression of such a teaching signal, blood-oxygen level-dependent (BOLD) responses to outcomes in the striatum were modulated by expectation.

Positive learners showed significant functional connectivity between the insula and striatal regions, whereas negative learners showed significant functional connectivity between the insula and amygdala regions.

The degree to which a participant tended to learn from success in avoiding than experiencing shocks was predicted by the structure of a participants’ striatum, specifically by higher gray matter density where the response to shocks was consistent with a prediction error signal.

Higher gray matter density in the putamen (and lower gray matter density in the caudate) predicted better learning from shocks and poorer learning from success in avoiding shocks.”

The researchers termed the subjects’ pain responses “learning” instead of conditioning. The difference between the two terms in the experimental contexts was that the subjects weren’t presented with 100%-certain choices to avoid pain.

The experiments were also rigged to force choices at similar rates among subjects because:

“Participants who learned more from painful outcomes developed a propensity to avoid gambling, whereas participants who learned more from success in preventing pain developed a propensity to gamble.”

Human responses to pain don’t arise out of nowhere. The subjects’ pain histories were clearly relevant, but weren’t investigated.

The closest the study came to considering the subjects’ histories was:

“Before the experiment, participants completed an 80-item questionnaire composed of several measures of different mood and anxiety traits. Age, sex and mood and anxiety traits did not differ between participants later classified as positive and negative learners.”

Emotional content was neither included nor solicited. Emotions were inferred:

“Participants biased in favor of passive avoidance learning (i.e., learning what gambles should be avoided), striatal response to painful outcomes was consistent with an aversive prediction error, as seen in fear conditioning.”

As a result, there weren’t causal explanations for the subjects’ differing pain responses. How, when, and why did the behavioral, functional, and structural differences develop?

I didn’t see the level of detail needed to characterize striatal regions into the Empathy, value, pain, control: Psychological functions of the human striatum segments. I’d guess that the findings of “higher gray matter density in the putamen (and lower gray matter density in the caudate)” applied to the posterior putamen and the anterior caudate nucleus.

Two of the coauthors were also coauthors of If a study didn’t measure feelings, then its findings may not pertain to genuine empathy. The technique of Why do we cut short our decision-making process? was referenced. “Striatal structure and function predict individual biases in learning to avoid pain”

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 for 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 could 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 damage would also reverse 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 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 misrepresented 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 citations 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.” “Paradise Lost: The Neurobiological and Clinical Consequences of Child Abuse and Neglect”

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