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Val Corzine

Better Science 
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Better policy & Better LAw

Working to Eliminate Homelessness & Criminal Justice Involvement of People with Cognitive Disabilities


  • Current Scientific Research
  • Legal Analysis, and
  • Authenticity & Lived Experience

Jain
Makeba

TranslationAL Medicine Friday
​

See Keto diet, Mental Illness, Metabolic Disregulation and Microglia


The Endocrine System and Microglia

Working more to make substantial progress on this Table --​Thursday.
1.  History: 
  • The Historical Development of Immunoendocrine Concepts of Psychiatric Disorders and their Therapy
  • 2015 Study

2.  Maternal Immune Activation
  • Influence of innate immune activation on endocrine and metabolic pathways in infancy
    • 2021 Study
  • Immune-Endocrine Cross Talk
  • Activation of the maternal immune system induces changes in the placenta via IL-6
    • 2011 Study

3.  Misc.
  • Can Ashwagandha Benefit the Endocrine System
    • 2023 Study
  • Medical comorbidity in bipolar disorder:  relatioship between illnesses of the endocrine/metabolic meystem and treatment outcome.
    • 2010 Study
  • Neuroendorine Stress System in Bipolar
    • 2021 Study
  • Corticotropin-releasing hormone, microglia and mental disorders
    • 2014 Study
  • Microglia:  Neuroimmune-Sensors of Stress

​4.  Endocrine Disruptors

Major Paradigm shifts

​Maternal immune Activation, Microglia (& other glia) & Human Endogenous Retro Viruses

Val's Take/Conjecture
  • The Immune Connection to the Neuro-Developmental/Psychiatric Disorder Continuum is HUGE.
  • It is also COMPLICATED --- we're talking about something that begins IN UTERO and continues with:
    • ​molecular "CROSSTALK", as well as
    • DYSREGULATION of MOLECULAR PATHWAYS
  • ​"Microglia" --- immune cells in the brain are also associated with "emotional regulation."
​New research led by King's College London has found that thousands of DNA sequences originating from ancient viral infections are expressed in the brain, with some contributing to susceptibility for psychiatric disorders such as schizophrenia, bipolar disorder, and depression.  May 22, 2024
Ancient Viruses Linked to Mental Illness - Neuroscience News
Moreover, growing evidence supports the involvement of HERVs (Human Endogenous Retro Viruses) in neurodevelopmental disorders, such as autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and schizophrenia (SCZ) .
Endogenous Retroviruses Activity as a Molecular Signature of ...
​MIA alters placental and fetal expression of endogenous retroviral elements. MIA-induced alterations in endogenous retrovirus expression persist into adulthood. Differential expression of endogenous retroviruses defines MIA subgroups.
Susceptibility and resilience to maternal immune activation ...
Val's Take:  There is a gulf between Researchers and US Clinicians.

I think that had been there for awhile but the 2013  "invalid" DSM 5 sanctioned gross incompetence in a public way.

England is probably 10 or 20 years ahead of us in understanding the Immune Connection to Psychiatric Disorders.

I do think the proprietary nature of the American Psychiatric Association is in part to blame for incompetence in the US Mental Health Profession.

PTSD ---- and an Immunne Connection

​

Val's Take/Conjecture
  • I remember by Father-in-Law Dick Bayles, Jr. -- was part of the force that liberated Dachau.
  • He was also quite fond of saying, "No kiddin' when confronted with some true but unlikely statement.
  • To me that is very much the situation when it comes to the large role of the immune system and various forms of the Neuro-Developmental/ Psychiatric Continuum.
Microglia-mediated neuroimmune suppression in PTSD is associated with anhedonia (2024)
Involvement of microglia in disturbed fear memory regulation: Possible microglial contribution to the pathophysiology of posttraumatic stress disorder (2021)
The role of the immune system in posttraumatic stress disorder (2022)
Maternal Immune Activation and "Long-Lasting Transcriptional Changes in Fetal Microglia"

Preview:  Translational Medicine Friday

Astrocytes -- Another Glial Cell

involved with the Neuro-Developmental / Psychiatric Continuum
​

Val's Take/Conjecture
  • This weekend I'll work on making more progress on my Microglia Tables.  One is already finished and many people are checking that out --- see further down on the homepage..
  • Today --- introducing "ASTROCYTES."

