Translational Medicine Friday

One thing leads to another

3/16/2025

Val's Take: "You told me something wrong --- I know I listen too long --- but one thing leads to another --- I know you been lying to me."

I don't think the Mental Health Profession has been "lying to me," but . . .

There are major problems that are not being addressed in this gap between the researchers and the clinicians.

Once we go from Neuro-Developmental and Psychiatric Disorders as Brain Disorders --- to Multi-System Neuro Immune Disorders --- that implicates other medical disciplines.

"The wrong antidote is like a bone in the throat."

The hard issues regarding the Shaky Foundation of Psychiatric Diagnostics

The DSM 5 and the Criminal Justice Wheel of Fortune

New Understandings Matter

Science Up

fetal microglia, inflammation & neuronal Hyper-excitoxicity in neuro-developmental & Psychiatric Disorders

3/8/2025

Val's Take/ Conjecture

It's more complicated than this --- but Microglia are essentially the Brain's Innate Immune Cells.
Maternal Immune Activation appears to effect adult behavior by among other things:
- Dysregulating Amoeboid Microglia during pregnancy. Those Amoeboid Microglia ultimately become
- Ramified Microglia in the Adult Central Nervous System

Astrocytes are another type of glial cell, different than Microglia.
Astrocytes do a number of things, including maintaining glutamate homeostasis.
Glutamate excitotoxicity is involved with Neuro-Developmental and Psychiatric Disorders.

Microglial contribution to the pathology of neurodevelopmental disorders in humans (2023)

Dysfunctional mitochondrial processes contribute to energy perturbations in the brain and neuropsychiatric symptoms (2023)

Glutamate-Mediated Excitotoxicity in the Pathogenesis and Treatment of Neurodevelopmental and Adult Mental Disorders (2024)

"In the current narrative review, we will summarize the role of glutamate-induced excitotoxicity in both the pathophysiology and therapeutic interventions of neurodevelopmental and adult mental diseases with a focus on autism spectrum disorders, substance abuse, and psychiatric disorders.

"Indeed, glutamatergic drugs are under preclinical and clinical development for the treatment of different mental diseases that share glutamatergic neuroplasticity dysfunctions."

"Our mission: to help accelerate the next breakthrough in drug discovery, diagnostics and basic research."

Microglia subtype markers
(2022)

Amoeboid microglia
- Amoeboid microglia are associated with the developing CNS. In rats, amoeboid microglia have been shown to appear late in gestation and disappear soon after birth.
- Ultimately, amoeboid microglia grow long crenulated processes and transform into ramified microglia found in the adult CNS.
Ramified microglia
Reactive microglia
- Like macrophages, reactive microglia secrete inflammatory mediators, which orchestrate the cerebral immune response.

Chronic microglial activation is associated with neurological disorders including Alzheimer's disease, multiple sclerosis, and delayed neuronal death occurring after ischaemia.

In these instances, the persistent activation of microglia accompanied by the sustained secretion of inflammatory mediators is thought to have a deleterious effect on neuronal function and survival, thereby exacerbating disease processes.

CD45 - microglia
CD45 - macrophage
CD11b
CD68 - microglia
CD68 - macrophage

Astrocytes Maintain Glutamate Homeostasis in the CNS by Controlling the Balance between Glutamate Uptake and Release (2019)

Metabolism & Maternal Immune activation

3/2/2025

Val's Take/Conjecture

One of many things making these insights hard to come by beyond the need for advanced technology is that Neuro-Diversity is characterized by DIVERSITY.
Further, METABOLIC DYSREGULATION is different in different people --- it doesn't necessarily look the same.

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

Key findings: A novel evidence was proved that illustrated altering four immune and metabolism-related risk pathways, including starch and sucrose metabolism, ribosome, protein processing in endoplasmic reticulum, and retrograde endocannabinoid signaling pathway, which were prominent involvement in the process of MIA regulating abnormal fetal brain development to induce an increased risk of ASD.

Here, we have observed that almost all key genes within these risk pathways are significantly differentially expressed at embryonic days (E) 10.5-12.5, which is considered to be the optimal coincidence window of mouse embryonic brain development to study the intimate association between MIA and ASD using mouse animal models.

Significance: [The] search establishes that MIA causes dysregulation of immune and metabolic pathways, which leads to abnormal embryonic neurodevelopment, thus promoting development of ASD symptoms in offspring.

