january 2025
Samhsa's First Annual
Substance use Disorder Treatment month

Picture
Val Corzine

Better Science 
can lead to
Better policy & Better LAw

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


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

David Lynch -- RIP
Being A Madman

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 are 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)

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.

Preview:  Neuro-Diversity Wednesday

Giftedness,  Atypical Sexual Differentiation, and Neuro-developmental disorders

Val's Take/Conjecture
  • So there is a lot here.
    • Neuro-Developmental/Psychiatric Disorders are Multi-System "Disorders"
    • The Neuro-Developmental/Psychiatric Continuum includes:
      • The Brain and the Central Nervous System
      • The Immune System
      • The Endocrine System
        • Giftedness 
      • ​​The Metabolism, and
      • The Microbiome
    • Understanding "Giftedness" as a Neuro-Developmental Disorder and all that generally means including Neuro-Developmental Inflammation and Emotional Intensity/"Emotional Dysregulation"
Giftedness and atypical sexual differentiation: enhanced perceptual functioning through estrogen deficiency instead of androgen excess (2024)
Abstract

Syndromic autism spectrum conditions (ASC), such as Klinefelter syndrome, also manifest hypogonadism.

Compared to the popular Extreme Male Brain theory, the Enhanced Perceptual Functioning model explains the connection between ASC, savant traits, and giftedness more seamlessly, and their co-emergence with atypical sexual differentiation.

​Overexcitability of primary sensory inputs generates a relative enhancement of local to global processing of stimuli, hindering the abstraction of communication signals, in contrast to the extraordinary local information processing skills in some individuals.

Weaker inhibitory function through gamma-aminobutyric acid type A (GABAA) receptors and the atypicality of synapse formation lead to this difference, and the formation of unique neural circuits that process external information.

Additionally, deficiency in monitoring inner sensory information leads to alexithymia (inability to distinguish one's own emotions), which can be caused by hypoactivity of estrogen and oxytocin in the interoceptive neural circuits, comprising the anterior insular and cingulate gyri.

These areas are also part of the Salience Network, which switches between the Central Executive Network for external tasks and the Default Mode Network for self-referential mind wandering.

Exploring the possibility that estrogen deficiency since early development interrupts GABA shift, causing sensory processing atypicality, it helps to evaluate the co-occurrence of ASC with attention deficit hyperactivity disorder, dyslexia, and schizophrenia based on phenotypic and physiological bases.

It also provides clues for understanding the common underpinnings of these neurodevelopmental disorders and gifted populations.

Preview:  Translational Justice Monday

The Eggshell Skull Rule and Environmental Toxins

Val's Take/Conjecture
  • Maternal Immune Activation does seem to create idiosyncratic vulnerabilities, including types of immuno-compromised systems.
 
  • There are man-made toxins and natural toxins.
 
PESTICIDES
MICROPLASTICS
Previously we've conceptualized Neuro-Developmental, Psychiatric and Neuro-Degenerative Disorders as having to do with the Brain and Neurons.

More and more we are conceptualizing these disorders as NEURO-IMMUNE DISORDERS, and there are more components than that.

BUT the Immune System is a critical system --- and we can't understand these disorders without understanding the Immune Component.
THE EXPOSOME ACROSS THE LIFESPAN & TRANS-GENERATIONAL IMPLICATIONS
  • ​"The exposome concept refers to the totality of exposures from a variety of external and internal sources including chemical agents, biological agents, or radiation, from conception onward, over a complete lifetime.
  • "It encompasses also 'psychosocial components' including the impact of social relations and socio-economic position on health."

EGGSHELL SKULL RULE

The eggshell skull rule, also known as the thin skull rule, is a common law doctrine that makes a defendant liable for the plaintiff's unforeseeable and uncommon reactions to the defendant's negligent or intentional tort .

If the defendant commits a tort against the plaintiff without a complete defense , the defendant becomes liable for any injury that is magnified by the plaintiff's peculiar characteristics.

It is essential to emphasize that the eggshell skull doctrine does not entitle the plaintiff to compensation for an unrelated pre-existing injury.

