Blog Posts

Mitochondrial Dysfunctionin neuro-Developmental & Psychiatric Disorders

5/19/2025

Val's Take/Conjecture

When we think of "SUPPORTED EMPLOYMENT" we may think of someone with an IQ under 70 working at "menial work" that is often ESSENTIAL.
For many people with Neuro-Developmental and Psychiatric Disorders --- they may have:
- an average or above average IQ
- expanded Sensory Processing, and
- MITOCHONDRIAL DYSFUNCTION
- The employment needs to ACCOMMODATE --- all 3 of those things.

Bob Dylan
The Times They Are A Changin'

Mitochondrial dysfunction in psychiatric disorders (2024)

Abstract

Psychiatric disorders are a heterogeneous group of mental disorders with abnormal mental or behavioral patterns, which severely distress or disable affected individuals and can have a grave socioeconomic burden.

Growing evidence indicates that mitochondrial function plays an important role in developing psychiatric disorders.

This review discusses the neuropsychiatric consequences of mitochondrial abnormalities in both animal models and patients.

We also discuss recent studies associated with compromised mitochondrial function in various psychiatric disorders, such as schizophrenia (SCZ), major depressive disorder (MD), and bipolar disorders (BD).

These studies employ various approaches including postmortem studies, imaging studies, genetic studies, and induced pluripotent stem cells (iPSCs) studies.

We also summarize the evidence from animal models and clinical trials to support mitochondrial function as a potential therapeutic target to treat various psychiatric disorders.

This review will contribute to furthering our understanding of the metabolic etiology of various psychiatric disorders, and help guide the development of optimal therapies.

Moving beyond "Personality analysis" to Biomarkers

5/18/2025

Val's Take/Conjecture

Mental Health got caught up in symptom clusters and personality analysis by necessity --- the biomarkers were not available.
That's changing BUT even I have argued for the need for INTERIM PROCEDURES with regard to an Out-of-Date DSM.
- This isn't quite the same thing --- but they both represent the need to deal with practical realities.

This new study is out of the University of Michigan --- I'm a huge fan of the work they have done on bipolar disorder --- they were one of the first to demonstrate that Bipolar Disorder was DEVELOPMENTAL.

I think the study is not so much to diagnose bipolar disorder but to predict severity and based on personality.

It's pretty much what one would expect. [How much money was spent on this?]
We really need to focus on those biomarkers.
P.S. Researchers from the University of Cambridge have found biomarkers for bipolar disorder and depression and it was reported in JAMA Psychiatry in 2024.

With Bipolar Disorder, we really are talking about Developmental Multi-System Neuro-Immune Disorders.

If all there is --- is TALK THERAPY --- maybe that is better than nothing --- but it doesn't seem to be the most appropriate therapy or treatment for a Neuro-Immune Disorder.

Personality Could Help Predict Bipolar Disorder (May 2025)

University of Michigan
The Study of Bipolar Disorder is the Study of Humanity (2017)

The cells of people with bipolar disorder are developmentally different than the cells of people without bipolar disorder.

the Big Catch 22 ---- Hey now . . . MicrogliaL Dysregulation, idiosyncratic Sensory Processing & an Insufficient energy Supply

5/17/2025

Val's Take/Conjecture

The CATCH-22 is that Microglial Dysregulation as a result of Maternal Immune Activation:
- Ramps up Sensory Processing with INCREASED ENERGY NEEDS
- While at the same time Microglia is playing a role in Mitochondria Dysfunction.
  - Making ENERGY production LESS EFFICIENT.

So what you end up with are people with IDIOSYNCRATIC Sensory Processing --- that does have the potential to benefit the society and themselves --- BUT

those kids, adolescents and adults are more vulnerable to BURNOUTS and BREAKDOWNS.

BUT that is very hard for the Society to understand --- because you look fine or fine enough.

Further, it is generally not clear to the person either --- which can result in the person pushing themselves more --- only to find that they are making things worse.

Understood
ADHD, Dyslexia Advice for Kids:
Try Smarter, Not Try Harder

MIGRAINE

Migraine has a documented association with Neuro-Developmental & Psychiatric Disorders.
Neuro-Developmental & Psychiatric Disorders often come with Sensory Processing Disorders.
Migraine is now viewed as a "LOSS OF CONTROL" by the Hypothalamus over the limbic system.
Further, some researchers have maintained that "Migraine" is a "LOSS OF CONTROL OF INPUTS."

