Toxicant-Induced Neuroinflammation, Mitochondrial Collapse, and Electrochemical Destabilization

 

 Overview

 

This chapter isolates the neurological consequences of toxicant exposure sustained by the survivor, formerly blended with psychiatric outcomes in earlier assessments. It focuses on structural, functional, and epigenetic changes in the nervous system resulting from chronic, dermally absorbed exposure to permethrin and DEET in military settings, compounded by traumatic brain injury (TBI). These exposures disrupt critical pathways of neuroelectrical stability, resulting in a unique profile of non-convulsive seizure activity, autonomic dysregulation, mitochondrial energy collapse, and neuroinflammation.

 

The survivor's clinical progression is not a psychiatric anomaly—it is the predictable neurological footprint of systemically absorbed neurotoxins under stress-amplified conditions.

 

 

 

 Clinical Neurological Profile of the Survivor

 

• REM Sleep Behavior Disorder (RBD)

    

• Polyneuropathy involving both sensory and motor systems

    

• Visual hypersensitivity, photophobia, and sound-triggered distress

    

• Memory deficits and executive dysfunction

    

• Seizure-like activity without convulsions (temporal lobe origin)

    

• Autonomic instability and baroreflex failure

    

• Non-specific encephalopathy with neurocognitive slowing

    

• Brain fog and post-exertional neurological collapse

    

• Reduced verbal fluency and slowed processing speed

    

• mTBI sustained during service, following field exposure to permethrin-treated ACU prototype uniforms

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Molecular and Mechanistic Basis of Neurological Injury

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1. GABAergic System Disruption

Permethrin and DEET inhibit GABA-gated chloride channels, critically reducing inhibitory tone in the central nervous system. This disruption lowers the seizure threshold and contributes to persistent neural hyperexcitability. In the survivor, this manifests as subclinical seizures, brainstem overactivation, and episodic sensory overload—phenomena frequently misdiagnosed as panic attacks or anxiety disorders. Following mTBI, the injured brain becomes even more susceptible to GABAergic imbalance, compounding this vulnerability.

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2. Voltage-Gated Sodium Channel Dysregulation

Permethrin prolongs neuronal depolarization by altering sodium channel gating, preventing normal repolarization. This leads to erratic neuronal firing, increased peripheral nerve pain, seizure-prone networks, and cardiac conduction anomalies. When layered onto mTBI-related axonal shearing, this ionic dysregulation worsens white matter signaling and executive function.

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3. Mitochondrial Collapse and NAD⁺ Depletion

DEET and permethrin drive mitochondrial dysfunction by collapsing membrane potential, reducing ATP synthesis, and accelerating NAD⁺ depletion. In neural tissue—where energy demands are constant—this leads to cognitive fatigue, poor memory consolidation, and post-exertional neurological crashes. The survivor’s sustained energy failure is consistent with widespread mitochondrial distress, which is further aggravated by TBI-induced oxidative burden.

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4. Neuroinflammation via NF-κB Activation

Microglial priming in the hippocampus and limbic system triggers chronic NF-κB–mediated inflammation. This neuroimmune loop disrupts synaptic plasticity and emotional regulation, contributing to REM Sleep Behavior Disorder (RBD), depression, and impaired memory. TBI-related blood-brain barrier damage may allow even greater inflammatory infiltration, accelerating neuronal loss.

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5. Nurr1 and Nrf2 Dysregulation

Permethrin suppresses Nurr1, a nuclear receptor essential for dopaminergic neuron survival, and chronically elevates Nrf2, signaling ongoing oxidative stress. The result is dopaminergic instability, mood fluctuation, motor dysfunction, and vulnerability to Parkinsonian syndromes. mTBI magnifies this through direct injury to the basal ganglia and midbrain regions where Nurr1 is most active.

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6. Endocannabinoid System (ECS) Suppression

The ECS modulates neuroprotection, fear extinction, and emotional resilience. Permethrin blunts ECS tone, while DEET alters endocannabinoid metabolism, leaving neural circuits vulnerable to overactivation and inflammation. Post-TBI ECS suppression is linked to PTSD-like phenotypes and poor recovery, both of which are evident in the survivor’s clinical trajectory.

