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Val Corzine

Better Science 
can lead to
Better policy & Better LAw

​EDITORIAL: Keep mentally ill suspects in custody
​--See our response

Working to Eliminate Homelessness & Criminal Justice Involvement of People with Cognitive Disabilities


  • Current Scientific Research
  • Legal Analysis, and
  • Authenticity & Lived Experience

Playing for Change
Jackson Browne

Doctor My Eyes


PREVIEW NEURO-DIVERSITY WEDNESDAY

Neuro-Developmental & Psychiatric disorders as Multi-system disorders

Val's Take/Conjecture
  • Most of us understand that Down Syndrome is a "MULTI-SYSTEM DISORDER."
  • Neuro-Developmental Disorders such as Autism, and/or ADHD and Psychiatric Disorders such as Bipolar Disorder, Schizophrenia and Depression are also MULTI-SYSTEM DISORDERS.
  • Further, Bipolar Disorder, Schizophrenia and Depression are now recognized as NEURO-DEVELOPMENTAL DISORDERS.
  • Additionally, Down Syndrome, Autism, ADHD, Bipolar Disorder, Schizophrenia and Depression are all NEURO-IMMUNE DISORDERS.
PREVIEW

fetal microglia inflammation & neuronal Hyper-excitoxicity

​IN Neuro-developmental & Psychiatric Disorders

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)

PREVIEW:  Translational Medicine Friday

Maternal Immune Activation & AGING

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.

PREVIEW:  Olmstead Law & Order Thursday

​Executive Functioning, Pre-mature Aging & Staffing
​

Val's Take/Conjecture
  • ​The RATE OF AGING is IDIOSYNCRATIC and dependent on a number of factors among which is MATERNAL IMMUNE ACTIVATION.
  • Also, there are complicated sex differences in aging.
​
  • When we think of Aging in Older People
    • ​We're often thinking about Neuro-Degenerative Disorders that impact both cognition and mobility.
    • Further, we are prepared to fund Alzheimer's Units and Locked Nursing Home Wards 
      • ​Some of the people on those locked wards are younger people with "mental illness" or "brain injury" who could live in the community with sufficient supports.
      • There are a lot of people with "mental Illness" in jails or prisons, there are even more with "Neuro-Developmental Disorders" and an IQ over 70.
      • Assertive Community Treatment (ACT) needs to be available to people transitioning out of the nursing home as well as the Jail or Prison.
Neonatal inflammation impairs developmentally-associated microglia and promotes a highly reactive microglial subset (2025)
So What?

"These findings suggest major changes in microglial subsets developmental trajectories and reactivity contributing to NDDs [Neuro-Developmental Disorders] induced by neonatal inflammation."
Staffing
  • There is so much that can be gained by Public Education,
  • A website dealing with the challenges and strengths of being a person with a Neuro-Developmental Disorder and an IQ over 70 --- could be very helpful.
  • AI could potentially be very helpful.
  • These new understandings are the precursors to better treatments and likely reduce the need for more Staff across education, employment, healthcare, etc.
  • Neuro-Diversity is often associated with many diverse chronic disease categories --- of course, it is.
  • If you've lived this --- you know there are a lot of Highs and Lows.
  • In the meantime, there is a need to re-allocate resources and staff.
For younger people with Neuro-Developmental Disorders and an IQ over 70
  • Historically, we haven't appreciated the underlying biology and executive functioning deficits or the idiosyncratic strengths.
  • At least sometimes the Societal Response has been --- "If you don't stop crying, I'm gonna give you something to cry about."​ ​
Prenatal maternal C-reactive protein prospectively predicts child executive functioning at ages 4-6 years (2020)
"These findings provide novel, prospective evidence that maternal inflammation uniquely predicts child cognitive flexibility deficits, and that these associations depend on the timing of exposure before or during pregnancy."
Aggression and its correlation with plasma C-reactive protein levels in patients with schizophrenia: A hospital based cross-sectional study (2023)
The effects of Maternal Immune Activation are not static over the life span, although those effects are not uniform and are idiosyncratic.