I had 3 or 4 years of MIGRAINES that I certainly found painful and inconvenient --- but didn't view them as a precursor to more serious psychiatric problems.

Then I had something that may or may not have been a MINI STROKE ---- but created a situation in which I was unable to tell the difference between fantasy and reality.
- THAT IS DANGEROUS.

At the time, I was hospitalized and had a kind of crash landing to reality with the help of various anti-psychotics.

That was 18 years ago, and I haven't had a similar episode.
- But it does illustrate the problem that Mental Health America identified which was STAGE 4 diagnosis of serious mental health problems.

It is why we need biomarkers and we're getting them. I also think we need to take MIGRAINES more seriously than we do.

Finally, Microglial Dysregulation, Sensory Processing and Mitochondria Dysfunction are keys to understanding Neuro-Developmental & Psychiatric Disorders.

Migraine as an inflammatory disorder with microglial activation as a prime candidate (2023)

The status of knowledge on migraines: The role of microglia (2023)

Migraine attacks as a result of hypothalamic loss of control (2021)

"The hypothalamus as a metronome of internal processes is suggested to control these limbic circuits: migraine attacks may occur as a result of the hypothalamus losing control over the limbic system."

Grateful Dead
IKO IKO

Atypical Sensory Processing in Neurodevelopmental Disorders: Clinical Phenotypes in Preschool-Aged Children (2024)

"A positive correlation was found between sensory processing abnormalities and behavioral problems.

. . .

"Our results suggest that sensory processing difficulties should be considered regardless of developmental level and in children with behavioral problems."

Sensory processing difficulties in psychiatric disorders: A meta-analysis (2022)

Highlights

• Many individuals with psychiatric disorders report difficulties in sensory processing.

*  This meta-analysis examined sensory processing patterns in psychiatric conditions.

•  We detected a general pattern of sensory processing difficulties in psychopathology.

•  Sensory processing difficulties are considered to be a transdiagnostic phenotype.

•  Further research may improve long-term prognosis and treatment in psychiatry.

"In clinical practice, many individuals with psychiatric disorders report difficulties in sensory processing, including increased awareness or sensitivity to external stimuli.

. . .

"In conclusion, sensory processing difficulties can be considered as a non-specific transdiagnostic phenotype associated with a broad spectrum of psychiatric conditions.

"Further research into the relevance and role of sensory processing difficulties in psychiatric disorders may improve long-term prognosis and treatment."

Development and sensory experience dependent regulation of microglia in barrel cortex (2020)

*Researchers at City University of New York

"Findings suggest that both developmental age and sensory experience has profound impact on microglia morphology.

"Following chronic sensory deprivation, microglia undergo a morphological transition from a monitoring or resting state to an altered morphological state, by exhibiting expanded cell body size and retracted processes.

. . .

"Our results indicate that microglia may be recruited to participate in the modulation of neuronal structural remodeling during developmental critical periods and in response to alteration in sensory input."

Researcher Staci Bilbo: prenatal inflammation alters Microgial phenotype and behavior

5/15/2025

Staci D. Bilbo, PhD
Director of Research, Lurie Center for Autism
MassGeneral Hospital for Children
Lurie Family Associate Professor of Pediatrics, and Program in Neuroscience, Harvard Medical School
[Currently at Duke University]

Prenatal inflammation by combined environmental stressors alters microglial phenotype and behavior (2018)

Researcher Jonathan Kipnis --- A pioneer in Neuro-immunology

4/25/2025

Val's Note: Kipnis was formerly at the University of Virginia, now at the Washington University in St. Louis.

He is also an academic editor of the Journal of Experimental Medicine which publishes papers on immunology, cancer biology, vascular biology, microbial pathogenesis, neuroscience and stem cell biology.

Vaccinations & Neuro-Diversity --- The Need for a more Nuanced Approach

4/25/2025

Val's Take/Conjecture

If you ask Google AI about autism or ADHD, it's going to come back and say current research finds that Vaccinations do not "CAUSE" autism or ADHD.

I asked Google AI about vaccinations and NEUROIMMUNE Disorders, this is the result:

Vaccinations are generally safe and recommended for people with neuroimmune disorders, but timing and specific vaccine types should be considered.