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7. Autonomic and Baroreflex Collapse

Toxicant injury and mTBI together destabilize autonomic nuclei in the brainstem and hypothalamus. The survivor’s bradycardia-tachycardia cycling, vasovagal instability, and impaired stress response reflect this breakdown in brain–heart signaling. Baroreflex failure and limbic dysfunction produce unpredictable shifts in blood pressure, heart rate, and respiratory rhythm—hallmarks of a toxic neurocardiogenic syndrome.

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Seizure-Prone Networks and Silent Neurological Injury

 

The temporal lobes—especially the hippocampus—are epicenters for focal seizure generation. Injury from permethrin, DEET, and TBI produces a seizure phenotype that often lacks convulsions but includes:

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• Ictal bradycardia or asystole

    

• Disrupted respiratory and cardiac rhythm

    

• Visual and auditory aura-like symptoms

 

These “silent seizures” are frequently dismissed as psychological events in military and VA evaluations, leading to delayed diagnosis and inappropriate psychiatric labeling.

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Diagnostic Blind Spots

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• REM Sleep Behavior Disorder is often overlooked or misclassified as sleep apnea, despite its strong predictive value for neurodegeneration.

 

• Non-convulsive seizures evade routine EEG detection and remain underexplored in chemically or TBI-exposed veterans.

 

• Environmental exposure history is rarely integrated into neurological workups, erasing causality from view.

 

• Autonomic dysfunction is routinely misattributed to stress or mood disorders, instead of being recognized as brainstem and limbic system pathology.

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Key Insight

 

We cannot afford another generation of veterans with neurological damage erased by diagnostic neglect.

 

What presents as mood swings, brain fog, sleep disturbance, or “unexplained” cardiovascular symptoms is, in reality, the molecular fingerprint of neurotoxic and traumatic injury. These are not isolated psychiatric complaints—they are the predictable downstream effects of synaptic collapse, mitochondrial failure, and neuroinflammation.

 

mTBI does not occur in a vacuum. When layered on top of toxicant exposure, it accelerates the brain’s decline—amplifying epigenetic shifts, disrupting energy metabolism, and impairing recovery pathways.

 

This chapter reframes neurological injury as a multi-hit syndrome of environmental and traumatic origin. The literature doesn’t merely support this reclassification. It demands it.

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Chapter 11. Literature Review

Neurological Conditions and Convulsive Disorders
Bioenergetic Collapse, Synaptic Dysregulation, and Cognitive Decline in Chemically Exposed Veterans

 

 

 

 

Naughton, S.X., Yang, E.J., Iqbal, U., et al. "Permethrin Exposure Primes Neuroinflammatory Stress Response to Drive Depression-Like Behavior Through Microglial Activation in a Mouse Model of Gulf War Illness." Journal of Neuroinflammation 21 (2024): Article 222. 

https://doi.org/10.1186/s12974-024-03215-3

https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-024-03215-3

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Naughton and colleagues demonstrate how chronic exposure to permethrin primes hippocampal microglia, leading to a neuroinflammatory stress response and the emergence of depression-like behavior in rodents. These effects are not only relevant to affective disorders but signal a progressive deterioration in limbic and prefrontal networks. This mechanistic model mirrors the survivor's clinical presentation—marked by REM Sleep Behavior Disorder (RBD), mood instability, and cognitive dysfunction. The study's confirmation of microglial activation in the hippocampus provides a key biological explanation for the survivor’s early-onset neurodegeneration and sleep disruption following chemical exposure.

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Carloni, M., Nasuti, C., Fedeli, D., et al. "Early Life Permethrin Exposure Induces Long-Term Brain Changes in Nurr1, NF-κB and Nrf2." Brain Research 1515 (2013): 19–28. 

https://doi.org/10.1016/j.brainres.2013.03.048  

https://www.sciencedirect.com/science/article/abs/pii/S0006899313004885?via%3Dihub

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This pivotal study links early permethrin exposure to long-lasting suppression of Nurr1, a nuclear receptor essential for dopaminergic neuron survival and synaptic plasticity. Simultaneously, it shows overactivation of NF-κB and disruption of Nrf2 oxidative stress pathways. These findings are especially relevant to the survivor’s dopaminergic instability, executive dysfunction, and movement-related abnormalities. Nurr1 deficiency in particular corresponds with the survivor's dysregulated emotional processing and REM-associated parasomnias. The study also reinforces that once these transcriptional changes are triggered by chemical exposure, they persist and worsen with age—reflecting the survivor’s own neurodegenerative trajectory.

