CFS, a Conditioned Immune Response?
December, 2024
Who This Is For
Let me explain who this website and article are for. Are you experiencing recurring symptoms that doctors can’t explain—symptoms like pain, fatigue, headaches, or brain fog? Do they appear after certain activities, leaving you with a cycle of crashes? Perhaps you have periods where you feel better, but then something as simple as a bit of exercise, socializing, or even working at the computer sets you off again, making you feel worse afterward.
Have you visited various doctors, maybe multiple times, trying to find answers for more than six months, only to come up empty-handed? Are you constantly worried because there’s no clear explanation for these symptoms, and are they affecting not only your life but also your expectations for the future? Are you endlessly Googling or using ChatGPT to find a cure? Maybe you’ve tried all sorts of diets, supplements, and theories—straining to understand why your symptoms started in the first place.
If doctors found anything at all, it might have been something minor—perhaps a slight immune system anomaly, a bit of inflammation, or another small irregularity. Yet, these doctors might have implied, directly or subtly, that the issue is “all in your head.” This likely made you angry, because you know your symptoms are real. You feel they aren’t taking you seriously, and you resent the idea that you’re just making them up.
If you’ve answered “yes” to most of these questions, then you’ve come to the right place.
First off, you are not unique in the way you think you are. You’re not some special snowflake with a mysterious illness that no one has ever encountered—this isn’t an episode of “Dr. House.” In fact, what you have is quite common, well-understood (but not well enough), and can be overcome. Many people have experienced it, and they have recovered.
So, here’s the bottom line: the doctors are right. It is indeed all in your head. Your symptoms are very real, but their root is in your nervous system and how it’s responding, not in some elusive, undiscovered physical disease.
At this point, you can get angry, close this website and move on to the next convoluted theory. Maybe you’ll decide you have a rare mitochondrial disorder impacting your energy production and begin pursuing magic fixes, obscure supplements, or intricate drug cocktails that promise recovery by tinkering with molecular-level processes. Alternatively, you could overhaul your diet — cut out carbs, go vegan, try Ayurveda, meditate daily, eliminate histamines, detox heavy metals, blame common Lyme antibodies, or cling to some other low-probability condition.
But I’m telling you now: none of that will help.
I’m offering you a chance to shift your perspective on your illness. After all, what you currently believe hasn’t helped you recover, has it? So why not consider embracing new information? You can dismiss this viewpoint or accept it, but the very act of questioning your old assumptions is progress. Remember, insanity is doing the same thing over and over again while expecting different results. Take this opportunity to change your perspective and discover something new.
Theory
Chronic Fatigue Syndrome (CFS) develops through an intricate interplay of classical conditioning and immune system responses. Classical conditioning, famously demonstrated by Ivan Pavlov in 1897 through his experiments with dogs, occurs when a neutral stimulus—such as a ringing bell—becomes linked to an unconditioned stimulus, like food, through repeated pairings. Over time, Pavlov’s dogs began to salivate upon hearing the bell alone, illustrating how a learned association can trigger a physiological response.
This concept was further expanded by Robert Ader and Nicholas Cohen in 1974, who showed that even immune responses could be conditioned. In the case of CFS, such conditioning can happen rapidly, often following a triggering event like a viral infection, physical trauma, or extreme stress. The brain and immune system enter a feedback loop, where normal activities become associated with immune activation. Before long, these everyday actions can provoke an exaggerated response from the immune system—much like Pavlov’s dogs learned to salivate at a bell—leading to symptoms like Post-Exertional Malaise (PEM) and perpetuating a cycle of chronic fatigue.
In CFS, this conditioning can occur rapidly, often in the aftermath of a triggering event such as a viral infection like Covid, physical trauma, or extreme stress. The brain and immune system enter a feedback loop, with triggers—such as moderate physical activity—prompting an exaggerated immune response. The hypothalamus serves as the control hub, connecting the brain and immune system via hormonal and neural pathways. Stress or learned triggers activate the hypothalamic-pituitary-adrenal (HPA) axis, leading to the release of cortisol and norepinephrine, which modulate immune cell activity. This process can result in an overproduction of pro-inflammatory cytokines and autoantibodies, hallmark biomarkers commonly observed in CFS patients. These biomarkers reflect a dysregulated immune system and reinforce the association between everyday activities and immune overactivation. Over time, the body becomes "trained" to associate routine actions with immune responses, creating a self-perpetuating cycle that leads to debilitating symptoms like Post-Exertional Malaise (PEM). This rapid and learned response underscores the profound impact that an initial illness or trauma can have, setting the stage for a chronic condition driven by the interplay of neuroimmune mechanisms.
Ivan Pavlov (✝ 1936) is best known for discovering classical conditioning. His famous experiments with dogs showed that a neutral stimulus, such as a bell, could elicit a salivary response after repeated pairings with an unconditioned stimulus, like food.