  • Something needs to be brought to bear on this challenge of people with Neuro-Developmental Disorders and an IQ over 70 who make up big chucks of:
    • the Homeless
    • Criminal Justice
    • Child Welfare populations
    • as well as a problematic Elite

PREVIEW:  Neuro-Diversity WednesdaY

Mental Exhaustion Drives Aggressive Behavior (2024)

Val's Take/Conjecture
  • FATIGUE is a driving issue in many Neuro-Diverse challenges.
  • We are starting to recognize the association between Neuro-Diversity and other disorders and diseases involving fatigue such as:
    • ME/CFS (Chronic Fatigue Syndrome),
    • Fibromyalgia
    • Multiple Sclerosis 
    • Hyper-Mobility Syndromes
    • etc.
  • The disorders listed above tend to hit women much harder than men, although there are exceptions.
When it comes to some Neuro-Diverse men and energy and aggression, the conversation is complicated.

It's not that women aren't using AGGRESSION as well to gin their energy up, but they may not be getting away with it and even women who are getting away with it---
  • those women are not likely to be as physically aggressive.
So when someone like Elon Musk says --- "Hey, I'm this high energy, aggressive Neuro-Diverse guy"
  • Yeah, but
  • You wouldn't be so aggressive, if you had the energy not to be.
Further, the aggression doesn't create energy, it mobilizes what energy is there by the release of stress hormones.

​Childhood neurodivergent traits, inflammation and chronic disabling fatigue in adolescence: a longitudinal case–control study  (2024) 
​Conclusions:  Our results indicate higher risk of chronic disabling fatigue for children with neurodivergent traits, likely linked to higher levels of inflammation. The implementation of transdiagnostic screening criteria to inform support strategies to counteract risk early in life is recommended.
​Stress, hypothalamic-pituitary-adrenal axis, hypothalamic-pituitary-gonadal axis, and aggression (2024)
All adolescents need support making the transition to Adulthood, and Neuro-Diverse kids with an IQ over 70 need support in order to avoid Homelessness or Criminal Justice involvement.

That "Executive Functioning" from ages 4-6 may undergo previously unpredicted upheavals due to complex dysregulations of the brain's immune cells, among many other things.

PREVIEW:  Translational Medicine Friday

The Immune Frontier in Psychiatry

Decades in the making -- It is ready to take a starring role 

​

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.
  • This weekend --  Addressing Immune System Dysregulation in the Justice-Involved Population.
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.

PREVIEW:  Olmstead Law & Order Thursday

ACCOMMODATING "FATIGUE" and IDIOSYNCRATIC BIO-ENERGETICS

In Neuro-Developmental and Psychiatric Disorders

Val's Take/Conjecture
  • When We're Talkin' Neuro-Diversity, We're Talkin' Neuro-Diversity
  • ​It is that Diversity that makes Neuro-Diversity so complicated to understand in the absence of BIO-MARKERS --- although researchers are identifying biomarkers.
  • Neuro-Diverse kids, adolescents and adults are more different from one another than Neuro-Typical people are different than one another.
  • When I use the word "Neuro-Diverse," I generally mean someone who was subject to Maternal Immune Activation IN UTERO and has some greater form of systemic developmental inflammation.
  • This DIVERSITY which has so many benefits is also putting a lot of pressure on policymakers and system designers at various levels to provide systems that are even adequate, much less good or excellent.
​​There are some Neuro-Diverse folks often viewed as having "ADHD" --- who need a lot of physical activity --
  • ​Need that at School and for much of the day, and
  • A Work Environment with a lot of Physical Activity that will pay them a living wage.
  • Further, HYPER-MOBILITY is more and more associated with Psychiatric Disorders

Editorial:  Neurodevelopmental, neuropsychiatric and psychosocial correlates of joint hypermobility and related disorders (2022)
  • ​​For some people, just saying MORE EXERCISE is the Answer is going to lead to DISASTER.
    • Whether or not they have ME/CFS (Chronic Fatigue Syndrome), they may need any Exercise Routine carefully tailored to their "FATIGUE LEVEL" and that may not be "the average person."​
    • Further, their Metabolism may be dysregulated as the result of DEVELOPMENTAL ISSUES.
For kids who need significantly more physical activity at school, "fidget spinners" and "brain breaks" may be far from adequate educational responses.