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Shetty, G.A., Hattiangady, B., Shetty, A.K. "Chronic Oxidative Stress, Mitochondrial Dysfunction, Nrf2 Activation and Inflammation in the Hippocampus Accompany Heightened Systemic Inflammation and Oxidative Stress in an Animal Model of Gulf War Illness." Frontiers in Molecular Neuroscience 10 (2017): Article 182.

https://doi.org/10.3389/fnmol.2017.00182 

https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2017.00182/full

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This investigation reveals persistent mitochondrial failure and redox imbalance in hippocampal tissues following Gulf War chemical exposure. The findings include reduced ATP production, heightened inflammation, and neurogenic failure—all of which are modeled within BioSymphony’s neurodiagnostic profile of the survivor. These systemic deficits match the survivor’s reported symptoms of chronic fatigue, short-term memory loss, and cognitive slowness. Crucially, this study provides further evidence that low-dose chronic exposure is sufficient to trigger systemic bioenergetic collapse, particularly in individuals with concurrent physical stress or injury, such as the survivor’s mild TBI.

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Wong, Victor S., and Brett Langley. “Epigenetic Changes Following Traumatic Brain Injury and Their Implications for Outcome, Recovery, and Therapy.” Neuroscience Letters 625 (2016): 26–33. 

https://doi.org/10.1016/j.neulet.2016.04.009.

https://www.sciencedirect.com/science/article/abs/pii/S0304394016302142?via%3Dihub

 

Wong and Langley provide a critical review of how mild and moderate TBI leads to long-term changes in gene expression via DNA methylation, histone modification, and microRNA regulation—a pattern that persists long after the acute injury phase. Of particular importance to the survivor’s case is the study’s emphasis on mitochondrial epigenetics, or “mitoepigenetics,” where trauma-induced transcriptional dysregulation directly impairs mitochondrial DNA expression and energy production. This finding aligns with the survivor’s chronic neurofatigue, REM Sleep Behavior Disorder, and executive dysfunction, all of which are mapped in BioSymphony’s omic scans as markers of neuroenergetic failure.

 

Moreover, the authors propose that epigenetic scarring from TBI makes the brain more susceptible to further damage from secondary insults—including toxicant exposures. This is highly relevant for the survivor, whose TBI occurred after extensive dermal and systemic absorption of permethrin and DEET in field conditions. In this context, the TBI was not a separate event but a synergistic insult, compounding an already dysregulated neuroimmune state and accelerating injury pathways. This review lends molecular credibility to BioSymphony’s modeling of cross-sensitization, where toxicant exposure reduces recovery capacity from trauma and vice versa.

 

Wong and Langley’s work reinforces the need for epigenetic biomarkers and mitochondrial function assays in any diagnostic workflow for veterans with suspected chemically induced neurological decline. Their findings serve as a scientific foundation for why traditional neuroimaging and standard labs often miss what is, in essence, a molecularly embedded injury. BioSymphony translates this hidden pathology into visible, actionable insight—bridging the diagnostic gap Wong and Langley describe.

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López-Aceves, T.G., Vargas, J.T., Ramírez-Leyva, D., et al. "Exposure to Sub-Lethal Doses of Permethrin Is Associated with Neurotoxicity: Changes in Bioenergetics, Redox Markers, Neuroinflammation and Morphology." Toxics9, no. 12 (2021): 337. 

https://doi.org/10.3390/toxics9120337 

https://www.mdpi.com/2305-6304/9/12/337

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This study confirms that even sub-lethal doses of permethrin cause significant ATP depletion, glial reactivity, and oxidative stress. These cellular stress markers align directly with BioSymphony’s omic scans of the survivor, which show depleted NAD⁺, mitochondrial decay, and dendritic loss in hippocampal and frontal circuits. López-Aceves et al.’s histopathological findings lend weight to the survivor’s memory instability, mood dysregulation, and seizure-like activity—particularly under exertion or thermal stress. This work reinforces the idea that chronic neurotoxicity does not require acute overdose—just repetition, bioaccumulation, and a failure to detect molecular decay.

