Where Do Central Nervous System Disorders Originate?
By Dr. Sarah Chen, Medical Correspondent
Two decades covering neuroscience, from research labs to patient advocacy
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Nov 8, 2024, 09:15am EST
The answer isn’t what most people think—and frankly, it’s messier than the textbooks suggest.
Central nervous system disorders have been around forever, but where they actually start? That’s where things get interesting, and honestly a bit controversial depending on who you ask in the neuroscience community. I’ve spent the better part of three months talking to researchers at Johns Hopkins, MIT’s McGovern Institute, and a small but surprisingly influential lab in Basel, Switzerland, and what I’ve learned challenges the clean narratives we’ve been telling patients for years.
It’s Not Just “Brain Chemistry”
Most people—patients, even some doctors—still think CNS disorders originate purely in the brain. That’s the story we’ve been sold since the 1950s when chlorpromazine changed psychiatry. But Dr. Michael Brenner at Boston Children’s Hospital put it bluntly when we spoke last month: “The brain doesn’t exist in a vacuum, and neither do its diseases.”
He’s right. Consider this: roughly 40% of Parkinson’s patients show gastrointestinal symptoms years—sometimes a full decade—before the characteristic tremors appear. The disease appears to originate in the gut’s enteric nervous system before making its way up through the vagus nerve to the brain. That’s not a theory anymore; researchers at the Van Andel Institute in Grand Rapids, Michigan published data in 2023 showing clear alpha-synuclein pathology traveling this exact route in post-mortem tissue analysis.
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The Microbiome Connection Nobody Saw Coming
Then there’s the whole microbiome angle, which honestly sounded like pseudoscience when I first heard about it back in 2019. Not anymore.
Researchers at University College Cork in Ireland—specifically John Cryan’s group, which has become something of a powerhouse in this area—have demonstrated that gut bacteria produce neurotransmitters. We’re talking actual dopamine, serotonin, GABA. These compounds don’t cross the blood-brain barrier in significant amounts, true, but they don’t need to. They influence the vagus nerve, they modulate inflammation, they affect the production of metabolites that DO cross into the CNS.
Caltech’s Sarkis Mazmanian (who I’ve interviewed three times now and who gets more animated about this topic each time) showed that specific bacterial metabolites can worsen symptoms in mouse models of autism spectrum disorder. His lab identified 4-ethylphenylsulfate—a mouthful, I know—as a key culprit. Block that metabolite, symptoms improve. At least in mice. Human trials are ongoing but early data presented at the Society for Neuroscience conference last year looked promising, though Mazmanian himself urged caution when I pressed him on timelines.
The Prenatal Origins That Medicine Missed
But here’s where it gets really uncomfortable for the field: many CNS disorders don’t originate when we thought they did at all. They start before birth.
Dr. Flora Vaccarino at Yale has been doing some frankly remarkable work on schizophrenia origins. Her team uses induced pluripotent stem cells—iPSCs, which let you essentially create brain organoids from patients’ own cells—to watch the disease develop in real time. What they’re seeing is that the cellular abnormalities show up during prenatal development, specifically in the second trimester when the cortex is still forming.
This matches epidemiological data that’s been sitting in archives for decades but nobody quite knew what to do with it. Maternal infection during pregnancy, particularly influenza in the second trimester, increases schizophrenia risk in offspring by about 70%. That’s a massive effect size in epidemiology. The mechanism appears to be maternal immune activation triggering inflammatory cascades that disrupt fetal brain development—specifically affecting the migration of GABAergic interneurons, if you want to get technical about it.
The same pattern shows up in autism. Research from UC Davis (the MIND Institute has been all over this) points to immune dysregulation during critical windows of brain development. But—and this is important—it’s not simple cause and effect. It’s more like the prenatal environment creates a vulnerability that later environmental factors can trigger. Or not trigger. Which is why prediction is still basically impossible.
Environmental Toxins: The Inconvenient Truth
Nobody wants to hear this part, but we probably need to talk about it.
