Blog Posts

Immune Disorders, Neuro-Developmental Disorders and Biomarkers

6/21/2025

Association of aging related genes and immune microenvironment with major depressive disorder (2025)

Conclusion: The process of aging, immune dysregulation, and MDD [Major Depressive Disorder] closely interconnected.

MMP9, IL7R, S100B, and EGF may be used as novel diagnostic biomarkers and potential therapeutic targets for MDD, especially MMP9.

Shared molecular mechanisms and transdiagnostic potential of neurodevelopmental disorders and immune disorders (2024)

Highlights

•Neurodevelopmental disorders share a common genetic foundation with immune disorders but exhibit a higher degree of polygenicity.
•This study identified thirty genomic loci with significant associations in both types of diseases, including eight novel loci.
•The shared loci were mapped to genes enriched in three classes of pathways.
•The pleiotropic loci show a significant association with blood cell traits, potentially serving as more accessible and feasible biomarkers for patient stratification.

Maternal Immune Activation Activates Inflammatory Genes in the Fetus

6/21/2025

Maternal Immune Activation Alters Fetal Brain Development and Enhances Proliferation of Neural Precursor Cells in Rats (2020)

"Maternal immune activation (MIA) caused by exposure to pathogens or inflammation during critical periods of neurodevelopment is a major risk factor for behavioral deficits and psychiatric illness in offspring. . . .

"We identified a robust increase in expression of genes related to antiviral inflammation following maternal PolyI:C exposure, and a corresponding decrease in transcripts associated with nervous system development."

Impact of maternal immune activation and sex on placental and fetal brain cytokine and gene expression profiles in a preclinical model of neurodevelopmental disorders (2024)

What is a Neuro-Immune Transcriptome?

6/21/2025

Neuroimmune transcriptome changes in patient brains of psychiatric and neurological disorders (2023)

The Australian Researcher Cynthia Shannon Weickert participated in this --- she has been on the forefront of research involving the immune system and psychiatric disorders.

She has a twin brother with "Schizophrenia."

Professor Cyndi Shannon Weickert (Neuroscience Research Australia) talks with ABC Radio National's Dr Norman Swan on the Health Report (2012)

Is an Overactive Immune System a Cause of Schizophrenia?

Paradigm shift: Mood Disorders are not just brain disorders, they are multi-System Disorders

6/21/2025

Val's Take/Conjecture

The lead author of the article to the right is Dr. Antonio Teixeira at the University of Texas.
Dr. Teixeira literally edited the book on Immunopsychiatry -- published by Oxford University Press.

Dr. Antonio L Teixeira

This book is designed to be a clinician's introduction. It was published by Oxford University Press in 2019.

Neuro-Developmental & Psychiatric Disorders as Multi-System Disorders

Addressing Multi-System Developmental Neuro-Immune Disorders --- Is the Mental Health Profession up to addressing this alone?

Psychoneuroimmunology of Mood Disorders (2025)

Abstract

Recent research has shed light on the intricate relationship between mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BD), and inflammation.

This chapter explores the complex interplay:

involving immune and metabolic dysfunction in the pathophysiology of these disorders,
emphasizing their association with autoimmunity/inflammatory conditions,
chronic low-grade systemic inflammation,
T cell overactivation, and
immunosenescence [age-related decline in functionality of the immune system].

[bullets added]

This perspective underscores the notion that MDD [Major Depressive Disorder] and BD [Bipolar Disorder] are not solely brain disorders, highlighting their nature as multi-system conditions.

ADHD, Autism, Bipolar Disorder, Depression & Schizophrenia As Multi-System Disorders

REGULATING AGGRESSION THROUGH THE IMMUNE SYSTEM

6/21/2025

Val's Take/Conjecture

Stephen Hawking maintained that addressing Aggression was the top problem facing humanity.
But the biological basis of the challenge doesn't necessarily match with the MYSTIQUE we may have imagined.

Link Between the Immune System and Aggression

The Role of Interleukin 1β in Aggression in Animal Models (2023)

Study: Antibiotics in Infancy Linked to Increased Aggression (2024)

Plasma and cerebrospinal fluid inflammatory markers and human aggression (2023)

Associations of the immune system in aggression traits and the role of microglia as mediators (2024)

*Japanese Researcher

Abstract

There is an important relationship between the immune system and aggressive behavior.

Aggressive encounters acutely increase the levels of proinflammatory cytokines, and there are positive correlations between aggressive traits and peripheral proinflammatory cytokines.