Robert Ader (✝ 2011), the founder of neuro psychoimmunology, expanded on Pavlov’s work by showing that immune responses can be conditioned as well. His experiments with rats demonstrated that immune responses could be triggered by pairing a novel taste with an immunosuppressive drug. The immune system became conditioned to respond solely to the taste.
The Root Cause of Chronic Fatigue
Chronic fatigue can be traced back to a mismatch between the environment humans evolved to survive in and the modern world we live in. Evolution designed humans to face immediate, life-threatening challenges, such as hunting predators, gathering food, or defending against rivals. These challenges were short-lived but intense, activating stress responses to help us survive.
In today’s world, these immediate threats have been replaced by“imaginary stressors”—social pressures, work deadlines, or existential worries. While these are not life-threatening, our bodies interpret them as such, triggering the same ancient fight-or-flight responses. This chronic activation of stress mechanisms leads to inflammation, immune dysfunction, and ultimately conditions like chronic fatigue.
The Evolutionary Basis of Predictive Immune Responses
Our bodies evolved to prepare for likely injuries in advance. When anticipating a life-threatening fight, for example, the immune system would activate preemptively, readying itself to heal wounds. This predictive immune response was a survival advantage in a world of acute stress. However, in today’s world, where stress is persistent and imaginary rather than short-lived and real, this mechanism becomes maladaptive. The immune system is constantly activated without an actual injury to address, leading to systemic inflammation and fatigue.
The Role of Imagination in Human Evolution
Humans’ ability to imagine things that do not exist has been central to our survival and dominance. Shared beliefs, such as religion, nations, and money, allowed large-scale cooperation, enabling groups of humans to outcompete rivals like Neanderthals or even physically stronger animals like apes. For example, while individual humans are weaker than apes, a thousand humans unified by shared beliefs could systematically kill competing groups.
Imagination also enabled humans to plan for dangers and secure resources, ensuring survival. However, this same capacity now causes us to overthink and invent stressors, keeping us in a state of heightened alertness even in the absence of real threats.
Chronic Stress vs. Acute Stress
Humans evolved to handle acute stress, which is short-lived and resolves quickly. Examples include fighting a predator or escaping danger. Afterward, the body returned to a state of relaxation, or homeostasis. Chronic stress, on the other hand, is persistent and low-grade, such as ongoing financial worries or societal pressures. Unlike acute stress, chronic stress disrupts homeostasis, keeping the body in a heightened state of alertness indefinitely.
Homeostasis and Its Disruption
Homeostasis is the body’s natural balance between the fight-or-flight (stress) state and the rest-and-digest (relaxation) state. In a healthy individual:
- Acute stress activates the body for survival, and afterward, the body returns to a relaxed baseline.
- Chronic stress, however, shifts the baseline upward. What was once relaxing now feels slightly stressful, and the body cycles between “very stressed” and “less stressed” states, with no true relaxation.
This constant activation contributes to a conditioned immune response, inflammation, and chronic fatigue.
Proposed Solution: Reintroducing Acute Stress
To recalibrate our stress responses, we can mimic the life-threatening challenges our ancestors faced through controlled acute stressors:
- Physical Challenges: Activities like high-intensity exercise simulate the intense physical demands of survival scenarios.
- Cold or Heat Exposure: Practices like ice baths or saunas replicate the harsh environmental conditions humans evolved to endure.
- Structured Challenges: Competitions or tasks requiring focus and effort can replicate the mental intensity of survival situations.
These practices reset the body’s stress responses, shifting homeostasis back toward a balanced state. They also provide perspective, reducing the impact of imaginary stressors by reminding the body of what real challenges feel like.
The Stress Response Has Remained Largely Unchanged for Millions of Years
The way the human brain processes and reacts to stress is rooted in ancient evolutionary adaptations that have remained fundamentally the same for hundreds of millions of years.
Ancient Origins of the Stress Response
- The fight-or-flight response, regulated by the HPA axis (Hypothalamic-Pituitary-Adrenal axis), evolved over 500 million years ago in early vertebrates.
- This system helped our ancestors respond to immediate survival threats, such as predators or physical danger, by:
- Releasing cortisol and adrenaline to prepare the body for action.
- Suppressing non-essential functions like digestion and long-term immunity to conserve energy for immediate survival.
- Imagine a Homo sapien encountering a lion on the savannah. The moment the brain registers the threat, the fight-or-flight response activates. Adrenaline floods the bloodstream, increasing heart rate and pumping oxygen to the muscles, while cortisol suppresses digestion and other non-critical systems. This allows the Homo sapien to sprint away or fight with every ounce of energy available. Once the lion is gone, the stress response shuts off, and the body quickly returns to a calm state, resuming digestion, repair, and other normal functions. This acute stress response is what ensured survival in our ancestral environment.