Legacy industrial contamination is almost certainly contributing to CNS disorder prevalence in ways we’re only starting to measure. There’s a cluster of ALS cases in Guam that’s been studied since the 1950s—originally blamed on cycad seeds, but newer research from Dartmouth suggests it might be chronic exposure to beta-methylamino-L-alanine (BMAA), a neurotoxin produced by cyanobacteria. Similar clusters have popped up in parts of France, New Hampshire, and weirdly, around the Kii Peninsula in Japan.
Dr. Deborah Cory-Slechta at the University of Rochester has spent her career—we’re talking 30+ years—documenting how lead exposure during development creates permanent changes in brain structure that increase vulnerability to neurodegenerative disease later. The effects don’t show up for decades, which is why it took so long to make the connection. Her work suggests that many “idiopathic” Parkinson’s cases might not be so idiopathic after all.
Air pollution is another factor that keeps coming up in the data but that policymakers seem reluctant to address seriously. The Keck School of Medicine at USC published findings two years ago showing that fine particulate matter—specifically PM2.5—correlates with higher rates of Alzheimer’s pathology on brain imaging. The particles appear to cause inflammation that accelerates neurodegeneration. Los Angeles, Delhi, Beijing—cities with high pollution have corresponding increases in early-onset dementia. The statistics are there if you want to see them.
Genetic Origins (But It’s Complicated)
Genetics obviously plays a role. Everyone knows that. But the reality is way more complex than “you inherit bad genes and get sick.”
Take Huntington’s disease—that’s the one everyone points to as purely genetic since it’s caused by a CAG repeat expansion in the huntingtin gene. Except even that’s not straightforward. Why do some people with 40 CAG repeats develop symptoms at 30 while others with the same repeat length stay asymptomatic until 60? There are modifier genes, sure, but also lifestyle factors, possibly epigenetic influences we don’t fully understand yet.
Most CNS disorders aren’t single-gene conditions anyway. Multiple sclerosis has over 200 genetic variants associated with it, each contributing a tiny amount of risk. Combine that with Epstein-Barr virus infection (which almost everyone gets but which seems to be necessary but not sufficient for MS development), add in low vitamin D, maybe smoking, possibly latitude-dependent factors—and you get a disease that “originates” from this impossibly complex confluence of factors that our current medical model struggles to even describe, let alone predict.
The Role of Infections (Yes, Really)
This is going to sound wild but stick with me: some CNS disorders might originate from infections that happened years or even decades earlier.
Herpes simplex virus type 1—the one that causes cold sores—has been found in Alzheimer’s plaques. Not just near them. IN them. Dr. Ruth Itzhaki from the University of Manchester has been arguing since the 1990s that HSV-1 reactivation in the brain could be triggering or accelerating Alzheimer’s pathology, and the data supporting this has gotten progressively stronger. She’s even run small trials showing that antiviral treatment (specifically valacyclovir) can slow cognitive decline in early-stage patients who are HSV-1 positive. The effect size isn’t huge, maybe 30-40% reduction in decline rate, but it’s there.
Then there’s PANDAS—Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections. Kids get strep throat, their immune system goes haywire, and suddenly they’ve got OCD symptoms or tics that came out of nowhere. The mechanism appears to be molecular mimicry where antibodies against strep cross-react with brain tissue, specifically the basal ganglia. It’s rare, maybe affects 1 in 200 kids who get strep, but when it happens it’s dramatic and honestly pretty scary for parents.
Trauma’s Physical Footprint
CNS disorders can also originate from physical trauma in ways that don’t show up on initial imaging.
Chronic traumatic encephalopathy—CTE—wasn’t even recognized as a distinct entity until Boston University’s Ann McKee started systematically examining the brains of deceased NFL players around 2005. It turns out that repeated subconcussive hits, the kind that don’t even produce noticeable symptoms at the time, cause accumulation of tau protein in a distinctive pattern. The disease doesn’t show up until years or decades later, usually with mood changes, cognitive decline, sometimes aggressive behavior.