​A common example of this doctrine is that a person's skull was very thin due to the person’s own health condition, if the person gets into an accident, the other person who caused the accident will be liable for the actual damages , although the average person would not suffer the same serious injuries in the same accident as the person with the thin skull.

What are the implications of the "Eggshell Skull Rule" and the "Exposome" for Neuro-Diverse people with Maternal Immune Activation?

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."

PREVIEW:  Translational Medicine Friday

What is Excitotoxicity?
​

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 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 between 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)

Preview:  Olmstead Law & Order Thursday

Planning for Coloradans with Neuro-Developmental Disabilities & IQ Over 70
​

Val's Take/ Conjecture
  • It's important to have some hard conversations about STAFFING and it's relationship to BIOMARKERS.
  • We're not adequately STAFFING education or adequately accommodating employment needs because it's so expensive. 
  • It's not that we are not trying to do anything --- BUT we are talking about Neuro-Diverse people who are often IDIOSYNCRATIC --- it takes time and energy to figure that out.  A lot of time and energy.
  • WE ARE STARTING TO GET BIOMARKERS.
  • There are a lot of moving parts -- but evolving to a more traditional medical discipline doesn't seem out of reach.
  • Further, this seems to involve the IMMUNE SYSTEM among many other things.

Schizophrenia: more same than different to neurodevelopmental disorders?

"The neurodevelopmental continuum is based on emerging evidence for shared genetic risk and overlapping pathogenic mechanisms of neurodevelopmental disorders in early ages –

Intellectual disability, autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD) – with schizophrenia and bipolar disorder."
[Va]'s Take:  Many researchers are including aspects of Depression in that NEURO-DEVELOPMENTAL CONTINUUM].

Preview:  Neuro-Diversity Wednesday

Emotional Dysregulation & Neuro-Diversity

Val's Take - Conjecture
  • Maternal Immune Activation is associated with dysregulation of Microglia in the yok-sac.
  • Dysregulated microglia is associated with "anxiety" and "anxiety-like behaviors."
  • We need Microglia to manage Stress over the lifespan.
  • I think it is actually Neuro-Diverse people who have often come up with various practices to alleviate out-sized Stress --- and a lot of those strategies can help.
  • We're still at this in 2025 because "Anxiety" is not innocuous --- in humans and other animals.
  • Further, it is not just a handful of humans who are dealing with serious emotional dysregulation, and it's not just people who don't have any power. 
MicroRNA-dependent control of neuroplasticity in affective disorders (2021)

​Emerging role of non-coding RNAs in neuroinflammation mediated by microglia and astrocytes (2023)

​​Emotional dysregulation (ED) is a transdiagnostic variable underlying various psychiatric disorders, including addictive behaviors (ABs) (2024)
​miRNAs and Substances Abuse: Clinical and Forensic Pathological Implications: A Systematic Review
When I think of  Anxiety -- I think of Monk--- but Anxiety often comes with Anger and Aggression.

Some concept of "Justice" is often what we use to manage that -- but that can become more difficult than we realized.

​Emotional Dysregulation and Adaptive Functioning in Preschoolers With Autism Spectrum Disorder or Other Neurodevelopmental Disorders (2022)
miRNA regulation of social and anxiety-related behaviour (2020)

​MicroRNAs as potential diagnostic biomarkers for bipolar disorder (2025)
​Inhibition of NKCC1 Ameliorates Anxiety and Autistic Behaviors Induced by Maternal Immune Activation in Mice (2024)
Microglia govern the extinction of acute stress-induced anxiety-like behaviors in male mice (2024)

Metabolomics, immuno-methylomics, Biomarkers 

​And slowly moving to better diagnostics

Val's Take/Conjecture
  • The New Insight that Neuro-Developmental and Psychiatric Disorders are not just disorders of the Brain -- is opening up new opportunities for biomarkers.
    • ​Brain surgery is not required.
  • It is also profoundly re-conceptualizing what Neuro-Developmental & Psychiatric Disorders are and understanding relationships with:
    • ​Auto-Immune Disease
    • Cancer, and
    • ​Neurodegenerative Disorders