Shared genetic architecture and bidirectional clinical risks within the psycho-metabolic nexus (2025)

Interpretation: The study highlights the intertwined genetic and clinical relationships between psychiatric disorders and metabolic dysregulations, emphasizing the need for integrated approaches in diagnosis and treatment.

Molecular and metabolic heterogeneity of astrocytes and microglia (2023)

Abstract

Astrocytes and microglia are central players in a myriad of processes in the healthy and diseased brain, ranging from metabolism to immunity.

The crosstalk between these two cell types [Astrocytes & Microglia] contributes to pathology in many if not all neuroinflammatory and neurodegenerative diseases.

Recent advancements in integrative multimodal sequencing techniques have begun to highlight how heterogeneous both cell types are and the importance of metabolism to their regulation.

We discuss here the transcriptomic, metabolic, and functional heterogeneity of astrocytes and microglia and highlight their interaction in health and disease.

Sensory processing, Synapses, Energy, the Immune System & Emotional Dysregulation

2/28/2025

Val's Take/Conjecture

Carly is not a person with an "INVISIBLE DISABILITY" --- people around her knew she had some challenges even if they misunderstood the nature of those challenges.
CARLY IS A SLOW PROCESSOR AND SHE IS INTELLIGENT.

Most people with ADHD, Autism, Dyslexia, etc. have invisible disabilities --- that is most other people do not see the disability-- and they also often do not see the need for accommodation.

And that also often includes the person themselves.
Even though I'm not a big fan of DSM 5 diagnostic categories --- they can alert people that there is an issue.
Like the situation for Carly, the true nature of the challenges is often misunderstood.

Microglia: Synaptic modulator in autism spectrum disorder (2022)

"Mounting evidence indicates that microglia, the resident immune cells of the brain, are required for proper brain function, especially in the maintenance of neuronal circuitry and control of behavior.

"Dysfunction of microglia will ultimately affect the neural function in a variety of ways, including the formation of synapses and alteration of excitatory-inhibitory balance."

Mitochondrial Biogenesis in Neurons: How and Where (2021)

"Neurons rely mostly on mitochondria for the production of ATP and Ca2+ (Calcium ion) homeostasis."

Dissecting depression symptoms: Multi-omics clustering uncovers immune-related subgroups and cell-type specific dysregulation (2025)

Burden of Proof

More Conjecture

Greater sensory processing demands as the result of greater number of synapses
- create greater ENERGY needs in people with Neuro-Developmental and Psychiatric Disorders .
The CATCH-22: Many of these Neuro-Developmental & Psychiatric Disorders have idiosyncratic and varied "DYSREGULATIONS," including Metabolic Dysregulations involving Mitochondria, and Microglia -- the Brain's Innate Immune Cells.
It it is very hard to say current understandings are TOTALLY WRONG --- but newer understandings go back in the CHAIN OF CAUSALITY and explain things that current understandings often do get wrong.
Further, researchers are not done yet.

Star Institute posted this 20/20 episode on YouTube in 2012.
Star Institute is in Centennial, Colorado.

The video is of Carly Fleishmann with non-verbal autism.

What about the kid or adult who is verbal but is nonetheless getting overwhelmed with sensory input of one or more types?

Concepts of Neuroinflammation and Their Relationship With Impaired Mitochondrial Functions in Bipolar Disorder (2021)

Abstract

Bipolar disorder (BD) is a chronic psychiatric disease, characterized by frequent behavioral episodes of depression and mania, and neurologically by dysregulated:

neurotransmission,
neuroplasticity [for people with ADHD and/or Autism they may have hyper-plasticity],
growth factor signaling, and
metabolism,
as well as oxidative stress, and
neuronal apoptosis [apoptosis is a type of cell death],
contributing to chronic neuroinflammation.

These abnormalities result from complex interactions between multiple susceptibility genes and environmental factors such as stress.

The neurocellular abnormalities of BD can result in gross morphological changes, such as reduced prefrontal and hippocampal volume, and circuit reorganization resulting in cognitive and emotional deficits.

The term "neuroprogression" is used to denote the progressive changes from early to late stages, as BD severity and loss of treatment response correlate with the number of past episodes.

In addition to circuit and cellular abnormalities, BD [Bipolar Disorder] is associated with dysfunctional mitochondria, leading to severe metabolic disruption in high energy-demanding neurons and glia.