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Raisch, T., and Raunser, S. "The Modes of Action of Ion-Channel-Targeting Neurotoxic Insecticides: Lessons from Structural Biology." Nature Structural & Molecular Biology 30, no. 10 (2023): 1411–1427.

https://doi.org/10.1038/s41594-023-01113-5 

https://www.nature.com/articles/s41594-023-01113-5

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Raisch and Raunser’s structural analysis of pyrethroid interaction with ion channels confirms how permethrin rewires sodium (Nav), calcium (Cav), and chloride (GABA-A) channels. These disruptions induce prolonged depolarization, synaptic fatigue, and reduced inhibitory tone. The survivor’s history of seizure-like symptoms—absent overt convulsions—along with autonomic instability and vagal hypersensitivity, is directly explained by this ion channel dysregulation. Their research supports BioSymphony’s model of “silent seizure networks” and baroreflex failure caused by limbic-hypothalamic instability, offering a pathophysiological framework to make invisible injuries visible.

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Abou-Donia, M.B., et al. "Locomotor and Sensorimotor Performance Deficit in Rats following Exposure to Pyridostigmine Bromide, DEET, and Permethrin, Alone and in Combination." Toxicological Sciences 60, no. 2 (2001): 305–314. 

https://doi.org/10.1093/toxsci/60.2.305 

https://academic.oup.com/toxsci/article-abstract/60/2/305/1644070?redirectedFrom=fulltext

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This study remains a landmark in understanding Gulf War toxicant synergy. It demonstrates how exposure to DEET, permethrin, and pyridostigmine bromide in combination triggers profound locomotor and neurological deficits in rats. The survivor’s own postural instability, progressive polyneuropathy, and visual/auditory hypersensitivity replicate these findings nearly identically. The authors show how neuroinflammation and cholinergic disruption—not just gross injury—drive subtle yet destructive neurological decline. The study also underscores the heightened impact of such exposures under physical stress, validating the survivor’s deterioration during and after extended field training.

 

 

Bordoni, L., Nasuti, C., Mirabilio, A., Gabbianelli, R. “Early Impairment of Epigenetic Pattern in Neurodegeneration: Additional Mechanisms Behind Pyrethroid Toxicity.” Experimental Gerontology 124 (2019): 110629. 

https://doi.org/10.1016/j.exger.2019.06.002.

 

In this pivotal study, Bordoni and colleagues investigated the long-term neurological consequences of early-life exposure to permethrin, one of the primary pyrethroid compounds used in military-treated uniforms. The researchers found that even low-dose neonatal exposure caused significant disruption of global DNA methylation and altered expression of the Nurr1 gene—an essential regulator of dopaminergic neurons and synaptic plasticity. These findings are particularly important to veterans exposed during their neurodevelopmentally vulnerable years or in highly plastic adult neural circuits following trauma.

 

In the case of the Survivor, who sustained mTBI following dermal exposure to permethrin-treated ACU prototypes, these findings offer a critical mechanistic explanation for his dopaminergic instability, REM Sleep Behavior Disorder (RBD), emotional regulation challenges, and executive dysfunction. The epigenetic disruption observed by Bordoni et al. is not transient; it impairs neural repair, promotes neuroinflammation, and may propagate into transgenerational neurological risk.

 

Notably, the study’s implication that peripheral epigenetic changes can mirror central nervous system deteriorationbolsters BioSymphony’s diagnostic logic. In the Survivor, peripheral transcriptomic data has shown methylation abnormalities and reduced Nurr1-related expression in both neural and adrenal signatures—aligning closely with Bordoni’s observations.

 

By integrating these findings into Chapter 11, we not only reinforce the epigenetic cascade theory of post-toxicant neurodegeneration, but also provide a data-driven foundation for personalized omics-based screening in chemically exposed veterans.

 

 

Kim, U.J., Hong, M., & Choi, Y.H. “Environmental Pyrethroid Exposure and Cognitive Dysfunction in U.S. Older Adults: The NHANES 2001–2002.” International Journal of Environmental Research and Public Health, vol. 18, no. 22, 2021, p. 12005.

https://doi.org/10.3390/ijerph182212005.

