​Val's Take/Conjecture This view of Neuro-Developmental and Psychiatric Disorders as multi-system conditions is relatively new and has many ramifications. In addition, Neuro-Degenerative Disorders such as Parkinson's, Huntington's Disease and Alzheimer's are now viewed as multi-system disorders. What are the ramifications of Neuro-Developmental & Psychiatric Disorders as Multi-System Disorders? For Treatment For Criminal Justice Involvement and Homelessness  ​If we don't know, who bears the burden? Burden of Proof Schizophrenia, a disease of impaired dynamic metabolic flexibility: A new mechanistic framework (2024)  "Mounting evidence from a variety of transcriptomic, proteomic, metabolomics and brain imaging studies points toward the possibility that schizophrenia is a systemic disorder and involves abnormal glucose and energy metabolism both in the periphery and in brain." ​Pathway Network Analyses for Autism Reveal Multisystem Involvement, Major Overlaps with Other Diseases and Convergence upon MAPK and Calcium Signaling (2016)

Psychoneuroimmunology of Mood Disorders (2025) ​Abstract Recent research has shed light on the intricate relationship between mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BD), and inflammation. This chapter explores the complex interplay involving immune and metabolic dysfunction in the pathophysiology of these disorders, emphasizing their association with autoimmunity/inflammatory conditions, chronic low-grade systemic inflammation, T cell overactivation, and immunosenescence. ​This perspective underscores the notion that MDD [Major Depressive Disorder] and BD [Bipolar Disorder] are not solely brain disorders, highlighting their nature as multi-system conditions. ​ADHD symptoms in neurometabolic diseases: Underlying mechanisms and clinical implications (2016)

​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. ​Maternal Immune Activation and Schizophrenia–Evidence for an Immune Priming Disorder (2021) ​"Schizophrenia is a complex neurodevelopmental disorder affecting around 19. 8 million people worldwide." ​​ ​Towards a neurodevelopmental model of bipolar disorder: a critical review of trait- and state-related functional neuroimaging in adolescents and young adults (2025) ​ ​Minor physical anomalies in schizophrenia and bipolar I disorder and the neurodevelopmental continuum of psychosis  (2014)

​ ​Psychoneuroimmunology of Mood Disorders (2025) ​Abstract ​Recent research has shed light on the intricate relationship between mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BD), and inflammation. ​This chapter explores the complex interplay involving immune and metabolic dysfunction in the pathophysiology of these disorders, emphasizing their association with autoimmunity/inflammatory conditions, chronic low-grade systemic inflammation, T cell overactivation, and immunosenescence. This perspective underscores the notion that MDD [Major Depressive Disorder] and BD [Bipolar Disorder] are not solely brain disorders, highlighting their nature as multi-system conditions. ​ ​Brain methylome remodeling selectively regulates neuronal activity genes linking to emotional behaviors in mice exposed to maternal immune activation (2023) "Thus, MIA [Maternal Immune Activation] induces maladaptive methylome remodeling in brain and selectively regulates neuronal activity gene methylation linking to emotional behavioral abnormalities in offspring." How we unwittingly put ourselves and others in catch 22s The Legal System, Trauma-Informed Care and the Living Hell of Catch 22s

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: Multiple Sclerosis Myalgic Encephalomyelitis (Chronic Fatigue Syndrome) Type 1 Diabetes​ Cancer  Down Syndrome Substance Issues Cerebral Palsy Etc. 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.

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

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. Prolonged exertion of self-control causes increased sleep-like frontal brain activity and changes in aggressivity and punishment (2024)

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.

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) 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)

Val's Take/Conjecture BIO-ENERGETICS is expressed in many DIVERSE ways in Neuro-Diverse people. Further, a common strategy for Neuro-Diverse folks is "HYPER-FOCUS." That can look like ENORMOUS MENTAL ENERGY --- ​which in some ways it is. BUT it is also a strategy to CONSERVE ENERGY and REDUCE TRANSITIONS. ​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 (2024): Focus on Neurotransmission Dysregulation, Neuroinflammation, Oxidative Stress, and Mitochondrial Dysfunction

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."