Immune System Gene Linked to Hyperactivity, ADHD and Autism
​
​Nov. 21, 2024
Duke University Study

​Val's Take/Conjecture

• The Ancient Greeks had the "Four Humors" and Chinese Medicine has the "Five Elements."
  • These conceptualizations are not necessarily stictly accurate.
  • BUT they give people a way of understanding a monumentally complex biology --- that is within their grasp.
• In 2013, Thomas Insel, head of the National Institute of Mental Health, said the DSM "lacks validity" --- and we'll be using it as our "DICTIONARY" --- until we can get something better. --- Hmmm . . . BUT it probably is going to take 20 to 30 years to flesh out something better that it based on the underlying biology rather than clusters of symtoms.
• That is happening.

​Professor Graham Rook
​"We Are Ecosystems"

​We are conceptualizing neurodevelopmental and psychiatric disorders as:

• Developmental, in many cases as a result of Maternal Immune Activation
• Involving:
  • the Immune System
  • the Central Nervous System
  • the Endocrine System
  • the Metabolism, and
  • the Microbiome
• It is a form of premature aging
• Individuals often have processings differences that can confer benefits and challenges.

Endocrine cross-talk between the gut microbiome and glial cells in development and disease. 2021)

"Glial cells make up the major cellular component of the nervous system. Glial development is usually investigated through perturbations of host genetics, although non-host-derived signalling molecules can also regulate glial cells. ..."

​Investigating the “two-hit hypothesis”: Effects of prenatal maternal immune activation and adolescent cannabis use on neurodevelopment in mice (2023)

Val's Take/Conjecture:  I think Cannabis Use is an issue, BUT to me the larger issue is Secondary Inflammatory Hits during the lifetime.

People with psychiatric disorders are much more vulnerable to Long Haul Covid.

We know that childhood illnesses can be much more serious in Adults.  For some people, that period in utero led to perhaps years worth of inflammation as compared to someone who did not experience Maternal Immune Activation.

The lifespan for people with psychiatric disorders is reduced.

​Life expectancy and years of potential life lost in people with mental disorders: a systematic review and meta-analysis (2023)

Endogenous Retroviruses Activity as a Molecular Signature of Neurodevelopmental Disorders (2019)

​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) .

​"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."

​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.

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?

​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 …"

​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."

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 maternal viral infection (2021)

​"Mid-pregancy 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 . . ."

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 Offspring (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  (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.

​Astrocyte regulation of synaptic signaling in psychiatric disorders  (2022)

​Affective Immunology: The Crosstalk Between Microglia and Astrocytes Plays Key Role?  (2020)

​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)

​
​Microglia-mediated neuroimmune suppression in PTSD is associated with anhedonia (2024)

​The role of the immune system in posttraumatic stress disorder (2022)

​Aggression, Social Stress, and the Immune System in Humans and Animal Models (2018)

​Examining the reciprocal associations between symptoms of depression and anxiety and contact with the criminal justice system (2024)

Val's Take/Conjecture

​We are starting to get Biomarkers in Mental Health.

Metabolomic Biomarker Signatures for Bipolar and Unipolar Depression -- JAMA Psychiatry 2023.

Biomarkers are desperately needed in Criminal Justice.

Clinicians have tried to exercise the best judgement they could --- it is subjective.

Researchers are working to provide those ALTERNATIVES.

Not only that they are putting forth Major Paradigm Shifts in our understanding of neuro-developmental & psychiatric disorders.

Those paradigm shifts include in utero maternal immune activation and dysregulation of the immune system, the central nervous system, the metabolism, the endocrine system and the microbiome.

​

• Researchers are building out a much more complete understanding of what is going on in the neuro-developmental/psychiatric continuum.
• This has the potential to transform Mental Health Practice and get the many stakeholders on the same page.

What's important about the Council on Criminal Justice article --- this major, mainstream organization seems to appreciate the important need to move to biomarkers even if we're not quite there yet.

The Metabolic Mind folks have gone to great lengths to provide a nuanced view of Keto and in fact recommending "Medical Keto."

That is important because "Keto" can be an extremely unhealthy diet.

Unfortunately, "Medical Keto" is not available to most people with mental illness --- something the Metabolic Mind folks are aware of.

One of the things that really helped me understand one of the benefits of Keto --- a study found Keto could improve Microglia functioning.

I would love to have access to Medical Keto.

On the other hand, human beings have been trying to use Highly Prescriptive Diets for EONS to manage their physical and mental health.

For people on the Neuro-Developmental/Psychiatric Continuum ---- we're really talking about "DEVELOPMENTAL HEALTH."

Further, "Metabolic Dysregulation" can be another feature of Maternal Immune Activation.

Theoretically "Medical Keto" could be a safe option for people to access.  I'm a big proponent of that.

On the other hand, I'm also greatly interested in the development of treatments that more directly address dysregulated microglia than KETO.

But repair and replacement of Microglia may be down the road and researved for the most serious brain injuries at least initially.

Metabolic Mind
​Who should use Keto for Mental Illness?

​Dysregulation of immune and metabolism pathways in maternal immune activation induces an increased risk of autism spectrum disorders (2023)

​Ketone body β-hydroxybutyrate (BHB) preserves mitochondrial bioenergetics (2023)

​The ketone body β-hydroxybutyrate shifts microglial metabolism and suppresses amyloid-β oligomer-induced inflammation in human microglia (2023)

Microglia and lipids: how metabolism controls brain innate immunity (2021)

In the last years, single-cell analyses have revealed that microglia exhibit diverse phenotypes during development, growth and disease. Emerging evidence suggests that such phenotype transitions are mediated by reprogramming of cell metabolism. Indeed, metabolic …