​Metabolomic Biomarker Signatures for Bipolar and Unipolar Depression (2024)
Infant microbes and metabolites point to childhood neurodevelopmental disorders (2024)
Association Between Human Blood Metabolome and the Risk of Psychiatric Disorders (2023)
The microRNA profile of brain-derived extracellular vesicles: A promising step forward in developing pharmacodynamic biomarkers for psychiatric disorders (2025)

"[A]nalyzing the miRNA expression profile of brain-derived EVs in blood may allow us to non-invasively assess miRNA dysregulation and thus to gain knowledge about the pathophysiology of psychiatric disorders and identify potential new predictive targets.
​miRNA regulation of social and anxiety-related behaviour (2020)

​"[O}verview of recent expression profiling and genetic association studies in human patient-derived samples in an attempt to highlight the most promising candidates for biomarker discovery and therapeutic intervention."
Dissecting depression symptoms: Multi-omics clustering uncovers immune-related subgroups and cell-type specific dysregulation (2025)


Exploring the use of immunomethylomics in the characterization of depressed patients: A proof-of-concept study (2025)
"DNA-methylation based cell-type profiles may be valuable in the immunological characterization and stratification of patients with MDD [Major Depressive Disorder].

"Future models should consider the inclusion of more cell-types and cytokines for better prediction of treatment outcomes."
Claudin-5 and occludin levels in patients with psychiatric disorders - A systematic review (2025)

"Recent research has underscored the critical role of blood-brain barrier (BBB) integrity in psychiatric disorders, highlighting disruptions in tight junction (TJ) proteins, specifically claudin-5 and occludin.

"These proteins are pivotal in maintaining the BBB's selective permeability, which is essential for brain homeostasis.

​"Altered levels of the TJ proteins have been observed in various psychiatric conditions, suggesting potential as biomarkers for the pathophysiology of these disorders."
Large-scale metagenomic analysis of oral microbiomes reveals markers for autism spectrum disorders (2024)
MicroRNA-dependent control of neuroplasticity in affective disorders (2021)
Plasma and CSF neurofilament light chain distinguish neurodegenerative from primary psychiatric conditions in a clinical setting (2024)
Peripheral mitochondrial DNA as a neuroinflammatory biomarker for major depressive disorder (2025)

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

Val's Take/Conjecture
  • It's been over a decade since the US National Institute of Mental Health said the DSM 5 lacked scientific validity.
  • Since then, researchers around the world have corroborated that concern and begun their own efforts to address it.
  • There are more and more entities and researchers around the world articulating the "crucial need" for a "biology-informed framework."​
  • This has implications for Criminal Justice and State Disability Housing, Placement and Service provision.
Abstract

Current nosology claims to separate mental disorders into distinct categories that do not overlap with each other.

This nosological separation is not based on underlying pathophysiology but on convention-based clustering of qualitative symptoms of disorders which are typically measured subjectively.

Yet, clinical heterogeneity and diagnostic overlap in disease symptoms and dimensions within and across different diagnostic categories of mental disorders is huge.

While diagnostic categories provide the basis for general clinical management, they do not describe the underlying neurobiology that gives rise to individual symptomatic presentations.

The ability to incorporate neurobiology into the diagnostic framework and to stratify patients accordingly will be a critical step forward for the development of new treatments for mental disorders.

Furthermore, it will also allow physicians to provide patients with a better understanding of their illness's complexities and management.

To realize this ambition, a paradigm shift is needed to build an understanding of how neuropsychiatric conditions can be defined more precisely using quantitative (multimodal) biological processes and markers and thus to significantly improve treatment success.

The ECNP [European College of Neuropharmacology] New Frontiers Meeting 2024 set out to develop a consensus roadmap for building a new diagnostic framework for mental disorders by discussing its rationale, outlook, and consequences with all stakeholders involved.