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Kim et al. conducted one of the most robust epidemiological investigations into the neurocognitive impact of pyrethroid exposure in a nationally representative sample of older adults. Utilizing data from the 2001–2002 NHANES cohort, the study assessed urinary 3-phenoxybenzoic acid (3-PBA) levels as biomarkers of pyrethroid exposure and compared these to scores from the Wechsler Adult Intelligence Scale Digit-Symbol Coding Test (DSCT), a widely accepted neurocognitive performance measure.

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After multivariable adjustment for confounders including age, sex, race/ethnicity, physical activity, smoking, income, BMI, hypertension, and diabetes, higher 3-PBA levels correlated with significantly reduced DSCT scores (−3.82, 95% CI: −6.92, −0.71). This inverse relationship between exposure and cognition persisted even after controlling for major health and lifestyle variables, establishing strong statistical credibility. The authors contextualize their findings within the growing literature on excitotoxic injury, highlighting that pyrethroids can cause chronic overstimulation of neurons leading to mitochondrial exhaustion and structural degeneration.

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This study is profoundly relevant to the Survivor’s case. The survivor’s documented cognitive decline, particularly slowed processing speed, verbal fluency loss, and memory dysfunction, mirrors the neurocognitive metrics evaluated in the DSCT. BioSymphony’s cognitive biomarker profile corroborates mitochondrial collapse, NAD+ depletion, and disrupted redox signaling – mechanisms directly linked to excitotoxicity and bioenergetic exhaustion as proposed by Kim et al.

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Moreover, while Kim et al. focused on older adults, the implications for previously healthy veterans are even more acute. The Survivor’s exposure occurred during peak physical fitness, with far higher environmental and dermal concentrations than the general population. The study measured exposure from household and environmental sources yet still observed cognitive impairment; the Survivor’s prolonged dermal absorption through permethrin-treated uniforms, under conditions of heat, sweat, and co-exposure to DEET, likely resulted in significantly greater systemic burden.

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Crucially, Kim et al. challenge the assumption that pyrethroids are benign at low doses. They call for urgent reevaluation of environmental risk thresholds. BioSymphony echoes this call, demonstrating that chronic subclinical exposure, especially when layered with mTBI and autonomic dysregulation, produces a predictable and debilitating cognitive collapse. The Survivor’s trajectory is not anomalous—it is emblematic of a broader failure to recognize the cumulative neurotoxicity of pyrethroids.

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This literature serves as a cornerstone in Chapter 11, firmly anchoring the Survivor’s cognitive deterioration within a recognized pattern of environmentally induced neurodegeneration. It underscores the imperative for exposure-aware neurological screening in veterans and supports BioSymphony’s mechanistic modeling approach as a necessary evolution in veteran care.

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U.S. Environmental Protection Agency (EPA). "Permethrin Facts (RED Fact Sheet)." EPA, June 2006.

https://www3.epa.gov/pesticides/chem_search/reg_actions/reregistration/fs_PC-109701_1-Jun-06.pdf

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The EPA formally identifies permethrin as “likely to be carcinogenic to humans” and confirms that developmental neurotoxicity occurs at doses achievable through uniform wear and occupational exposure. This classification affirms the survivor’s exposure timeline and aligns with BioSymphony’s reconstructed exposure burden of 1,785–2,220 mg dermally absorbed permethrin. The EPA’s acknowledgment of central nervous system effects from subacute doses validates the survivor’s neurological complaints as toxicant-driven, not idiopathic.

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Summary Insight

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The neurological symptoms documented in the survivor—REM behavior disorder, seizure-like activity, cognitive slowing, and polyneuropathy—are not separate entities but parts of a single toxicant-induced syndrome. Together, these peer-reviewed studies establish a coherent mechanistic chain: from dermal absorption and mitochondrial failure to epigenetic interference and chronic neuroinflammation.

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This literature review makes clear what BioSymphony has modeled: that chemically exposed veterans suffer from predictable and measurable neurological injury. Our task is no longer to ask if the exposures were harmful. The literature confirms they were. Our task now is to deliver diagnostics and interventions that meet these survivors where they are—with science that sees what others overlook.