Further kids in general, especially neuro-diverse kids need individualized programming and attention.

THAT MEANS ADEQUATE STAFFING which many Colorado schools do not have.

​Increased physical activity can spur cognitive development, help children manage symptoms of ADHD (2024)
“I’m really interested in looking at what a typical day looks like for a child with ADHD, and the typical activity levels,” Logan said.

“There’s hyperactivity and inattention. So we might see differences in activity levels depending on which symptom is greater in a child. Hyperactivity-based children are very active.

"Maybe those children need more bouts of physical activity throughout the day to really burn off some energy and to refocus when they come back in for the school day.

"That goes in line with where physical activity guidelines are going… more physical activity spread throughout the day might be more beneficial for us.”
Benefits of Exercise May Vary Greatly in Primary Mitochondrial Disease (2022)

Val's Conjecture

I think the benefits of exercise and the frequency and intensity of exercise vary greatly among individuals generally,  and among Neuro-Diverse people with MITOCHONDRIAL DYSFUNCTION.

PREVIEW:  

The Cognitive Errors of Modern American Society

Intelligence, Sexuality, Energy & Equality

Val's Take/Conjecture
  • I have talked about being PRO-LIFE because I think my own experiences and reading of the research would indicate that many if not most of us are COMPLICATED MIXED BAGS.
  • Further, people who are on some eugenics crusade or similar bandwagon --- tend to have their own neuro-developmental and/or psychiatric issues ---
    • which are often related to Neuro-Developmental Inflammation
Pharrell Williams
​Freedom
  • ​It "appears" that there may be a CATCH-22 when it comes to "INTELLIGENCE," "BIO- ENERGY," "EMOTIONAL REGULATION" and "INFLAMMATION" ----
    • affecting everyone who is "AGING" --- which is everyone and
    • prematurely affecting people with more Neuro-Developmental Inflammation.
  • Previously, we've viewed males as more subject to Neuro-Developmental Disorders and Women as more subject to Psychiatric Disorders.
    • What about that Neuro-Developmental/Psychiatric Continuum?
    • It's not that females can't be a safety risk, BUT males with:
      • neuro-developmental and/or psychiatric disorders
      • and/or brain injury and/or
      • substance issues
      • are more of a safety risk.
    • On the other hand, much of this can be traced to Maternal Immune Activation (even the Brain Injury which is often associated with ADHD).
    • Further, there is also Paternal Immune Activation, and
    • These biological issues often have Generational Histories.
To me, Pharrell Williams is presenting a sophisticated view of "Freedom" --- that sees the Universe made of the same things.
We do have amazing INTELLECTUAL POWER --- and we are NOT CLONES -- we're DIVERSE.
We're struggling to conceptualize LGBTQ+ (which is pretty diverse community in itself).

Google AI says that LGBTQ+ is not a neuro-developmental disorder --- but does say ---

LGBTQ+ is associated with "Autism."  Hmmm . . .

Our neuro-developmental/psychiatric categories are messy and in the process of revision and being re-conceptualized in profound ways.
Further, there are significant sex differences between Males and Females --- and that can be expressed in tremendous diversity under Maternal Immune Activation.
Finally, I'm not really buying the idea that these intense human conflicts are between Neuro-Typical people and Neuro-Diverse people.