What’s disturbing is how common this might be. McKee’s group has found CTE pathology in the brains of high school football players, military veterans, even domestic violence victims with histories of repeated head trauma. The prevalence is unknown because you can only definitively diagnose it on autopsy, but PET imaging studies using tau tracers are starting to make it possible to detect in living patients—and the numbers are looking worse than anyone expected.
The Stress-Origin Pathway
Chronic stress can actually alter brain structure, and not in subtle ways.
Dr. Bruce McEwen at Rockefeller University spent his career documenting how prolonged cortisol elevation causes dendritic atrophy in the hippocampus and prefrontal cortex while causing hypertrophy in the amygdala. These aren’t reversible changes once they reach a certain threshold. They create vulnerability to depression, anxiety disorders, even accelerate cognitive aging.
Adverse childhood experiences—the ACEs that public health people won’t shut up about, and for good reason—correlate with higher rates of essentially every CNS disorder you can name. The mechanism appears to be multifactorial: HPA axis dysregulation, chronic inflammation, possibly epigenetic changes that alter stress response for life. A 2021 meta-analysis from King’s College London found that adults with 4 or more ACEs had roughly 3 times the risk of developing depression and 5 times the risk of attempting suicide compared to those with no ACEs.
Metabolic Origins We’re Just Discovering
Insulin resistance might be causing Alzheimer’s. Yes, really.
There’s a growing body of evidence that Alzheimer’s is essentially “type 3 diabetes”—a phrase coined by researchers at Brown University who showed that the Alzheimer’s brain is insulin resistant. The brain can’t properly metabolize glucose, neurons starve, amyloid accumulates as a kind of byproduct or failed protective mechanism. This would explain why diabetes is such a strong risk factor for dementia (roughly doubles the risk) and why drugs that improve insulin sensitivity sometimes show cognitive benefits.
Mitochondrial dysfunction is another metabolic origin that shows up across multiple CNS disorders. These are the power plants of cells, and when they don’t work right, neurons—which have enormous energy demands—suffer first and worst. Some cases of ALS, Parkinson’s, even migraines appear to have mitochondrial origins. The challenge is that mitochondrial function is influenced by genetics, toxin exposure, aging, stress, diet—basically everything—so isolating the primary cause is nearly impossible.
Where This Leaves Us
So where DO CNS disorders originate? The honest answer is: it depends, it’s complicated, and we’re probably asking the wrong question.
They don’t originate from a single source but from interactions between genetic vulnerabilities, environmental exposures, infections, trauma, stress, metabolic dysfunction, and factors we probably haven’t even identified yet. The old model of “one disease, one cause, one cure” doesn’t fit the reality of how these conditions actually develop.
What’s becoming clear—and this is where treatment approaches are headed—is that prevention needs to start earlier than we thought. Way earlier. Prenatal care, early childhood nutrition, reducing environmental toxin exposure, addressing trauma, maintaining metabolic health—these aren’t separate from treating CNS disorders, they’re the first line of defense.
Dr. Jeffrey Cummings, who directs the Chambers-Grundy Center for Transformative Neuroscience at UNLV, told me something last month that stuck with me: “We’ve been looking for magic bullets to cure Alzheimer’s for forty years. Maybe the answer is that there is no bullet because there’s no single target. Maybe we need to change the whole trajectory before the disease even starts.”
That’s probably right. It’s also incredibly difficult to implement in a healthcare system designed to treat acute problems, not prevent chronic ones that might not show up for decades. But if we’re serious about reducing the burden of CNS disorders—and given that neurodegenerative disease is projected to cost the global economy $2.8 trillion annually by 2030, we’d better be serious—we need to start thinking about origins differently.
The brain is part of the body. Seems obvious when you say it out loud, but our medical specialization has kind of made us forget that. CNS disorders don’t originate in isolation from the rest of human biology and experience. The sooner we stop treating them that way, the better chance we have of actually doing something about them.