Astrocyte regulation of synaptic signaling in psychiatric disorders  (2022)
Affective Immunology: The Crosstalk Between Microglia and Astrocytes Plays Key Role?  (2020)
​
Almost a century ago, Julius Wagner-Jauregg first reported the impact of immunological disturbance on psychological function.

This finding stirred up researchers' enthusiasm about bidirectional communication between immunological dysfunction and mental disorders.

To date, understanding the etiology of mental disorders, such as schizophrenia, autism spectrum disorder, anxiety disorder, as well as mood disorders, is one of the most actively explored topics in immunology.
We're starting to get more than a rough idea about what is going on with the Neuro-Developmental/Psychiatric Continuum:
  • It often starts in utero with Maternal Immune Activation (MIA).
  • That MIA dysregulates Microglia in the yok-sak in the placenta.
    • Microglia are innate immune cells in the brain.
  • This ultimately leads to abnormal development of neurons.
  • Additionally, other glial cells seem to create abnormal "myelation" of the neurons.
    • To me that sounds very much like Multiple Sclerosis.
    • One of the things I heard a researcher say a few years ---- the Immune System seemed to be involved with psychiatric disorders but it wasn't a classic autoimmune disease.
    • On the other hand, some MIA is the result of mom's auto-immune disease and people on the Neuro-Developmental/Psychiatric Continuum do have autoimmune diseases such as Thyroid Disorders.
  • Really understanding that we are talking about Developmental Disorders that involve multiple systems of the body and a BIG DRIVER is the IMMUNE SYSTEM is the key to real PROGRESS.
Verywell Health
Aberrant astrocyte protein secretion contributes to altered neuronal development in multiple models of neurodevelopmental disorders (2022)
Astrocyte involvement in metabolic regulation and disease (2024)

Val's Take:  Astrocytes are involved with thyroid disorders --- and those are very common among people with psychiatric disorders.
See Also:
​
Interaction between Oligodendrocytes and Interneurons in Brain Development and Related Neuropsychiatric Disorders (2024)

Preview:  Olmstead Law & Order Thursday

chevron overturned, HUD "OLMSTEAD VOUCHERS," 2nd Trump Administration & Olmstead
​

Val's Take/Conjecture
  • In 2015, CMS (the Centers for Medicare & Medicaid Services) determined that Medicaid would NOT COVER HOUSING but would cover "Housing-Related Services" and even "Olmstead Planning."
  • Under the first Trump Administration, Attorney General Jeff Sessions withdrew over 20 pieces of US Department of Justice "Guidance."​
  • But it would be the US Supreme Court that overturned the Chevron Doctrine this year in 2024 and held such Executive Agency Guidance was not binding.
  • The 1999 Olmstead Supreme Court decision was about a "Comprehensive, Effectively Working State Plan for People with Disabilities"  --- "moving at a reasonable pace."​
  • The most glaring failure has been the failure to provide adequate housing for people with disabilities.
  • In Denver, the city took on the task of housing people with disabilities ---- it was seemingly was after the fact that city officials realized these were people with disabilities and needed a fair amount of case management, etc.
    • Val's Take:  One of the things that is so confusing about the Neuro-Developmental/Psychiatric Continuum 
      • Most of the people on it do have an IQ over 70, sometimes a lot over 70
      • They are dealing with idiosyncratic pre-natal Neuro-Developmental Disorders to the Immune System, Microbiome, and Endocrine System as well as the Central Nervous System.
      • Further, the environmental INFLAMMATORY HITS can be exaggerated by pre-natal Maternal Immune Activation.
      • Biomarkers are important for individualized, personalized treatment.
HUD Takes Action to Support Community Living for People with Disabilities (August 2024)
After 25 years of Olmstead, it became painfully obvious that there were not enough housing resources for people with disabilities in most states, and it wasn't getting addressed ---- except maybe by Denver Mayor Mike Johnston and he was relying at least in great part on Federal Housing Vouchers.
Could a 2nd Trump Administration roll back "Olmstead Housing Vouchers" --- It could but it may not want to.
If HUD can cover Housing Vouchers, I think that makes the process of "Olmstead Planning" much easier for all the Stakeholders.
I don't think a 2nd Trump Administration is going to be focused on Olmstead Enforcement --- but there could be encouragement of reasonable, flexible plans to address the needs of people of disabilities who are institutionalized or at risk of institutionalization.