The Primitive Brain Drives the Stress Response
- Key brain structures responsible for the stress response are extremely old:
- Brainstem (~500 million years old): Controls basic survival instincts.
- Limbic System (~150–200 million years old): Handles fear, aggression, and emotional processing through the amygdala and related structures.
- These regions automatically trigger stress responses when detecting danger, even in modern contexts.
- The neocortex (~2–3 million years old), responsible for rational thought, can interpret threats but cannot override the primal stress response completely.
- Key brain structures responsible for the stress response are extremely old:
Stress in Hunter-Gatherer Societies
- Until recently, the stress response was perfectly suited to the hunter-gatherer lifestyle:
- Acute, short-term threats like predators, injuries, or food scarcity activated the stress response temporarily.
- After the threat passed, the system quickly deactivated, allowing the body to recover.
- This balance ensured survival without the chronic activation seen in modern humans.
Modern Life: A Mismatch
- The stress response remains unchanged, but modern stressors are fundamentally different:
- Instead of acute threats, humans face chronic stressors like work deadlines, financial pressures, and social conflicts.
- The brain and HPA axis treat these as life-threatening, continuously releasing stress hormones like cortisol.
- Prolonged activation of the stress response leads to:
- Chronic inflammation, which underlies diseases like heart disease and autoimmune disorders.
- Mental health issues such as anxiety, depression, and burnout.
- Physical breakdown, including immune dysfunction and metabolic disorders like diabetes.
Why Hasn’t the Stress Response Changed?
- Evolution is a slow process, requiring thousands to millions of years to adapt.
- The stress response was so effective for immediate survival that it remained conserved in all vertebrates, including humans.
- Modern changes—such as agriculture (~12,000 years ago), industrialization (~200 years ago), and technology (~50 years ago)—are far too recent for the brain or stress response to have adapted.
- Even trivial aspects of our biology, like the continuous growth of fingernails, remain unchanged. If something as simple as fingernail growth hasn’t evolved, why would we expect our bodies to differentiate between worries about a mortgage payment and the fear of being killed by a predator? The body only recognizes danger as an immediate threat to life, and the stress response prepares accordingly.
- Evolution has not yet accounted for modern stressors like financial worries, social pressures, or existential anxieties—and likely never will. It would take millions of years for such adaptations to occur, but even that seems improbable. In today’s world, the concept of “survival of the fittest” no longer drives evolution, as humans have transcended natural selection through societal advancements. As a result, our bodies remain biologically tuned to an ancient environment, unable to adapt to these new forms of stress.
Conclusion
The human stress response, driven by ancient brain structures and the HPA axis, has remained fundamentally unchanged for hundreds of millions of years. While it served our ancestors well in responding to acute, short-term threats, it struggles to cope with the chronic, psychological stressors of modern life. This mismatch highlights how deeply rooted our biology is in evolutionary history, even as our environment has drastically changed.
Even something as seemingly insignificant as the continuous growth of our fingernails remains unchanged, a reminder of how deeply rooted our biology is in our evolutionary past. We were designed to thrive as hunter-gatherers in the wild, not to navigate the complexities of the modern world. A few thousand years of societal advancements have barely scratched the surface of our innate design—our bodies and minds are still fundamentally tuned to the challenges of a much older way of life.
How Classical Conditioning Works
In classical conditioning, we use the following terms:
The following stages illustrate how PEM could develop through a process of classical conditioning:
The body responds naturally to Excessive Activity, Stress & Ongoing Infection with Fatigue & Sickness Feeling.
Excessive Activity, Stress & Ongoing Infection (Unconditioned Stimulus)
Fatigue & Sickness Feeling (Unconditioned Response)
During this stage, Normal Activity (Conditioned Stimulus) becomes associated with the Excessive Activity, Stress & Ongoing Infection because they occur simultaneously or consecutively. The body starts to link this Normal Activity with the resulting Fatigue & Sickness Feeling.
Excessive Activity, Stress & Ongoing Infection (Unconditioned Stimulus)
+
Normal Activity (Conditioned Stimulus)
Fatigue & Sickness Feeling (Unconditioned Response)
Eventually, the mere act of engaging in Normal Activity (Conditioned Stimulus) triggers a conditioned response Fatigue, Sickness Feeling (Conditioned Response), even in the absence of the original Excessive Activity, Stress & Ongoing Infection (Unconditioned Stimulus). The body has learned to associate normal activity with these negative outcomes, in the same way, Pavlov's dogs associated the bell with food and Ader's rats associated the taste with an immune response.