Endotoxin lipopolysaccharide (LPS) treatment, which results in peripheral immune activation, decreases aggressive behavior as one of the sickness behavioral symptoms.

In contrast, certain brain infections and chronic interferon treatment are associated with increased aggression.

Indeed, the effects of proinflammatory cytokines on the brain in aggressive behavior are bidirectional, depending on the type and dose of cytokine, target brain region, and type of aggression.

Some studies have suggested that microglial activation and neuroinflammation influence intermale aggression in rodent models.

In addition, pathological conditions as well as physiological levels of cytokines produced by microglia play an important role in social and aggressive behavior in adult animals.

Furthermore, microglial function in early development is necessary for the establishment of the social brain and the expression of juvenile social behaviors, including play fighting.

Overall, this review discusses the important link between the immune system and aggressive traits and the role of microglia as mediators of this link.

How can microglia (the brain's immune cells) affect Mental States?

6/21/2025

Microglia-Derived Interleukin-6 Triggers Astrocyte Apoptosis [Cell Death] in the Hippocampus and Mediates Depression-Like Behavior
(2025)

Chinese Researchers

Microglia Sing the Prelude of Neuroinflammation-Associated Depression (2025)

Chinese Researchers

Abstract

Major depressive disorder (MDD) is a psychiatric condition characterized by sadness and anhedonia and is closely linked to chronic low-grade neuroinflammation, which is primarily induced by microglia.

Nonetheless, the mechanisms by which microglia elicit depressive symptoms remain uncertain.

This review focuses on the mechanism linking microglia and depression encompassing the breakdown of the blood-brain barrier, the hypothalamic-pituitary-adrenal axis, the gut-brain axis, the vagus and sympathetic nervous systems, and the susceptibility influenced by epigenetic modifications on microglia.

These pathways may lead to the alterations of microglia in cytokine levels, as well as increased oxidative stress.

Simultaneously, many antidepressant treatments can alter the immune phenotype of microglia, while anti-inflammatory treatments can also have antidepressant effects.

This framework linking microglia, neuroinflammation, and depression could serve as a reference for targeting microglia to treat depression.

Neuro-Diversity, Inflammation, Sensory Processing Differences --- and Trauma

6/21/2025

Val's Take/Conjecture

People with Neuro-Developmental and Psychiatric Disorders are more vulnerable to POST TRAUMATIC STRESS DISORDER.
There may be many reasons for that --- and the 3Ms are relevant:
- Maternal Immune Activation
- Dysregulation of MIcroglia, and
- MItochondrial Dysfunction.

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

Investigating the effects of maternal immune activation on sensory processing: Timing, immune mechanisms, and gene-environment interactions (2021)

By Faraj Haddad
University of Western Ontario

Mitochondrial dysfunction as a possible trigger of neuroinflammation at post-traumatic stress disorder (PTSD) (2023)

*Ukrainian and Canadian Researchers

Sensory alterations in post-traumatic stress disorder (2024)

Genetic insights into the role of mitochondria-related genes in mental disorders: An integrative multi-omics analysis (2025)

*Chinese Researchers

Conclusions: These findings suggested that dysfunction in mitochondria-related genes may underlie the molecular mechanisms of ADHD and SCZ, providing novel biomarkers for diagnosis and therapeutic interventions.

[Val's Take: At least in some to many cases, it is likely that dysfunction in mitochondria-related genes began IN UTERO with Maternal Immune Activation.

This also goes to the idea of a Neuro-Developmental - Psychiatric Continuum that is BLURRED and not distinct as the DSM.]

Trans-Cranial Magnetic Stimulation AS A Treatment for MICROGLIAL Dysregulation

6/20/2025

[Microglia are the innate immune cells of the brain & central Nervous system]

Val's Take/Conjecture

These studies provide more corroboration that Neuro-Developmental & Psychiatric Disorders are NEURO-IMMUNE DISORDERS.
Further, many of our current treatments are being re-evaluated in light of new understandings and paradigms.
Additionally, researchers are working to refine treatments such as Transcranial Magnetic Stimulation (TMS) to make them more targeted and effective based on these new understandings and paradigms.

Low-frequency repetitive transcranial magnetic stimulation alleviates abnormal behavior in valproic acid rat model of autism through rescuing synaptic plasticity and inhibiting neuroinflammation
(2024)

"Prenatal VPA exposure increased the level of inflammation cytokines and promoted the excessive activation of microglia.