This framework would instantiate a set of principles and procedures by which research could continuously improve precision diagnostics while moving away from traditional nosology. In this meeting report, the speakers' summaries from their presentations are combined to address three key elements for generating such a roadmap, namely:
​
​* the application of innovative technologies,
​
*understanding the biology of mental illness, and

*translating biological understanding into new approaches.

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.

PREVIEW:  Translational Medicine Friday

MiCROGLIA & Substance Use

Val's Take/Conjecture
  • Neuro-Developmental Disorders and Substance Use Issues are very prevalent in the Criminal Justice System​ and have challenged reform efforts.
  • My big mantra has been --- we need A PUBLIC HEALTH APPROACH to CRIMINAL JUSTICE.
  • Okay, that's great --- we need the updated understandings and treatments to fully make that a reality.
  • That is what the researchers are giving us.
  • Further, many of our current treatments are helping people.
  • We tend to want to think our Doctors are perfect and their treatments are perfect.
  • On the other hand, we can feel very "betrayed" if we're paying a lot of money for something or the State is paying a lot of money for something that is less than perfect.
  • Finally, the seriousness of some of these situations has made the mental health profession as a whole:
    • great champions for access and the need to seek treatment
    • but not always forthcoming about the critical need for better understandings and improved treatments.
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 …"
Glial mechanisms underlying substance use disorders. 
​(2019)

"Although there is an extensive body of literature examining the neuronal mechanisms of substance use disorders, effective therapies remain elusive.

​"Glia, particularly microglia and astrocytes, have an emerging and meaningful role in a variety of proces …"

New Years day 

more research out in January 2025

PREVIEW:  Translational JUstice Monday

Building Individualized Supports

For People with Neuro-Developmental Disorders & An IQ Over 70

One of the concerns that I have is the focus on "MOTIVATION" in both Mental Health and the Justice System.
I think at least some researchers would say much of this is not so much an ISSUE of "MOTIVATION" as "BRAIN ENERGY."
One of the things that has been very CONFUSING is that many BRIGHT PEOPLE seem to have the ENERGY for some things and not others --- so that is a MOTIVATION issue, right?  I would say often not.
Additionally, neuro-diverse kids, adolescents and adults are more different from one another than neuro-typical folks are different from one other.

When I use the term neurotypical, I generally mean someone who did not experience Maternal Immune Activation (MIA).
Further, the HOPE that DEVELOPMENTAL DISORDERS really had negligible effects if you had an IQ over 70 is not reality, and more and more researchers and clinicians recognize that.
Part of the issue has been that when we thought of DEVELOPMENTAL DISORDERS we often thought of INTELLECTUAL DISABILITIES.
We weren't necessarily thinking of  people with average or high intelligence and  HIGHLY DYSYSREGULATED SYSTEMS of the body that would greatly impact EMOTIONAL REGULATION, and other health issues including CANCER.

Preview:  Translational Medicine Friday


Val's Take/Conjecture
  • "Maternal Immune Activation" involves the Immune System and occurs In Utero.
  • Among other things, Maternal Immune Activation impacts Adult Behavior.
  • So the first hit is "Maternal Immune Activation."
  • But during the course of our lives we have many and varied experiences of INFLAMMATION and STRESS.
  • It's a BRAVE NEW WORLD out there and some researchers are already proposing:
    • "immunomodulatory" treatments for depression, and
    • targeting microglia in treatment efforts.
  • The point I want to make is that when we talk about "RESILENCE" --- there are actually very complicated mechanics to that.
  • Additionally, UNPREDICTED CHRONIC STRESS seems to be an issue for mammals and us.
    • The Unpredictability of Neuro-Developmental and Psychiatric Disorders is taking a huge toll on Individuals, Families, Communities and Societies.
    • There is CONSCIOUS AWARENESS of the need for:
      • Updated Paradigms
      • Biomarkers, and
      • Better Treatments that address Multi-System Disorders

​
​Genes Participating in the Ensheathment of Neurons Are Affected by Postnatal Stress and Maternal Immune Activation in the Pituitary Gland (2023)
​


​Fetal brain response to maternal inflammation requires microglia (2024)
​

In utero infection and maternal inflammation can adversely impact fetal brain development.