Preview:  Neuro-Diversity Wednesday

A search for "Balance" and Disrupters of "Homeostasis"
​

Val's Take/Conjecture
  • Maternal Immune Activation was probably fairly common in Ancient Times.
  • In Modern Times, it has been fairly common-- affecting approximately 1/5 to a 1/4 of the population.
  • But it is only recently that we are starting to get a more complete BIOLOGICAL NARRATIVE.
Adult microglial TGFβ1 is required for microglia homeostasis via an autocrine mechanism to maintain cognitive function in mice (2024)
Modulating microglia activation prevents maternal immune activation induced schizophrenia-relevant behavior phenotypes via arginase 1 in the dentate gyrus (2020)

Translational Justice Monday

The Need for more professional & Public education on the role of

Microglia in Psychiatric disorders

Val's Take/Conjecture
One of the big psychological challenges in Modern Times is Illness that is not completely understood now, and yet the expectation is that treatments or cures will be available in the future.
For People with Neuro-Developmental / Psychiatric Disorders and an IQ over 70 --- outdated conceptualizations put many at risk of homelessness and/or incarceration.​

Further, the needs and types of support needed are often different than what is being provided.

Updated paradigms have the real possibility of directly addressing underlying Developmental processes and subsequent inflammatory exposures that may be magnified by dysregulated microglia, etc.
CME

January 12, 2021 Psychiatric Times

Microglial Involvement With Psychiatric Diseases

Author(s):
Haley Alleson Vecchiarelli, PhD,
Eva Simoncicova
+1 More
This CME article briefly outlines the role that microglia play in neuropsychiatric disorders.

Preview:  Neuro-Diversity Wednesday

Epigenetics, Maternal Immune Activation & Neuro-developmental Differences

Note: the studies below will be moved to the upcoming 5th Draft on Maternal Immune Activation.

Val's Take/Conjecture
  • Understanding the Neuro-developmental/Psychiatric Continuum as:
    • Developmental Disorders
    • Often proceeded by Maternal Immune Activation
    • With Epigenetic Activation.
      • It is often not so much that someone has a particular gene --- but a particular gene is getting activated through epigenetics.
Exploring the epigenetic landscape: The role of 5-hydroxymethylcytosine in neurodevelopmental disorders (2024)

Recent advances in genetic and epigenetic research have underscored the significance of 5-hydroxymethylcytosine (5hmC) in neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD) and intellectual disability (ID), revealing its potential as both a biomarker for early detection and a target for novel therapeutic strategies.

This review article provides a comprehensive analysis of the role of 5hmC in NDDs by examining both animal models and human studies.

By examining mouse models, studies have demonstrated that prenatal environmental challenges, such as maternal infection and food allergies, lead to significant epigenetic alterations in 5hmC levels, which were associated with
  • NDDs in offspring,
  • impacting social behavior,
  • cognitive abilities and
  • increasing ASD-like symptoms.

In human studies, researchers have linked alterations in 5hmC levels NDDs through studies in
  • individuals with ASD,
  • fragile X syndrome,
  • TET3 deficiency and
  • ID

specifically identifying significant epigenetic modifications in genes such as GAD1, RELN, FMR1 and EN-2, suggesting that dysregulation of 5hmC played a critical role in the pathogenesis of these disorders and highlighted the potential for targeted therapeutic interventions.

Moreover, we explore the implications of these findings for the development of epigenetic therapies aimed at modulating 5hmC levels.

The review concludes with a discussion on future directions for research in this field, such as machine learning, emphasizing the need for further studies to elucidate the complex mechanisms underlying NDDs and to translate these findings into clinical practice.