Inactivated vaccines are considered safe, while live vaccines are generally avoided during immunotherapy.

Vaccinations must also be avoided during relapses or exacerbations of neuroimmune diseases.

In fact, medical professionals do have guidelines regarding vaccinations and people with Neuro-Immune Disorders such as Multiple Sclerosis.

The emerging neuroimmune hypothesis of bipolar disorder: An updated overview of neuroimmune and microglial findings (2024)

The immunological perspective of major depressive disorder: unveiling the interactions between central and peripheral immune mechanisms (2025)

Neuro-Immune Aspects of Schizophrenia with Severe Negative Symptoms: New Diagnostic Markers of Disease Phenotype (2025)

Psychiatric adverse events following COVID-19 vaccination: a population-based cohort study in Seoul, South Korea (2024)

"COVID-19 vaccination increased the risks of depression, anxiety, dissociative, stress-related, and somatoform disorders, and sleep disorders while reducing the risk of schizophrenia and bipolar disorder.

"Therefore, special cautions are necessary for administering additional COVID-19 vaccinations to populations vulnerable to psychiatric AEs (Adverse Events)."

"CAUSE"

When it comes to "CAUSE" and not only Neuro-Developmental & Psychiatric Disorders but also classic Neuro-Immune Disorders & Cancer ----
- There is often NOT 1 Cause --- they are "MULTI-FACTORAL"
- The Multitude of these FACTORS are driving the need for Individualized, Personalized Medicine.

ON THE OTHER HAND

People with Neuro-Developmental & Psychiatric Disorders, Classic Neuro-Immune Disorders and Cancer ----
- Are the very people who would be most at risk for the most serious outcomes of some of these diseases.

Understanding Neuro-Developmental & Psychiatric Disorders as Neuro-Immune Disorders

Neuroimmunity at the edge: The skull as a brain - periphery immunological hub in autism spectrum disorder (2025)

Evaluating the link between immune characteristics and attention deficit hyperactivity disorder through a bi-directional Mendelian randomization study (2024)

Conclusion: Studies indicate that the immune system’s response influences the emergence of ADHD.

The findings greatly improve our understanding of the interplay between immune responses and ADHD risk, aiding in the development of treatment strategies from an immunological perspective.

I just don't think it is that counter-intuitive that there might need to be some special considerations with regard to vaccines and Neuro-Immune Neuro-Developmental & Psychiatric Disorders.

We need to get out of the Anti-Vaxx/Conspiracy Theorist construction of this debate.

Recognizing legitimate issues and nuance supported by the evidence might help.

Maternal Immune ActivatioN, Gene Expression & the Immune System --- DNA & RNA Methylation

4/20/2025

"DNA methylation is the addition of a methyl group to the molecular structure of DNA, which then alters the gene expression."

DNA and RNA methylation directly linked for the first time (2025)

Val's Take/ Conjecture

I think "Lifestyle Choices" are important AND so are DNA Methylation Patterns established In Utero.
There is a certain amount of "FETAL PROGRAMMING" that seems to be going on that we feel highly uncomfortable acknowledging.
These are DEVELOPMENTAL DISORDERS --- if we are missing that --- we're missing the boat.

RNA m6A methylation in psychiatric disorders (2023)

Genetic evidence for causal effects of immune dysfunction in psychiatric disorders: where are we? (2024)

"Here we synthesize these new findings from genomics and genetic causal inference studies on the role of immune dysfunction in major psychiatric disorders and reconcile these new data with pre-omics findings.

"By reconciling these evidences, we aim to identify key gaps and propose directions for future studies in the field."

In Utero Exposures, Infant Growth, and DNA Methylation of Repetitive Elements and Developmentally Related Genes in Human Placenta (2011)

"DNA methylation patterns are essential for the growth and maintenance of tissue-specific expression profiles in different cell types during development, and these patterns become set during in utero development."

Circadian Rhythms Correlated in DNA Methylation and Gene Expression Identified in Human Blood and Implicated in Psychiatric Disorders (2024)

Towards a neurodevelopmental model of bipolar disorder: a critical review of trait- and state-related functional neuroimaging in adolescents and young adults (2025)

DNA and RNA methylation, initially thought to operate as distinct pathways, have been shown to interact closely, shifting our understanding of gene regulation. (2025)

Inhibition of aging-induced DNA hypermethylation by si-Dnmt3a/3b in pre-implantation embryos improves aberrant social behavior in offspring (2025)

"Our study indicates that male aging exert an influence not only on DNA methylation modification in sperm and pre-implantation embryo, but also on neurobehavioral abnormalities of their offspring.

