Translational Medicine Friday

Mitochondria, Energy & Life --- Martin Picard

5/24/2025

Val's Take/Conjecture:

Colombia University Researcher Martin Picard is not just proposing a paradigm shift in mental health --- but in our view of life itself!

Many who now view mental illness as a Metabolic Disorder are proposing a KETO DIET.

Human beings have been trying to find the Magic Diet or Elixir for thousands of years and they have often come up short.

One of the concerns that I have is that when treatments don't work as well as we hoped --- we often blame the patient. That is true across board --- but menta health patients are uniquely vulnerable because of the stigma in the society.

So I think a KETO DIET may very well help some people --- while focusing on PRECISION MEDICINE and the right treatment, at the right time, for the right patient.

Scientific American
Could Mitochondria Be Rewriting the Rules of Biology?
(May 2025)

Additionally, I have had concerns that NEURO-DEVELOPMENTAL and PSYCHIATRIC DISORDERS are not sufficiently recognized as DEVELOPMENTAL with IN-UTERO DYSREGULATION of MICROGLIA.

It seems as though repair of Mitochondria can influence the regulation of Microglia in a positive way. (See: Mitochondrial Regulation of Microglial Immunometabolism in Alzheimer’s Disease)

mitochondria link to mental illness -- Dr. Ana Andreazza

5/23/2025

Val's Note: This is a long video from 2 months ago.

Understanding MITOCHONDRIAL DYSFUNCTION and its relationship to MENTAL ILLNESS is a fairly significant paradigm shift and the research of the last decade or so does support this focus on MITOCHONDRIA.

This has the potential to be TRANSFORMATIVE in our UNDERSTANDINGS and TREATMENT of Mental Illness.

I've seen a lot of people who have been criminally shamed and/or punished for essentially mitochondria dysfunction. Further, not understanding MITOCHONDRIA DYSFUNCTION leads us to write off people who are homeless as lazy or just needing a break when they actually have serious systemic biological dysregulations.

The Intersection of Mitochondrial Function and Psychiatric Disorders: Biomarkers, Gene Variants, and Patient Stratification

Metabolic Health Summit
The Mitochondrial Link to Mental Illness | Ana Andreazza, PhD

This video is highly technical and it certainly doesn't present that all the questions are answered.

On the other hand, this research is RELEVANT to individuals and our systems, even if the research is not completed. It raises REASONABLE DOUBT about current approaches and paradigms.

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)

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