Maternal systemic illness, even in the absence of direct fetal brain infection, is associated with an increased risk of neuropsychiatric disorders in affected offspring. . .

Using a rodent maternal immune activation (MIA) model in which polyinosinic:polycytidylic acid is injected into pregnant mice, we demonstrate long-lasting transcriptional changes in fetal microglia that persist into postnatal life.

We find that MIA induces widespread gene expression changes in neuronal and non-neuronal cells; importantly, these responses are abolished by selective genetic deletion of microglia, indicating that microglia are required for the transcriptional response of other cortical cell types to MIA.

These findings demonstrate that microglia play a crucial durable role in the fetal response to maternal inflammation, and should be explored as potential therapeutic cell targets.

The inflammatory underpinning of depression: An historical perspective (2024)


​"Synthesizing insights from this extensive research, the review presents an integrative model of the biological foundations of inflammation-associated depression.

It posits that we have reached a critical juncture where the translation of this knowledge into personalized immunomodulatory treatments for depression is not just possible, but imperative.

Preview:  Neuro-diversity Wednesday

Neuro-Diversity, microglia, Synapses & Energy


Synapses: The Brain's Energy-Demanding Sites (2022)

Abstract

The brain is one of the most energy-consuming organs in the mammalian body, and synaptic transmission is one of the major contributors.

To meet these energetic requirements, the brain primarily uses glucose, which can be metabolized through glycolysis and/or mitochondrial oxidative phosphorylation.

The relevance of these two energy production pathways in fulfilling energy at presynaptic terminals has been the subject of recent studies.

In this review, we dissect the balance of glycolysis and oxidative phosphorylation to meet synaptic energy demands in both resting and stimulation conditions.

Besides ATP output needs, mitochondria at synapse are also important for calcium buffering and regulation of reactive oxygen species.

These two mitochondrial-associated pathways, once hampered, impact negatively on neuronal homeostasis and synaptic activity.

Therefore, as mitochondria assume a critical role in synaptic homeostasis, it is becoming evident that the synaptic mitochondria population possesses a distinct functional fingerprint compared to other brain mitochondria.

Ultimately, dysregulation of synaptic bioenergetics through glycolytic and mitochondrial dysfunctions is increasingly implicated in neurodegenerative disorders, as one of the first hallmarks in several of these diseases are synaptic energy deficits, followed by synapse degeneration.
Metabolome subtyping reveals multi-omics characteristics and biological heterogeneity in major psychiatric disorders (2023)
​
Abstract
Growing evidence suggests that major psychiatric disorders (MPDs) share common etiologies and pathological processes. However, the diagnosis is currently based on descriptive symptoms, which ignores the underlying pathogenesis and hinders the development of clinical treatments. This highlights the urgency of characterizing molecular biomarkers and establishing objective diagnoses of MPDs. Here, we collected untargeted metabolomics, proteomics and DNA methylation data of 327 patients with MPDs, 131 individuals with genetic high risk and 146 healthy controls to explore the multi-omics characteristics of MPDs.

First, differential metabolites (DMs) were identified and we classified MPD patients into 3 subtypes based on DMs.

The subtypes showed distinct metabolomics, proteomics and DNA methylation signatures.

Specifically, one subtype showed dysregulation of complement and coagulation proteins, while the DNA methylation showed abnormalities in chemical synapses and autophagy.

Integrative analysis in metabolic pathways identified the important roles of the citrate cycle, sphingolipid metabolism and amino acid metabolism.

Finally, we constructed prediction models based on the metabolites and proteomics that successfully captured the risks of MPD patients.

Our study established molecular subtypes of MPDs and elucidated their biological heterogeneity through a multi-omics investigation.