"Repairing DNA methylation in pre-implantation embryos may offer a promising avenue for ameliorating abnormal social behavior in offspring."

The Genesis of Schizophrenia: An Origin Story (2024)

"Ultimately, rather than a focus on therapeutic intervention during adolescence or adulthood, principles of prediction and prophylaxis in the pre- and perinatal and neonatal stages may best comport with the biology of schizophrenia to address the early-stage perturbations that alter the normative neurodevelopmental trajectory."

Paternal immune activation in neuro-Developmental & Psychiatric Disorders

4/20/2025

Is paternal immune activation just as important as maternal immune activation?

Time to rethink the bi-parental immune priming of neurodevelopmental model of schizophrenia (2023)

Highlights

Paternal immune activation might enhance schizophrenia risk.

Epigenetic processes might mediate the effects of paternal immune activation.

Bi-parental immune priming seems to drive schizophrenia immunopathogenesis.

Depletion of the paternal gut microbiome alters sperm small RNAs and impacts offspring physiology and behavior in mice (2025)

"This study demonstrates that the gut-germline axis influences sperm small RNA profiles and offspring physiology, with specific impacts on offspring affective and/or coping behaviors.

"These findings may have broader implications for other animal species with comparable gut microbiota, intergenerational epigenetics and developmental biology, including humans."

Paternal immune activation by Poly I:C modulates sperm noncoding RNA profiles and causes transgenerational changes in offspring behavior (2024)

The missing half: Paternal immune activation's role in transgenerational sex differences (2024)

More Immune Connections to Neuro-Developmental & Psychiatric Disorders: Mast Cells

4/19/2025

"Mast cells (MCs) are tissue cells that are derived from bone marrow stem cells that contribute to allergic reactions, inflammatory diseases, innate and adaptive immunity, autoimmunity, and mental disorders."

Activation of Mast Cells by Neuropeptides: The Role of Pro-Inflammatory and Anti-Inflammatory Cytokines (2023)

Mast Cells in Autism Spectrum Disorder-The Enigma to Be Solved? (2024)

Identification of immune-related biomarkers in peripheral blood of schizophrenia using bioinformatic methods and machine learning algorithms (2023)

Beyond Confirmed Mast Cell Activation Syndrome: Approaching Patients With Dysautonomia and Related Conditions (2024)

[This is an interesting article and what it is talking about among other things is that --- it is hard to work with these patients with compassion --- they burn clinicians out.

As more of a MULTI-SYSTEM approach to neuro-developmental and psychiatric disorders is developed--- that should help.

Also, if patients are getting more effective and comprehensive treatments --- they may be a lot easier to deal with.]

RCCX Theory and Giftedness: A Promising New Line of Research (2019)

"Because it appears that mast cell activation problems exist in the gifted population in greater frequency than in the general population, we urge those in the gifted populations with health issues not solved by drugs in those categories to discuss the possibility of mast cell activation problems with their doctors."

Dr. Anne Maitland -- Mount Sinai
Neuropsychiatric Manifestations of Mast Cell Activation Disease (MCAS)

Neuropsychiatric Manifestations of Mast Cell Activation Syndrome and Response to Mast-Cell-Directed Treatment: A Case Series (2023)

Abstract

Mast cell activation syndrome (MCAS) is an immune disease with an estimated prevalence of 17%.

Mast cell chemical mediators lead to heterogeneous multisystemic inflammatory and allergic manifestations.

This syndrome is associated with various neurologic and psychiatric disorders, including headache, dysautonomia, depression, generalized anxiety disorder, and many others.

Although MCAS is common, it is rarely recognized, and thus, patients can suffer for decades.

The syndrome is caused by aberrant mast cell reactivity due to the mutation of the controller gene.

A case series is presented herein including eight patients with significant neuropsychiatric disorders that were often refractory to standard medical therapeutics. Five patients had depression, five had generalized anxiety disorder, and four had panic disorder.