"rTMS significantly alleviated the prenatal VPA-induced abnormalities including behavioral and synaptic plasticity deficits, and excessive neuroinflammation.

"TMS maybe a potential strategy for autism therapy via rescuing synaptic plasticity and inhibiting neuroinflammation."

Neuroprotective and plasticity promoting effects of repetitive transcranial magnetic stimulation (rTMS): A role for microglia (2025)

"Given their critical involvement in neurodegenerative and neuropsychiatric disorders, modulating microglial function presents a promising therapeutic avenue.

"In this context, rTMS is emerging as a potential strategy to influence microglial activity, suggesting that these cells serve as both targets and key mediators of rTMS-induced plasticity, neuroprotection, and therapeutic outcomes.

"Findings from in vitro and in vivo studies highlight how these interactions contribute to the therapeutic benefits of rTMS across various neuropsychiatric disorders."

Microglial Cytokines Mediate Plasticity Induced by 10 Hz Repetitive Magnetic Stimulation (2023)

"We conclude that rTMS affects neural excitability and plasticity by modulating the release of cytokines from microglia."

Transcranial Magnetic Stimulation for Developmental Neuropsychiatric Disorders with Inflammation (2023)

The Kynurenine Pathway and multi-System Neuro-Developmental & Psychiatric disorders

6/19/2025

"The immune-KYN-neuroendocrine interaction"

Val's Take/Conjecture

One of the big paradigm shifts of the 21st Century is recognizing Neuro-Developmental and Psychiatric Disorders as MULTI-SYSTEM DISORDERS, not just BRAIN DISORDERS.

In 1987, the Psychoneuroimmunology Research Society (PNIRS) established the Brain, Behavior, and Immunity Journal --- that also now includes the Endocrine System.

The KYNURENINE PATHWAY has emerged not only as a common molecular pathway for Neuro-Developmental, Psychiatric and Neuro-Degenerative Disorders --- but also much of our chronic disease epidemic of Diabetes, Auto-Immune Disorders, Cancer, etc.

Maternal Immune Activation is associated with increased risk of Type 1 and Type 2 Diabetes and Cancer and thought to increase the risk of adult on-set Auto-Immune Disease in offspring.
- Further, those illnesses often come with psychiatric symptoms.

Diet and Exercise are important, but if we're not recognizing "NEURO-DEVELOPMENTAL IMPAIRMENT" of MULTIPLE SYSTEMS OF THE BODY through various biological mechanisms such as:

Maternal Immune Activation
Paternal Immune Activation
Microglia Dysregulation
Immune Dysregulation
Endocrine Dysregulation
Dysregulation of the KYNURENINE PATHWAY
Microbiota Dysregulation
Metabolic Dysregulation
Etc.

---- We're going to have an incomplete and highly misleading understanding of what's going on.

Diverse Physiological Roles of Kynurenine Pathway Metabolites: Updated Implications for Health and Disease (2025)

Abstract

Tryptophan is an essential amino acid critical for human health. It plays a pivotal role in numerous physiological and biochemical processes through its metabolism.

The kynurenine (KYN) pathway serves as the principal metabolic route for tryptophan, producing bioactive metabolites, including KYN, quinolinic acid, and 3-hydroxykynurenine.

Numerous studies are actively investigating the relationship between tryptophan metabolism and physiological functions.

These studies are highlighting the interactions among metabolites that may exert synergistic or antagonistic effects, such as neuroprotective or neurotoxic, and pro-oxidative or antioxidant activities.

Minor disruptions in the homeostasis of these metabolites can result in immune dysregulation, contributing to a spectrum of diseases.

These diseases include neurological disorders, mental illnesses, cardiovascular conditions, autoimmune diseases, and chronic kidney disease.

[See also Targeting the kynurenine pathway: another therapeutic opportunity in the metabolic crosstalk between cancer and immune cells (2025)]

Therefore, understanding the physiological roles of the KYN pathway metabolites is essential for elucidating the contribution of tryptophan metabolism to health regulation.

The present review emphasizes the physiological roles of KYN pathway metabolites and their mechanisms in disease development, aiming to establish a theoretical basis for leveraging dietary nutrients to enhance human health.

Implications of Kynurenine Pathway Metabolism for the Immune System, Hypothalamic-Pituitary-Adrenal Axis, and Neurotransmission in Alcohol Use Disorder (2024)

Abstract

In recent years, there has been a marked increase in interest in the role of the kynurenine pathway (KP) in mechanisms associated with addictive behavior.