This paper not only advances our understanding of the epigenetic landscape of NDDs but also opens up new avenues for diagnosis and treatment, offering hope for individuals affected by these conditions.
Disorders Share Risk Gene Pathways for Immune, Epigenetic Regulation

Genome-wide findings add to evidence blurring traditional psychiatric categories (2015)

Brain changes in a maternal Immune activation model of neurodevelopmental brain disorders (2019)

Progress in Neurobiology

The link between maternal infection and these phenotypic changes is not fully understood, but there is increasing evidence that maternal immune activation induces prolonged immune alterations in the offspring’s brain which could underlie epigenetic alterations which in turn may mediate the behavior and brain changes.
Maternal immune activation in rodent models: A systematic review of neurodevelopmental changes in gene expression and epigenetic modulation in the offspring brain. (2021)

Neurosci Biobehav Rev.

Maternal immune activation (MIA) during pregnancy is hypothesised to disrupt offspring neurodevelopment and predispose offspring to neurodevelopmental disorders such as schizophrenia.

The many sources of maternal immune activation

Val's Take/Conjecture
  • When researchers started identifying Maternal Immune Activation --- they identified it with "INFECTION."
  • Then "AUTOIMMUNE DISEASE"
  • "OBESITY"
  • "SMOKING"
  • Etc.
Autoimmune Disease is in a kind of weird relationship with Neuro-Developmental and Psychiatric Disorders.
Maternal immune activation and neuroinflammation in human neurodevelopmental disorders. (2021)

Maternal health during pregnancy plays a major role in shaping health and disease risks in the offspring. ...Diverse maternal inflammatory factors, including obesity, asthma, autoimmune disease, infection and psychosocial stress, are associated …
See also:  "Paternal Immune Activation":

Paternal immune activation by Poly I:C modulates sperm noncoding RNA profiles and causes transgenerational changes in offspring behavior.

 Brain Behav Immun. 2024

Paternal pre-conceptual environmental experiences, such as stress and diet, can affect offspring brain and behavioral phenotypes via epigenetic modifications in sperm. Furthermore, maternal immune activation due to infection during gestation can reprog …
Maternal immune activation in neurodevelopmental disorders. 

Developmental Dynamics 2018

The mechanisms through which MIA increases the risk of neurodevelopmental disorders have become a subject of intensive research. This review aims to describe how dysregulation of microglial function and immune mechanisms may link MIA and neurodevelopmental pathologi …
 Researchers are on the verge of cracking the Neuro-Developmental/Psychiatric Continuum.

It is really about Maternal Immune Activation and the consequences of that over the life course.

This is about the Brain and Central Nervous System, but it is really about the Immune System, as so many chronic illnesses are.

Further,  ADHD and Autism are DEVELOPMENTAL, but so are Schizophrenia and Bipolar Disorder.  

Some researchers also consider Depression a Neuro-Developmental Disorder.
MIA and Kynurenine Metabolites and Pathway

Maternal Inflammation with Elevated Kynurenine Metabolites Is Related to the Risk of Abnormal Brain Development and Behavioral Changes in Autism Spectrum Disorder.

T. Cells. 2023

Several studies show that genetic and environmental factors contribute to the onset and progression of neurodevelopmental disorders. Maternal immune activation (MIA) during gestation is considered one of the major environmental factors driving this process. ...Activation o …

The complicated domino effects of Maternal Immune Activation

Val's Take/Conjecture
  • There are several factors that can result in Maternal Immune Activation (MIA).
  • MIA is associated with Neuro-Developmental and Psychiatric Disorders in the Child.
    • Why is that?

Maternal immune activation induces sustained changes in fetal microglia motility (2020)


Maternal immune activation and neuroinflammation in human neurodevelopmental disorders (2021)

Evidence from human and animal studies indicates that maternal immune activation programmes the fetal brain and immune system through inflammatory and epigenetic mechanisms during key periods
  • of CNS [Central Nervous System],
  • microglial and
  • immune system development, and
  • colonization of gut microbiota.
Influence of Immune System Abnormalities Caused by Maternal Immune Activation in the Postnatal Period  (2023)

The developmental origins of health and disease (DOHaD) indicate that fetal tissues and organs in critical and sensitive periods of development are susceptible to structural and functional changes due to the adverse environment in utero. Maternal immune activatio …
Mid-pregnancy maternal immune activation increases Pax6 ...
Mid-pregnancy maternal immune activation increases Pax6-positive and Tbr2-positive neural progenitor cells and causes integrated stress response in the fetal brain in a mouse model of