[synapses are the connections between neurons not the neurons themselves but synapses take a lot of energy too]

Indeed, mitochondrial dysfunction involving electron transport chain (ETC) disruption is considered the primary cause of chronic oxidative stress in BD.

The ensuing damage to:

membrane lipids,
proteins, and
DNA
further perpetuates oxidative stress and neuroinflammation,
creating a perpetuating pathogenic cycle.

A deeper understanding of BD [Bipolar Disorder] pathophysiology and identification of associated biomarkers of neuroinflammation are needed to facilitate early diagnosis and treatment of this debilitating disorder.

The Immune Frontier in PsychiatryDecades in the making -- It is ready to take a starring role

2/24/2025

Val's Take/Conjecture

The journal Brain, Behavior and Immunity was started in 1987 by the Psychoneuroimmunology Research Society (PNIRS).
The journal publishes peer-reviewed basic, experimental, and clinical studies dealing with behavioral, neural, endocrine, and immune system interactions in humans and animals.
They were really on to something.

It's starting to become relatively CLEAR how something like MATERNAL IMMUNE ACTIVATION could be a big factor in Neuro-Developmental and Psychiatric Disorders.

"Inflammation" is a common term in the society and it's probably not going to be too long before "Maternal Immune Activation" is widely known even if people aren't familiar with all the complexity of that.

Low-dose interleukin-2 in patients with bipolar depression: A phase 2 randomised double-blind placebo-controlled trial (2025)

"This proof-of-concept trial shows that stimulating Tregs [Regulatory T cells] in patients with bipolar depression is safe and associated with clinical improvements.

"This supports a pathophysiological role of inflammation in BD and warrants pursuing the evaluation of IL-2LD as an adjunct treatment of major mood disorders."

Influence of Immune System Abnormalities Caused by Maternal Immune Activation in the Postnatal Period (2023)

"Exposure to maternal immune activation is a risk factor for neurodevelopmental disorders, psychosis, cardiovascular diseases, metabolic diseases, and human immune disorders.

"It has been associated with increased levels of proinflammatory cytokines transferred from mother to fetus in the prenatal period."

Understanding immune system dysfunction and its context in mood disorders: psychoneuroimmunoendocrinology and clinical interventions (2024)

Conventional and new immunotherapies for immune system dysregulation in postpartum mood disorders: comparisons to immune system dysregulations in bipolar disorder, major depression, and postpartum autoimmune thyroid disease (2025)

Cognitive disorders in patients with neuroimmunological disease (2025)

Summary: Autoimmune diseases should be considered as critical causal factors underlying new cases of neurocognitive disorder, especially in young patients.

These diseases are mediated by immune system reactions involving antibody production, T-cell-mediated damage, and demyelination.

Although the prognosis seems favourable in most conditions after immunotherapy, the magnitude of the therapeutic effect of immunotherapy on cognitive functioning remains unclear.

Chronological versus immunological aging: Immune rejuvenation to arrest cognitive decline (2025)

Abstract

The contemporary understanding that the immune response significantly supports higher brain functions has emphasized the notion that the brain's condition is linked in a complex manner to the state of the immune system.

It is therefore not surprising that immunity is a key factor in shaping brain aging. In this perspective article, we propose amending the Latin phrase "mens sana in corpore sano" ("a healthy mind in a healthy body") to "a healthy mind in a healthy immune system."

Briefly, we discuss the emerging understanding of the pivotal role of the immune system in supporting lifelong brain maintenance, how the aging of the immune system impacts the brain, and how the potential rejuvenation of the immune system could, in turn, help revitalize brain function, with the ultimate ambitious goal of developing an anti-aging immune therapy.

Mount sinai video -- fighting neuroimmune disorders

2/24/2025

Val's Take: Professor Scott Russo notes how much we've missed by just focusing on the brain and excluding the body.

This video does not get into Maternal Immune Activation, but does address Chronic Stress.

Icahn School of Medicine at Mount Sinai
Fighting Neuroimmune Disorders (2019)

Maternal Immune Activation & AGING

2/23/2025

Val's Take/Conjecture

Maternal immune Activation sets into motion a long list of dominoes that reverberate through out the lifespan.

Further, there is a Trans-Generational aspect to Maternal Immune Activation in which actions of prior generations can affect pregnancies in the present.