It seems to me that DIVERSE Neuro-Diverse Folks are well represented on all sides.
What's the Point?
  • We need to understand foundational biological issues better than what we actually do.
  • There are significant numbers of LGBTQ youth who are homeless.
    • The society seems confused as to whether sexual identity and orientation are a life-style choice or biologically driven.
    • We don't seem to have a common understanding of what we're talking about.
  • With respect to cognitive disability in Criminal Justice, we're uncertain about biological drivers of intent.
    • ​Somebody like me, I am persuaded by some algebraic argument involving the biological basis of behavior ---
    • But even I want as much specificity as possible with regard to that underlying biology.

PREVIEW:  TRANSLATIONAL Medicine Friday

​Microglial Dysregulation in Aging and Neuro-Developmental & Psychiatric Disorders
​

Val's Take/Conjecture
  • Microglial Dysregulation is a primary sign of AGING.
    • And that can occur slowly over the lifespan, picking up speed with AGE.
  • For people on the Neuro-Developmental/Psychiatric Continuum--- that Microglial Dysregulation often  occurred IN UTERO.
  • The research that is going on with AGING and with the NEURO-DEVELOPMENTAL/PSYCHIATRIC Continuum has the potential --- to help just about everyone.
The antipsychotic chlorpromazine reduces neuroinflammation by inhibiting microglial voltage-gated potassium channels (2025)
*Korean Researchers
The Janus face of antipsychotics in glial cells: Focus on glio-protection (2023)
*Brazilian & German Researchers
"This review will provide a summary of the dual role of antipsychotics on neurochemical parameters associated with glial functions and will highlight the potential activity of glio-protective molecules to improve the action of antipsychotics."
The Battle of Marathon --- Nike, Nike
"The Quest to Recover the Fallen Soldiers of Marathon"
These "new understandings" seem MAINSTREAM among Researchers and Research Institutions around the World ---

If not inevitable, it seems pretty close to inevitable that Clinicians, the Public and Policymakers will have access to these new understandings in ways that are helpful in the next few years.

With respect to Psychiatric Medications ---- some of them are affecting Microglia both positively and negatively.

On the research side, there seems to be awareness and efforts to reduce if not eliminate negative effects on Microglia in medication whether it is classic "psychiatric" medication or other medications.
Olanzapine, Risperidone and Clozapine prescribing is associated with increased risk for Alzheimer’s Disease reflecting antipsychotic-specific effects on microglial phagocytosis (2023)
*UK & Swedish Researchers

Metabolism & Maternal Immune activation

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.

PREVIEW:  Neuro-Diversity Wednesday

CATCH 22: 

DO You have enough ATP to run all those synapses & that 'Hyper-Plastic' brain?
​

Val's Take/Conjecture
  • It was just a few years ago that everyone was talking about "Brain Plasticity."
  • I thought that was so cool UNTIL I came across the research that people with ADHD & Autism often have HYPER-PLASTIC BRAINS.
  • This idea of "BRAIN ENERGY" is linking some things together such as MICROGLIA DYSTREGULATION and EMOTIONAL DYSREGULATION,
    • Neuro-Diverse folks are often very bright in one or more respects and struggling to keep it together.

​
​Neuron-Glia Interactions in Neurodevelopmental Disorders (2020)


​Abstract

​Recent studies have revealed synaptic dysfunction to be a hallmark of various psychiatric diseases, and that glial cells participate in synapse formation, development, and plasticity.

Glial cells contribute to neuroinflammation and synaptic homeostasis, the latter being essential for maintaining the physiological function of the central nervous system (CNS).

In particular, glial cells undergo gliotransmission and regulate neuronal activity in tripartite synapses via ion channels (gap junction hemichannel, volume regulated anion channel, and bestrophin-1), receptors (for neurotransmitters and cytokines), or transporters (GLT-1, GLAST, and GATs) that are expressed on glial cell membranes.

In this review, we propose that dysfunction in neuron-glia interactions may contribute to the pathogenesis of neurodevelopmental disorders.