Numerous reports implicate KP metabolism in influencing the immune system, hypothalamic-pituitary-adrenal (HPA) axis, and neurotransmission, which underlie the behavioral patterns characteristic of addiction.

An in-depth analysis of the results of these new studies highlights interesting patterns of relationships, and approaching alcohol use disorder (AUD) from a broader neuroendocrine-immune system perspective may be crucial to better understanding this complex phenomenon.

In this review, we provide an up-to-date summary of information indicating the relationship between AUD and the KP, both in terms of changes in the activity of this pathway and modulation of this pathway as a possible pharmacological approach for the treatment of AUD.

The correlation of inflammation, tryptophan-kynurenine pathway, and suicide risk in adolescent depression (2024)

Accumulating evidence suggests a role for the tryptophan-kynurenine pathway (TKP) in the psychopathology of major depressive disorder (MDD).

Abnormal inflammatory profile and production of TKP neurotoxic metabolites appear more pronounced in MDD with suicidality. . . .

"Our findings indicated that serum inflammatory cytokines were robustly associated with IDO and KMO activity, along with significantly decreased serum level of TRP, increased level of 3-HK, and higher suicide risk in adolescent depression."
Accumulating evidence suggests a role for the tryptophan-kynurenine pathway (TKP) in the psychopathology of major depressive disorder (MDD).

Abnormal inflammatory profile and production of TKP neurotoxic metabolites appear more pronounced in MDD with suicidality. . . .

"Our findings indicated that serum inflammatory cytokines were robustly associated with IDO and KMO activity, along with significantly decreased serum level of TRP, increased level of 3-HK, and higher suicide risk in adolescent depression."

Maternal immune activation induces neurodevelopmental impairments of adult offspring through alterations in tryptophane-kynurenine pathway in the placenta (2024)

The kynurenine pathway: a finger in every pie (2020)

Abstract

The kynurenine pathway (KP) plays a critical role in generating cellular energy in the form of nicotinamide adenine dinucleotide (NAD+).

Because energy requirements are substantially increased during an immune response, the KP is a key regulator of the immune system.

Perhaps more importantly in the context of psychiatry, many kynurenines are neuroactive, modulating neuroplasticity and/or exerting neurotoxic effects in part through their effects on NMDA receptor signaling and glutamatergic neurotransmission.

As such, it is not surprising that the kynurenines have been implicated in psychiatric illness in the context of inflammation.

However, because of their neuromodulatory properties, the kynurenines are not just additional members of a list of inflammatory mediators linked with psychiatric illness, but in preclinical studies have been shown to be necessary components of the behavioral analogs of depression and schizophrenia-like cognitive deficits.

Further, as the title suggests, the KP is regulated by, and in turn regulates multiple other physiological systems that are commonly disrupted in psychiatric disorders, including endocrine, metabolic, and hormonal systems.

This review provides a broad overview of the mechanistic pathways through which the kynurenines interact with these systems, thus impacting emotion, cognition, pain, metabolic function, and aging, and in so doing potentially increasing the risk of developing psychiatric disorders.

Novel therapeutic approaches targeting the KP are discussed.

Moreover, electroconvulsive therapy, ketamine, physical exercise, and certain non-steroidal anti-inflammatories have been shown to alter kynurenine metabolism, raising the possibility that kynurenine metabolites may have utility as treatment response or therapeutic monitoring biomarkers.

Neuro-Diversity and Thyroid Problems

6/15/2025

Val's Take/Conjecture

In 2025, part of understanding Neuro-Developmental and Psychiatric Disorders is understanding them as MULTI-SYSTEM DISORDERS.
"Thyroid Disorders" and other Auto-Immune Diseases are also often implicating more than one Generation.
- Maternal Auto-Immune Disorders are a source of Maternal Immune Activation during pregnancy.
- And that Maternal Immune Activation can disrupt multiple systems of the body in offspring, including the ENDOCRINE SYSTEM and the THYROID.

Causal relationship between graves' disease and mental disorders: A bidirectional Mendelian randomization study (2025)

Conclusions: This bidirectional MR [Mendelian Randomized] study supports the role of GD [Graves Disease] in the causal association with an increased risk of bipolar disorder, which guides us to pay attention to the mental diseases of GD patients in the clinic.