We don't want to become Eugenicists or Nazis ---

But we don't want to swing to the other extreme of having a complete inability to recognize developmental differences or gender differences, and the very real consequences those differences can have on the lives of individuals throughout the lifespan.
Maybe we're not saying people are possessed by demons, but we attribute a lot to "Lifestyle Choices."
That "Lifestyle Choices" hook is meant to be empowering, but many times it is condemning and demonstrably fallacious.

In Rabbi Kushner's Book -- "When Bad Things Happen to Good People," he talks about how a rare aging disease took the life of his son.

Neurodevelopmental and Psychiatric Disorders are not rare, but they are idiosyncratic --- which can make them hard to see.

Further, Neurodevelopmental and Psychiatric Disorders are premature aging disorders insofar as they involve significant developmental inflammation and dysregulation of multiple systems of the body that will make normal aging very difficult.

Lactoferrin alleviates the adverse effects of early-life inflammation on depression in adults by regulating the activation of microglia (2025)

Prenatal immune origins of brain aging differ by sex (2024)

Abstract

With an increasing aging population and Alzheimer's disease tsunami, it is critical to identify early antecedents of brain aging to target for intervention and prevention.

Women and men develop and age differently, thus using a sex differences lens can contribute to identification of early risk biomarkers and resilience.

There is growing evidence for fetal antecedents to adult memory impairments, potentially through disruption of maternal prenatal immune pathways.

Here, we hypothesized that in utero exposure to maternal pro-inflammatory cytokines will have sex-dependent effects on specific brain circuitry regulating offspring's memory and immune function that will be retained across the lifespan.

Using a unique prenatal cohort, we tested this in 204 adult offspring, equally divided by sex, who were exposed/unexposed to an adverse in utero maternal immune environment and followed into early midlife (~age 50).

Functional magnetic resonance imaging results showed exposure to pro-inflammatory cytokines in utero (i.e., higher maternal IL-6 and TNF-α levels) was significantly associated with sex differences in brain activity and connectivity underlying memory circuitry and performance and with a hyperimmune state, 50 years later.

In contrast, the anti-inflammatory cytokine, IL-10 alone, was not significantly associated with memory circuitry in midlife.

Predictive validity of prenatal exposure was underscored by significant associations with age 7 academic achievement, also associated with age 50 memory performance.

Results uniquely demonstrated that adverse levels of maternal in utero pro-inflammatory cytokines during a critical period of the sexual differentiation of the brain produced long-lasting effects on immune function and memory circuitry/function from childhood to midlife that were sex-dependent, brain region-specific, and, within women, reproductive stage-dependent.

the neuro-immune system and substance use

2/21/2025

Val's Take/Conjecture

The "Neuro-Immune System" is a relatively new concept and it has taken off in the last 5 to 10 years.
It involves Glial Cells (including the Brain's Innate Immune Cells in Microglia) and various Molecular Pathways.
Researchers are identifying the "Neuro-Immune System" as a critical player in many diseases and disorders, including:
- Neuro-Developmental Disorders
- Psychiatric Disorders, and
- Substance Use Disorders

Researchers are zeroing in on "Microglia" and its relationship to Substance Use Disorders.

In Criminal Justice, there are a lot of People with Neuro-Developmental Disorders, Psychiatric Disorders, Substance Use Disorders and Brain Injury.
- Further, many people are contending with more than one issue.

"NEURO-INFLAMMATION" is a big common denominator.

On the other hand, one of the reasons why the issues are so complex and expensive to treat is they are not identical and often require a fair amount of individualized medicine and treatment.

There's a reason why these disorders have tended to cluster in the Criminal Justice System --- these disorders do have the potential to become dangerous.

There have been Criminal Justice Rehabilitation Efforts for hundreds of years --- going back to England even before the US was a country.
But the way they conceptualized the "ROOT CAUSE" of the problem was often a MORAL FAILURE. [History of the Penitentiary]
And that is still going on. Some kind of "Religious and/or Moral Education" probably can help manage excess ANXIETY, ANGER, AGGRESSION, and EMOTIONAL DYSREGULATION.just as DIET and EXERCISE can help with managing some of that NEURO-INFLAMMATION.

There is evidence that Diet and Exercise can improve Cognitive Dysfunction and Neuro-Inflammation and the regulation of Microglia.

BUT in many cases these strategies can help but fall woefully short of solving the problem for some people.

We've been PUSHED to understand the underlying BIOLOGY of Substance Use and other issues -- because what we we're doing wasn't sufficient.