Understanding the mechanisms of neuron-glia interaction for synapse formation and maturation will contribute to the development of novel therapeutic targets of neurodevelopmental disorders.
Glutamate and microglia activation as a driver of dendritic apoptosis: a core pathophysiological mechanism to understand schizophrenia (2021)
Val's Take:  What I'm trying to say is that there is a DISCONNECT between the ENERGY NEEDS of NEURO-DIVERSE BRAINS and the ENERGY that is actually available to them due to dysregulation of Microglia and Mitchondria IN UTERO.

Further, there are other Glial cells such as Astrocytes and they seem to be maintaining glutamate homeostasis in the Central Nervous System.

Surprise, Surprise --- This also seems to be DYSREGULATED for those who experienced Maternal Immune Activation.
​

​Abnormal Brain Bioenergetics in First-Episode Psychosis (2021)
  • Val's Take:  In addition to understanding:
    • Maternal Immune Activation
    • BRAIN ENERGY &
    • Microglia ----

  • How does this relate to "HOMEOSTASIS"?​
 
  • One of the things the researchers are doing is they are getting to the CELLULAR and MOLECULAR PATHWAY LEVEL and finding that:
    • Dysregulations occurred IN UTERO via Maternal Immune Activation  which had epigenetic consequences and various "DYSREGULATIONS" pre-natally.
    • This often involves:
      • Microglia,
      • Mitchondria (and ATP production),
      • Astrocytes, 
      • And Glutamate which is associated with "NEURONAL EXCITOTOXITY"
​
​Why do Neuro-Diverse folks have excess Glutamate?
Glutamate-Mediated Excitotoxicity in the Pathogenesis and Treatment of Neurodevelopmental and Adult Mental Disorders (2024)
​Astrocytes Maintain Glutamate Homeostasis in the CNS by Controlling the Balance between Glutamate Uptake and Release (2019)
Specialized astrocytes mediate glutamatergic gliotransmission in the CNS (2023)
Maternal Immune Activation imprints translational dysregulation and differential MAP2 phosphorylation in descendant neural stem cells (2024)

Preview:  Neuro-Diversity Wednesday

From Neuro-developmental to Neuro-degenerative Disorders: The Vascular Continuum (2021)

Val's Take/Conjecture
  • A significant percentage of Neuro-Diverse YouTubers were identified "gifted" as kids and subsequently got a LATE DIAGNOSIS of a Neuro-Developmental Disorder in Adulthood.
    • May have done very well Academically, and/or
    • Had some Special Ability or Talent.
  • That Adulthood was often a lot different than they expected and often different than what the people around them expected of them.
What researchers are discovering is that Neuro-Diverse "BURNOUT" issues and "MELTDOWN" issues are related to ENERGY ISSUES.
Further, this isn't happening in a VACUUM in which there are nice, neat distinctions between people with Neuro-Developmental Disorders and those without --- this often involves Neuro-Developmental Inflammation and how that impacted one person.

There are many gradations and combinations -- but biomarkers are being identified.

Further, it is not necessarily that hard to recognize associations among Neuro-Developmental, Psychiatric and Neuro-Degenerative Disorders in 2025.

Researchers also recognize Psychiatric Components of other disease and/or disorder issues such as:
All the biological components are NOT IDENTICAL --- but some of the biological components are IDENTICAL or SIMILAR.

People with Neuro-Developmental &/or Psychiatric issues are often facing PHYSICAL issues that are not as dramatic as other diseases or disorders but nonetheless relevant and significant.

​The need to integrate PHYSICAL  HEALTH & MENTAL HEALTH & DEVELOPMENTAL HEALTH is great.


Next Week:
METABOLISM
Structural and functional integrity of the cerebral vasculature ensures proper brain development and function, as well as healthy aging.

The inability of the brain to store energy makes it exceptionally dependent on an adequate supply of oxygen and nutrients from the blood stream for matching colossal demands of neural and glial cells.

