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 …

Cytokine Imbalance in Schizophrenia. From Research to Clinic: Potential Implications for Treatment (2021)

• Gene polymorphisms of several cytokines are associated with the development of the schizophrenia syndrome. In patients with schizophrenia, presence of gene polymorphisms of proinflammatory cytokines, such as IL-1β and IL-6, have been linked to high serum levels of these cytokines. 

Inflammation in Bipolar Disorder (2018)

Elevated levels of pro-inflammatory cytokines

• Bipolar disorder (BD) is a severe and persistent mental illness associated with increased rates of several inflammatory medical comorbidities. Replicated evidence has demonstrated a strong association between BD and elevated levels of pro-inflammatory cytokines.

Inflammatory Cytokine: An Attractive Target for Cancer Treatment (2022)

"The pro-inflammatory cytokines are associated with advanced cancer stages, resistance to immunotherapy, and poor prognoses, such as in objective response and disease control rates, and progression-free and overall survival.

"In this review, we selected colorectal, pancreatic, breast, gastric, lung, and prostate cancers, which are well-reported for an association between cancer and inflammatory cytokines."

"The related cytokines and their effects on each cancer’s development and prognosis were summarized.

In addition, the treatment strategies targeting inflammatory cytokines in each carcinoma were also described here. By understanding the biological roles of cancer-related inflammatory cytokines, we may modulate the inflammatory tumor microenvironment for potential cancer treatment.

The causal relationship between 41 inflammatory cytokines and hypothyroidism: bidirectional two-sample Mendelian randomization study (2023)

"The high rate of comorbidity between hypothyroidism and psychiatric disorders deserves special attention, indicating the importance of consistent monitoring and timely identification of psychiatric symptoms to prevent disease exacerbation and facilitate therapeutic management."

Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases  (2011)

• Microglia are activated in response to a number of different pathological states within the CNS including injury, ischemia, and infection.
• Microglial activation results in their production of pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α
  

Maternal immune activation alters fetal and neonatal microglia phenotype and disrupts neurogenesis in mice

Maternal immune activation (MIA) alters microglial phenotypes in the brain of fetal and neonatal mouse offspring. MIA leads to excessive proliferation and overproduction of neural progenitors in the subventricular zone (SVZ). MIA reduces parvalbumin+ while increases Reelin+ interneurons in the prefrontal cortex.

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

Abstract

"Maternal health during pregnancy plays a major role in shaping health and disease risks in the offspring.

"The maternal immune activation hypothesis proposes that inflammatory perturbations in utero can affect fetal neurodevelopment, and evidence from human epidemiological studies supports an association between maternal inflammation during pregnancy and offspring neurodevelopmental disorders (NDDs).

"Diverse maternal inflammatory factors, including obesity, asthma, autoimmune disease, infection and psychosocial stress, are associated with an increased risk of NDDs in the offspring.

"In addition to inflammation, epigenetic factors are increasingly recognized to operate at the gene-environment interface during NDD pathogenesis.

"For example, integrated brain transcriptome and epigenetic analyses of individuals with NDDs demonstrate convergent dysregulated immune pathways.

"In this Review, we focus on the emerging human evidence for an association between maternal immune activation and childhood NDDs, including autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome.

"We refer to established pathophysiological concepts in animal models, including immune signalling across the placenta, epigenetic 'priming' of offspring microglia and postnatal immune-brain crosstalk.

"The increasing incidence of NDDs has created an urgent need to mitigate the risk and severity of these conditions through both preventive strategies in pregnancy and novel postnatal therapies targeting disease mechanisms."

Val's Take/Conjecture

• Ignorance is one of the most anxiety producing states, especially when the stakes are high.
• In 2013, the National Institute of Mental Health found that ADHD, Autism, Bipolar Disorder, Depression and Schizopheria were not distinct, and were blurred --- sharing common genes and mechanisms such as calcium channels.
  

National Institute of Mental Health
Five Mental Disorders Share Some of the Same Genes

See also:

Even back in 2013, the National Institute of Mental Health was recognizing the importance of the IMMUNE SYSTEM in Neuro-Developmental and Psychiatric Disorders --- it wasn't necessarily the dominant theme in the research.

Now over a decade later, the research is exploding all over the world, and we're talking about the importance of Maternal Immune Activation and the Microglia (immune cells in the Brain -- Central Nervous System) and the Mitochondria in those cells.

In 2024, we're seeing overlaps not only between Neuro-Developmental and Psychiatric Disorders, but also Endocrine Disorders, Autoimmune Disorders, Metabolic Dysregulation, Cancer, and Neuro-Degenerative Disorders.

Transcriptional and epigenetic decoding of the microglial aging process (2023)

The role of microglia in early neurodevelopment and the effects of maternal immune activation (2024)

Emerging epigenetic dynamics in gut-microglia brain axis: experimental and clinical implications for accelerated brain aging in schizophrenia (2023)

Microglia promote autoimmune inflammation via the noncanonical NF-κB pathway (2021)

Microglial Metabolic Reprogramming: Emerging Insights and Therapeutic Strategies in Neurodegenerative Diseases (2023)

Microglia, neurodegeneration and loss of neuroendocrine control (2020)

The Role of Microglia in Brain Metastases: Mechanisms and Strategies (2024)

Ensheathing glia promote increased lifespan and healthy brain aging (2023)