The Neuroimmune System and the Cerebellum (2023)

[provides a good overview of the Neuro-Immune System]

Microglia NLRP3 Inflammasome and Neuroimmune Signaling in Substance Use Disorders (2023)

"During the last decade, substance use disorders
(SUDs) have been increasingly recognized as neuroinflammation-related brain diseases. ...Recently, inflammasome-mediated signaling has been identified as playing critical roles in the microglia activation …"

Transcriptional and epigenetic regulation of microglia in substance use disorders. (2023)

"Microglia are widely known for their role in immune surveillance and for their ability to refine neurocircuitry during development, but a growing body of evidence suggests that microglia may also play a complementary role to neurons in regulating the behavioral aspects of substance use disorders."

CONTINUED

For me, a big issue from a "Moral Education" standpoint is that many people are coming with SIGNIFICANT NEURO-DEVELOPMENTAL INFLAMMATION and AFTER-ACQUIRED INFLAMMATION (including TRAUMA but many other things as well) and significantly reduced abilities to manage STRESS.

and if we don't understand their personal individual biology and situation -- a big default is often a punitive response.
That punitive response is meant to reassure the Community --- and it often does --- but it also sends a powerful message that we SACRIFICE people in our community.

New diagnostic framework, glutamate-mediated Excitotoxity in Neuro-Developmental & psychiatric disorDers

2/16/2025

Towards a consensus roadmap for a new diagnostic framework for mental disorders (2024)

"In general, the meeting indicated a crucial need for a biology-informed framework to establish more precise diagnosis and treatment for mental disorders to facilitate bringing the right treatment to the right patient at the right time."

Glutamate-Mediated Excitotoxicity in the Pathogenesis and Treatment of Neurodevelopmental and Adult Mental Disorders (2024)
Disruption of the mechanisms responsible for glutamate homeostasis may result in

the accumulation of excessive glutamate levels,
which in turn leads to increased calcium levels,
mitochondrial abnormalities,
oxidative stress, and
eventually cell atrophy and death.

This condition is known as glutamate-induced excitotoxicity and is considered as a pathogenic mechanism

in several diseases of the central nervous system,
including neurodevelopmental,
substance abuse, and
psychiatric disorders.

What is Excitotoxicity?

2/15/2025

Val's Take / Conjecture

"Excitotoxity" is actually associated with CELL DEATH across a wide range of diseases and disorders.
That wide range includes Neuro-Developmental & Psychiatric Disorders.
It does seem that dysregulated microglia that can result from Maternal Immune Activation, could promote inflammation and excess glutamate release and neurotoxity.

Further, there can be more overlap than we often appreciate.
Further, we talk so much about the lack of BIOMARKERS in Mental Health -- but that is a perennial battle in Medicine.
- Other areas of Medicine have more BIOMARKERS than Mental Health.
- But Mental Health is getting Metabolomic Biomarkers and others, and
- At least in the last few years, people have seen the Trifecta of Neuro-Developmental, Psychiatric and Neuro-Degenerative Disorders and researchers have been exploring the relationships among them to a greater and greater degree.
- More and more we're seeing relationships with other Disorders and Diseases as well.

RIPK1 activation in Mecp2-deficient microglia promotes inflammation and glutamate release in RTT (2024)

Glutamate-Mediated Excitotoxicity in the Pathogenesis and Treatment of Neurodevelopmental and Adult Mental Disorders (2024)

Discovery of the therapeutic potential of naltriben against glutamate-induced neurotoxicity (2025)

Editorial: Glutamate-Related Biomarkers for Neuropsychiatric Disorders (2019)

What Happens When You Have Too Much Glutamate?

What happens when you have too much glutamate?

Too much glutamate in the brain can cause nerve cells to become overexcited.

Overexcitement can lead to brain cell damage and/or death. In this case, glutamate is called an excitotoxin.

Having too much glutamate in the brain is associated with some conditions, including:

*Amyotrophic lateral sclerosis (Lou Gehrig’s disease).

*Multiple sclerosis.

*Alzheimer’s disease.

*Parkinson’s disease.

*Huntington’s disease.

*Stroke.

*Fibromyalgia.

*Chronic fatigue syndrome

Glutamate and microglia activation as a driver of dendritic apoptosis [a type of cell death]: a core pathophysiological mechanism to understand schizophrenia (2021)

The role of glutamate receptors in the regulation of the tumor microenvironment (2023)

Glutamate-induced excitotoxicity in Parkinson's disease: The role of glial cells (2020)

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