These results facilitate the understanding of pathological mechanisms and promote the diagnosis and prevention of MPDs [Major Psychiatric Disorders].
The Underlying Neurobiological Mechanisms of Psychosis:

Focus on

Synaptic elimination by microglia and disturbed higher brain functions (2021)
Highlights

Microglia engage in synaptic elimination by phagocytosis in mature brains.

Selective synaptic elimination changes excitatory/inhibitory (E/I) balance.

Microglia modulate neuropsychiatric disorders by synaptic elimination.

This review discusses Parkinson's and Alzheimer's diseases, ASD [Autism Spectrum Disorder], ADHD, and schizophrenia.
Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders (2017)
Key Points

Brain development is associated with the formation of excessive synapses that have to be removed in a controlled and timely manner to achieve refined mature circuitry.

Glial cells, including microglia and astrocytes, are the effectors of synaptic pruning, identifying and eliminating superfluous synapses.

Synaptic pruning depends on various molecules, including those controlling glial chemotaxis, target recognition and phagocytosis.

Autism spectrum disorders are associated with excessive synapses, autophagy and dysregulated microglial function.

Schizophrenia is linked to exaggerated synaptic pruning owing to elevated levels of complement proteins and microglial activation.

Epilepsy is thought to arise owing to immature circuitry that was not refined via synaptic pruning.

This initial epileptiform activity is followed by microglial activation and upregulation of complement components.
Synapses & Neuro-Developmental & Psychiatric Disorders

Synaptic changes in psychiatric and neurological disorders: state-of-the art of in vivo imaging (2024)
The stressed synapse 2.0: pathophysiological mechanisms in stress-related neuropsychiatric disorders (2022)
Immune synaptopathies: how maternal immune activation impacts synaptic function during development (2023)

"In the present review, we highlight this concept, which we define by the term “immune‐synaptopathy,” and we discuss recent evidence suggesting a bi‐directional link between the genetic architecture of individuals and maternal activation of the immune system in modulating brain developmental trajectories in health and disease."

Translational Justice Monday

The Cellular basis of Neuro-Developmental & Psychiatric Disorders

Val's Take/Conjecture
  • The pace of research does seem to be "quickening."​
  • It is likely 2025 will bring more in solidifying a biological understanding of neuro-developmental and psychiatric disorders.
  • There has been a skepticism in the public regarding mental illness without more precise information.
  • Even prior to the Grand Understandings and Treatments --- I think the public will be more likely to support Therapeutic Custodial Care over Incarceration if there is a firmer understanding of the biological issues.
  • Many advocates would have been concerned about this BRAVE NEW BIOLOGICAL understanding of psychiatric disorders.
  • Further, we should be vigilant.
  • Of course, the frightening limitations of our current understandings have made some of us ready for something different and better.
BIOLOGICAL PSYCHIATRY and "LIFESTYLE PSYCHIATRY"
  • Theoretically, there is no conflict between Biological Psychiatry and Lifestyle Psychiatry.
  • I do think addressing Lifestyle issues can help and even greatly improve Neuro-Developmental & Psychiatric Disorders --- and we should be doing that.
  • The concern that I have with "Lifestyle Psychiatry" is it often doesn't seem to appreciate that Neuro-Developmental & Psychiatric Disorders are largely DEVELOPMENTAL and begin IN UTERO.
  • Further, I do think there is a need to work one's way back in the CHAIN OF CAUSALITY --- because a lot of these problematic "LIFESTYLE CHOICES" are actually being driven by some problematic biology.

​Brain cell-type shifts in Alzheimer's disease, autism, and schizophrenia interrogated using methylomics and genetics (2024)
​
"We observe and replicate cell-type compositional shifts for
  • Alzheimer's disease (endothelial cell loss),
 
  • autism (increased microglia), and
 
  • schizophrenia (decreased oligodendrocytes), and

find age- and sex-related changes."
The microglial innate immune receptor TREM2 participates in fear memory formation through excessive prelimbic cortical synaptic pruning (2024)
​
"Our cumulative results suggest that prelimbic TREM2-mediated excessive microglial synaptic pruning is involved in the fear memory formation process, leading to development of abnormal stress-related behavior."

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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