Cellular Pathways
Paliperidone Reversion of Maternal Immune Activation-Induced Changes on Brain Serotonin and Kynurenine Pathways (2021)

Inflammation can alter the metabolism of tryptophan through the oxidative kynurenine pathway to compounds with neurotoxic and neuroprotective activity and compromise serotonin (5-HT) synthesis. Here we investigate the role of serotonergic and kynurenine …
Lasting and Sex-Dependent Impact of Maternal Immune Activation on Molecular Pathways of the Amygdala (2020)
Maternal Immune Activation Disrupts Dopamine System in the ...Jan 27, 2016 · Our study, the first to combine electrophysiological and microdialysis experiments on the dopamine system in a maternal immune activation model of schizophrenia, reveals that

Dysregulation of immune and metabolism pathways in maternal ...Jul 1, 2023 · Maternal immune activation regulates the dysregulation of four key risk KEGG pathways related to immunity, metabolism, and nervous system leading to abnormal embryonic

Val's Take
  • Compared to where we have been in our knowledge of the Neuro-Developmental/Psychiatric Continuum ---
  • Researchers around the world are providing a COHERENT UNDERSTANDING with a LEVEL of DETAIL that is MIND-BLOWING.
  • Neuro-Transmitters like Serotonin and Dopamine are still there ---- BUT the Context and Complexity has been expanded Exponentially.

Preview:  Translational Justice Monday

The Immune System & Behavior

prenatal inflammation, Neuro-developmental disorders and Emotional dysregulation

Val's Take/Conjecture
  • This is really about understanding the consequences of PRE-NATAL INFLAMMATION, including:
    • Pro-Inflammatory Cytokines
    • Neuro-Toxic Metabolites
    • Damaged Microglia (immune cells in the brain)
    • And other dysregulated biological pathways.
  • The more researchers can flesh out the complicated biological processes that are unleashed with Maternal Immune Activation, in general terms and biomarkers specific to the individual ----
    • The closer we can get to that public health approach to criminal justice.
Role of the immune-kynurenine pathway in treatment-resistant schizophrenia.  (2024)


Is depression the missing link between inflammatory mediators and cancer?  (2022)

Three major routes to depression in cancer in which proinflammatory mediators are implicated, seem likely.

Activation of the kynurenine pathway involving cytokines, increases tryptophan catabolism, resulting in diminished levels of serotonin which is widely acknowle …
Maternal immune activation and role of placenta in the prenatal programming of neurodevelopmental disorders (2023)
How Inflammation Affects the Brain in Depression (2021)

While it is unclear how the inflammatory response affects brain networks involved in the psychopathology of depression, it has been suggested that proinflammatory cytokines and several metabolites from inflammatory processes in the central nervous system (CNS) exert direct neurotoxic effects on the brain. 

These effects may lead to dysfunction of the neural circuits involved in emotion regulation and reward or cognitive processing, which is associated with overwhelming low mood, failure of...
Society of Biological Psychiatry
Dysfunction of Kynurenic Acid in Major Psychiatric Diseases
Val's Take/Conjecture
  • One of the big discoveries of the 21st Century is that NEURO-DEVELOPMENTAL & PSYCHIATRIC DISORDERS involve MULTIPLE SYSTEMS OF THE BODY.
  • That does include the Brain and the Central Nervous System (CNS).
  • It also includes the Immune System, the Microbiome and the Endocrine System.


  • Transgenerational Epigenetic Inheritance was discovered by Alexander Brink in 1956 as it relates to maize.
  • Since then Epigenetics has been identified as a Key Component of our most difficult chronic diseases, including:
    • Autoimmune Diseases
    • Cancer
    • Type 2 Diabetes
    • Neuro-Developmental Disorders, and
    • Psychiatric Disorders
This will focus largely on the contexts of:
  • Maternal Immune Activation
  • and Exposure to Endocrine-Disrupting Chemicals

2nd Draft:  More References with regard to Endocrine Disruptors and Neuro-Developmental & Psychiatric Disorders.

Policy Challenges

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