Val's Take: More and more Researchers are moving beyond DSM symptom clusters to INDIVIDUALIZED PRECISION MEDICINE and BIOLOGICAL MECHANISMS such as cell types, organelles, DNA, RNA, epigenetics, molecular pathways, the microbiome, the endocrine system, the immune system and yes the brain and the central nervous system and their relationships to each other trans-generationally, developmentally and over the life span. My understanding is that it was Researchers and Clinicians addressing Orphan Mitochondrial Diseases that only effect a small number of people --- who started to point out that MOST DISEASE and DISORDER involve some type of Mitochondrial Dysfunction --- as it turns out they were right. What I particularly appreciate about Dr. Madsen's video is that he appreciates the importance of Diet and Exercise while at the same time understanding that will often not be sufficient alone. Additionally, Dr. Madsen as others are pointing out the significant role of modern Environmental Toxins --- which like Climate Change is hugely inconvenient. Finally, the Reverse Aging Revolution folks understand that Mitochondrial Dysfunction ultimately affects everyone through the Aging Process ---- some of us sooner than others --- but Mitochondrial Dysfunction is of universal concern. | Unravelling the Brain with Dr. Josh Madsen The Hidden Crisis of Autism & Mitochondrial Dysfunction Explained (2025) Reverse Aging Revolution Producing Young Mitochondria Accessible For Everyone - Mitochondrial Transplantation For Longevity (2024) |
Val's Take: "You told me something wrong --- I know I listen too long --- but one thing leads to another --- I know you been lying to me." I don't think the Mental Health Profession has been "lying to me," but . . . There are major problems that are not being addressed in this gap between the researchers and the clinicians. Once we go from Neuro-Developmental and Psychiatric Disorders as Brain Disorders --- to Multi-System Neuro Immune Disorders --- that implicates other medical disciplines. "The wrong antidote is like a bone in the throat." |
| Val's Take/ Conjecture
   "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)
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.
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| Val's Take/Conjecture
 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.  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. |
Val's Take/Conjecture
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.
 "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."  "Neurons rely mostly on mitochondria for the production of ATP and Ca2+ (Calcium ion) homeostasis."  More Conjecture
| 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?  Abstract Bipolar disorder (BD) is a chronic psychiatric disease, characterized by frequent behavioral episodes of depression and mania, and neurologically by dysregulated:
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:
A deeper understanding of BD [Bipolar Disorder] pathophysiology and identification of associated biomarkers of neuroinflammation are needed to facilitate early diagnosis and treatment of this debilitating disorder. |
| Val's Take/Conjecture
 "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." "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."  |   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.  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. |
Val's Take: Professor Scott Russo notes how much we've missed by just focusing on the brain and excluding the body. This video does not get into Maternal Immune Activation, but does address Chronic Stress. | Icahn School of Medicine at Mount Sinai Fighting Neuroimmune Disorders (2019) |
| Val's Take/Conjecture
We don't want to become Eugenicists or Nazis ---
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. |   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. |
| Val's Take/Conjecture
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 is evidence that Diet and Exercise can improve Cognitive Dysfunction and Neuro-Inflammation and the regulation of Microglia.
|  The Neuroimmune System and the Cerebellum (2023) [provides a good overview of the Neuro-Immune System]  "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 …"  "Microglia are widely known for their role in immune surveillance and for their ability to refine neurocircuitry during development, but a growing body of evidence suggests that microglia may also play a complementary role to neurons in regulating the behavioral aspects of substance use disorders." CONTINUED For me, a big issue from a "Moral Education" standpoint is that many people are coming with SIGNIFICANT NEURO-DEVELOPMENTAL INFLAMMATION and AFTER-ACQUIRED INFLAMMATION (including TRAUMA but many other things as well) and significantly reduced abilities to manage STRESS.
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 Towards a consensus roadmap for a new diagnostic framework for mental disorders (2024) "In general, the meeting indicated a crucial need for a biology-informed framework to establish more precise diagnosis and treatment for mental disorders to facilitate bringing the right treatment to the right patient at the right time." |  Glutamate-Mediated Excitotoxicity in the Pathogenesis and Treatment of Neurodevelopmental and Adult Mental Disorders (2024) Disruption of the mechanisms responsible for glutamate homeostasis may result in
This condition is known as glutamate-induced excitotoxicity and is considered as a pathogenic mechanism
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