Key vascular features including a dense vasculature, a tightly controlled environment, and the regulation of cerebral blood flow (CBF) all take part in brain health throughout life.

As such, healthy brain development and aging are both ensured by the anatomical and functional interaction between the vascular and nervous systems that are established during brain development and maintained throughout the lifespan.

During critical periods of brain development, vascular networks remodel until they can actively respond to increases in neural activity through neurovascular coupling, which makes the brain particularly vulnerable to neurovascular alterations. The brain vasculature has been strongly associated with the onset and/or progression of conditions associated with aging, and more recently with neurodevelopmental disorders.

Our understanding of cerebrovascular contributions to neurological disorders is rapidly evolving, and increasing evidence shows that deficits in angiogenesis, CBF [Cerebral Blood Flow] and the blood-brain barrier [BBB] re causally linked to cognitive impairment.

Moreover, it is of utmost curiosity that although neurodevelopmental and neurodegenerative disorders express different clinical features at different stages of life, they share similar vascular abnormalities.

In this review, we present an overview of vascular dysfunctions associated with neurodevelopmental:
  • autism spectrum disorders,
  • schizophrenia,
  • Down Syndrome

And neurodegenerative
  • multiple sclerosis,
  • Huntington’s,
  • Parkinson’s, and
  • Alzheimer’s diseases) disorders,

With a focus on impairments in angiogenesis [the process of forming new blood vessels], CBF [Cerebral Blood Flow] and the BBB [Blood Brain Barrier].

Finally, we discuss the impact of early vascular impairments on the expression of neurodegenerative diseases.

Preview:  Translational medicine Friday

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

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."
More Later
  • Bottom Line:  I'm making an argument that 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?
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)
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 pathophysiology and identification of associated biomarkers of neuroinflammation are needed to facilitate early diagnosis and treatment of this debilitating disorder.

Preview:  Olmstead Law Order Thursday

Colorado Teachers complain of "DisreSpect" ---

What is the Role of Inadequate Staffing for students with An IQ over 70 and 'invisible disabilities'?

Val's Take/Conjecture
  • My observation is that some Schools have improved their staffing for High Needs Students.
    • Some schools may be struggling, but others even in less well funded school districts seem close to IDEAL.
      • There are notable exceptions.
    • This is severely restricted observation.
  • ​On the other hand,  kids with Medium Needs and "ADHD" and/or "Autism" are challenging staffing schedules.
    • There may be some paraprofessional support but it is often not enough.
    • What is enough? 
  • A legislative audit of School Staffing for kids with disabilities could provide the data that is needed.
    • This should include kids with an IQ over 70 and invisible disabilities.

the neuro-immune system and  substance use
​

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.
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
  • There is even 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.
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.

Reasoning to reform without perfect information

Val's Take
  • ​Those of us living now will not see the full benefit of research on Neuro-Developmental and Psychiatric Disorders that is such a long- term, multi-generational effort.

  • In 2025, most people can live in the Community with current treatment but some can't.

  • It's time to get rid of Medicaid's Exclusion of Payment for Institutes of Mental Disease (IMD) Rule while also:
    • Bringing Intensive Community Supports to Scale.
I posted the study to the right because it represents a different take on the research.

The point is not so much the Conclusion --- as that the researchers are still working on this and it is not done.

On the other hand, we have plenty of people with Schizophrenia and other Neuro-Developmental and Psychiatric Disorders incarcerated.

We have substantial reason to believe we are punishing people for a not sympathetic underlying biology.

It's not like we're not doing anything, but we're not doing enough.
​Genetic contribution to microglial activation in schizophrenia (2024)

"We conclude that microglia of the patients with SCZ (Schizophrenia) have gene expression aberrations related to inflammation response and extracellular matrix without contributing to increased microglial activation."

Anti-Social Personality Disorder as a

​Neuro-Developmental Disability
Associations of the immune system in aggression traits and the role of microglia as mediators (2024)

Policy Challenges

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