The past decade has ushered in a dramatic shift in how scientists understand chronic, multisystem illnesses such as ME/CFS, Long COVID, POTS, chronic pain syndromes, and environmental sensitivities. Increasingly, research points to dysregulation within the brain’s limbic threat-detection networks—the circuits that regulate safety, autonomic function, and stress responses—as a key mechanism sustaining symptoms long after the original trigger has resolved.
This perspective gained additional attention following a recent analysis, which highlighted emerging evidence of reduced brain norepinephrine (NE) in individuals with ME/CFS and Long COVID (1). Although the underlying study remains unpublished, the neurobiological pattern it proposes aligns closely with decades of research on autonomic imbalance, mitochondrial stress, and limbic system hypersensitivity in chronic complex illness.
While NE is produced across several brain regions, its regulation is tightly interwoven with limbic activity. The amygdala, hippocampus, and related networks continually evaluate threat and safety—and therefore heavily influence NE demand and autonomic arousal. When the limbic system becomes stuck in hypervigilance, downstream NE pathways and the systems they regulate can become destabilized.
This helps explain why symptoms persist even after the original stressor has passed: the issue is often not structural damage but a limbic system locked in a maladaptive pattern of overactivation.
Fortunately, neuroscience also shows that both limbic circuits and NE-regulating networks remain highly plastic. Through neuroplasticity, these disrupted pathways can be reshaped and normalized.
In This Blog, You’ll Learn:
- How chronic stress reshapes limbic and NE pathways
- Why low central NE may be a key driver of symptoms in ME/CFS and Long COVID
- The role of limbic hyperarousal and central sensitization
- Why traditional treatments often miss the neurological root cause
- How neuroplasticity reverses maladaptive neural loops
- How DNRS restores limbic regulation and NE balance
How Chronic Stress Rewires Limbic and Norepinephrine Pathways
A growing neurobiological model suggests that chronic limbic activation places continuous demand on norepinephrine release (1). Over time, this strain—especially in a metabolically compromised environment—contributes to reduced NE availability and dysregulation of stress-related pathways.
Research shows that chronic sympathetic activation and mitochondrial dysfunction both impair the ATP-dependent loading of norepinephrine vesicles, leading to functionally low NE even when the body remains in a high-arousal state (2,3).
Norepinephrine is essential for focus and cognitive clarity, wakefulness, autonomic stability, sensory filtering, and motivation.
The depletion of norepinephrine contributes to hallmark symptoms of ME/CFS and Long COVID.
Limbic System Overactivation and Central Sensitization
Chronic illness profoundly reshapes limbic processing—particularly in the amygdala, hippocampus, and insula. This dysregulation leads to central sensitization, a state characterized by:
- exaggerated responses to benign internal sensations
- misinterpretation of neutral stimuli as dangerous
- amplification of sensory input
- autonomic instability
Central sensitization is well established across ME/CFS, Long COVID, chronic pain, and fibromyalgia (4–7).
How Central Sensitization Keeps Symptoms Alive
Repeated exposure to threat (whether biological, emotional, or physiological) conditions the brain to overrespond. This can result in:
- exaggerated post-exertional symptoms
- heightened sensitivity to foods, chemicals, sound, or light
- misinterpretation of normal sensations as dangerous
- chronic autonomic dysregulation
Even when the original stressor has resolved, limbic threat pathways remain active unless they are deliberately retrained.
The Biochemical Consequences: Low NE and Chronic Symptoms
Low central norepinephrine contributes to cognitive slowing, impaired motivation, autonomic dysfunction, sensory sensitivity, disrupted sleep, and anxiety or hyperarousal.
Because norepinephrine vesicle loading depends on adequate energy production, individuals with mitochondrial stress, inflammation, or prolonged sympathetic activation are especially vulnerable to NE depletion (2,3).The Vicious Cycle of Chronic Illness
Limbic hyperarousal → Excessive NE demand → NE depletion →
Worsening symptoms → More threat signals → Deeper sensitization →
More triggers.
This cycle is powerful—but reversible.
Neuroplasticity and the Restoration of Limbic-NE Balance
Neuroscience shows that:
- limbic overactivation can be downregulated
- NE-regulating circuits can stabilize
- autonomic balance can be restored
- conditioned threat pathways can be weakened
- circuits of safety and resilience can be strengthened
Reducing limbic arousal decreases NE demand, allowing the brain to replenish depleted NE stores and restore normal regulation (1–3).
DNRS: Rewiring the Limbic System to Normalize Norepinephrine Regulation
DNRS (Dynamic Neural Retraining System) directly targets the limbic and autonomic networks implicated in chronic illness.
DNRS supports recovery by:
1. Interrupting maladaptive threat responses – Reduces excessive limbic-driven NE demand.
2. Downtraining amygdala-driven hyperarousal – Dampens false alarms and lowers sympathetic activation.
3. Reducing central sensitization – Retrains the brain to stop mislabeling neutral sensations as dangerous.
4. Building new neural pathways of safety – Structured practice strengthens circuits of calm, ease, and cognitive control.
5. Supporting cellular energy recovery – Lower stress signaling reduces ATP consumption, promoting healthier NE vesicle loading.
6. Enhancing top-down regulation – Strengthens prefrontal networks that quiet the limbic system.
DNRS rewires the neural circuits that generate ongoing symptoms—not just the symptoms themselves.
From Dysregulation to Resilience
As limbic overactivation decreases and norepinephrine regulation recovers, individuals often experience:
- improved energy
- clearer cognition
- reduced pain
- normalized autonomic function
- diminished sensory sensitivity
- greater emotional stability
- expanded capacity for activity
These changes reflect true neurological healing.
The Takeaway: Your Limbic System Can Rewire Toward Health
Modern neuroscience is clear: Chronic stress and illness can reshape the limbic system, but the limbic system can be rewired.
Through neuroplastic approaches like DNRS, individuals can calm limbic overactivation, restore norepinephrine balance, and rebuild the neurological foundations of well-being.
Your brain is adaptable.
Your symptoms are not fixed.
Recovery is possible because neuroplasticity is lifelong.
Hear about how Birch recovered from Long COVID with DNRS.
References
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- Johnson C. Low Brain Norepinephrine Levels in ME/CFS and Long COVID – Part II. HealthRising. 2025 Nov 16.
- Berridge CW, Waterhouse BD. The locus coeruleus–noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Rev. 2003;42(1):33–84.
- Kvetnansky R, Sabban EL, Palkovits M. Catecholaminergic systems in stress: structural and molecular genetic approaches. Physiol Rev. 2009;89(2):535–606.
- Nijs J, et al. Central sensitization in chronic fatigue syndrome: evolving concepts. J Clin Med.2020;9(2):335.
- Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain.2011;152(3 Suppl):S2–15.
- Komaroff AL, Lipkin WI. Insights from ME/CFS and Long COVID research. Nat Rev Immunol.2021;21:639–40.
- Davis HE, et al. Characterizing long COVID neurological features. Nat Rev Neurol. 2023;19:259–76.