Other psychiatric disorders included attention-deficit hyperactivity disorder, obsessive compulsive disorder, phobias, and bipolar disorder.

All eight patients were subsequently diagnosed with mast cell activation syndrome; six had comorbid autonomic disorders, the most common being postural orthostatic tachycardia syndrome; and four had hypermobile Ehlers-Danlos syndrome.

All patients experienced significant improvements regarding neuropsychiatric and multisystemic symptoms after mast-cell-directed therapy.

In neuropsychiatric patients who have systemic symptoms and syndromes, it is important to consider the presence of an underlying or comorbid MCAS [Mast Cell Activation Syndrome].

Atypical response to the common Epstein-barr Virus --- Auto-immune Disease, Cancer & Major Mental Illness

4/18/2025

Val's Take/Conjecture

It's estimated that 90 to 95% of the population have the Epstein-Barr Virus.
So the virus itself is far from rare --- what's rare in various diseases and disorders is an ATYPICAL RESPONSE to the Epstein-Barr Virus.

Further, Epstein-Barr often becomes a problem for people but often in the context of "Aging."
For younger people and re-activated Epstein Barr Virus as well as re-activated Microglia -- this may be a form of premature aging.

For people with Neuro-Developmental and Psychiatric Disorders, their Microglia may have been dysregulated IN UTERO and easily re-activated.

AUTO-IMMUNE DISEASE

Multiple Sclerosis (MS) is now greatly associated with the Epstein-Barr Virus.
Further, there is some overlap between MS and Bipolar Disorder.

Autoimmune responses to myelin-associated proteins as diagnostic and prognostic biomarkers of relapsing-remitting multiple sclerosis: Associations with human herpesvirus-6 and Epstein-Barr virus reactivation (2025)

Multiple sclerosis and bipolar disorder: an overlap between soma and psyche (2024)

"This clinical vignette with literature review is an illustration of the interesting, yet still unknown relationship between MS and affective disorders, where one might be influenced by the other but also have a common pathophysiology.

"This highlights that the dividing line between neurology and psychiatry, whose pathophysiology often takes place in the same organ, is often arbitrary."

Does Epstein-Barr virus and intracellular Toll-like receptors affect the course of Hashimoto [Thyroiditis] disease? Findings from studies on newly-diagnosed patients (2024)

Microglia as potential key regulators in viral-induced neuroinflammation (2024)

Awakening the sleeping giant: Epstein–Barr virus reactivation by biological agents (2024)

PSYCHIATRIC DISORDERS

Hypothesis: bipolar disorder is an Epstein-Barr virus-driven chronic autoimmune disease - implications for immunotherapy (2020)

Microbes and Mental Illness: Past, Present, and Future (2023)

"Perspectives on the etiology of mental illness have evolved from demonic possession toward multisystem biologically based models that include gene expression, environmental triggers, immune mediators, and infectious diseases.

"Microbes are associated with a number of mental disorders, including autism, schizophrenia, bipolar disorder, depressive disorders, and anxiety disorders, as well as suicidality and aggressive or violent behaviors. "

Atypical immune response to Epstein-Barr virus in major depressive disorder (2020)

CANCER

Epstein-Barr virus lytic replication and cancer (2025)

"Epidemiological studies have provided strong evidence that Epstein-Barr virus (EBV) lytic replication is linked to cancer development."

<<Previous

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Translational Medicine Friday

Mitochondrial Dysfunctionin neuro-Developmental & Psychiatric Disorders

Moving beyond "Personality analysis" to Biomarkers

the Big Catch 22 ---- Hey now . . . MicrogliaL Dysregulation, idiosyncratic Sensory Processing & an Insufficient energy Supply

Researcher Staci Bilbo: prenatal inflammation alters Microgial phenotype and behavior

Researcher Jonathan Kipnis --- A pioneer in Neuro-immunology

Vaccinations & Neuro-Diversity --- The Need for a more Nuanced Approach

Maternal Immune ActivatioN, Gene Expression & the Immune System --- DNA & RNA Methylation

Paternal immune activation in neuro-Developmental & Psychiatric Disorders

More Immune Connections to Neuro-Developmental & Psychiatric Disorders: Mast Cells

Atypical response to the common Epstein-barr Virus --- Auto-immune Disease, Cancer & Major Mental Illness

Translational Medicine Friday

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