Normal Activity (Conditioned Stimulus)
Fatigue, Sickness Feeling (Conditioned Response)
Implications of the Hypothesis
Immune System Dysfunction: CFS is rooted in a dysfunctional immune response to stressors, infections, or overexertion. This explains abnormal immune markers e.g. the presence of autoantibodies targeting the adrenergic and muscarinic receptors in CFS patients, as found by Dr. Scheibenbogen and her team at Charité University in Berlin. The immune aspect of the hypothesis opens the door to exploring treatments that target the immune system. Various immune-modulating therapies have been investigated for reducing CFS symptoms in early studies, showing potential for alleviating the condition. This suggests that modulating the immune response could be a viable treatment avenue. However, it's important to note that while these treatments might alleviate symptoms, they don't address the potential root cause of the disease, which, according to this hypothesis, is the conditioned immune response.
Treatment Approaches: For many years, the medical community was convinced that CFS had psychological causes, and patients felt dismissed because they believed it was a physical illness. Therefore, the medical community used to promote Graded Exercise Therapy (GET) and Cognitive Behavioral Therapy (CBT) as treatment methods. However, patients resisted this, feeling unheard and doubting these methods. Additionally, studies have been inconclusive in showing the effectiveness of these methods. The hypothesis that CFS is a conditioned immune response unites the psychological and physiological causes. It is a physical illness that has arisen through classical conditioning of the nervous and immune system. Thus, the mind and the body are both involved. Personally, after accepting the physical reality of the condition, a combination of GET and CBT helped me, as I was able to overcome my symptoms by slowly increasing activity and changing my thoughts and beliefs about the condition. Recovery stories also provide anecdotal evidence that these methods have helped others. Even in CBT and GET studies, there are many individual cases reporting improvement and recovery from their symptoms, even though the studies overall could not show significant results. The unclear study results can be explained by the difficulty of implementing these methods. To illustrate this point, consider a study examining the effectiveness of lifestyle changes such as eating less and exercising more for weight loss. Although these changes are theoretically effective, many individuals struggle to implement and sustain them over time, resulting in inconclusive results. The same principle applies to CFS recovery through GET and CBT, therefore despite the inconclusive study results, after all these methods can be the cure.
The Conditioned Response and Symptom Triggers: The fatigue and other symptoms experienced by CFS patients are a conditioned response to normal activities. This isn't solely due to ongoing stress or infections, but a learned response to activities that have become triggers. The conditioned response can manifest as any symptom of CFS, such as fatigue, pain, cognitive dysfunction, food intolerance, or chemical sensitivity. This process can technically produce a wide range of symptoms, as conditioning affects both the nervous system and the immune system as Pavlov and Ader have shown. In the same way, the conditioned stimulus can be any activity that has been paired with the unconditioned stimulus. This is why CFS patients often have different triggers, as each individual has a unique set of activities that have become associated with their symptoms.
A Pathway to Recovery: Patients can reverse their maladaptive conditioned immune response by gradually exposing themselves to activities that trigger their symptoms, much like allergy desensitization therapy.
Why does the medical community not know about this?
Recovery Requires Active Participation: There is no quick fix for CFS. Patients must be actively involved in their recovery, gradually exposing themselves to triggers and reconditioning their body's response. This requires consistent effort, patience, and a leap of faith in the hypothesis, that they can recover. Only the patient truly knows their unique triggers. During gradual exposure therapy, only the patient can gauge when they're ready to increase exposure levels. This element of self-awareness makes the treatment process more of an art than a science. Reconditioning your immune response can be even more challenging than losing weight or stopping drinking alcohol. While the steps to lose weight or quit alcohol are generally well-defined, CFS recovery requires identifying personal triggers and finding a way to expose yourself to them without triggering PEM. This complexity makes the treatment difficult to implement and contributes to its lack of widespread recognition. And by the time someone figures out how to successfully manage their recovery, they are often disengaged from the medical community, further hindering the spread of this knowledge.
Consider this analogy from World War II: military analysts studied planes returning from combat, noting damage concentrated on wings and fuselages. Initially, they planned to reinforce these areas. However, statistician Abraham Wald realized they were only looking at the "survivors." Planes hit in other areas didn't make it back.
Similarly, those who recover from CFS often disengage from the community, no longer seeking medical attention or participating in online discussions. This creates a "silent group" of recovered individuals, invisible to researchers and clinicians. The medical community's view of CFS then becomes distorted, focusing primarily on those still suffering. This leads to a misconception that there's no cure. The true picture of CFS must include the many who have recovered, but currently their stories are often absent from available data.
This parable is relevant to modern medicine, where specialization, while beneficial, can lead to tunnel vision. Like the blind men, specialists may focus intensely on isolated aspects such as immune dysfunction, neurological changes, or psychological stress, without understanding the full picture. This narrow focus can result in the underlying cause, like a conditioned immune response, being overlooked. Consequently, the fragmented nature of modern medicine may hinder comprehensive understanding and effective treatment of conditions like Chronic Fatigue Syndrome (CFS), which may encompass both the mind and the body.
What helped me
Don't Avoid Activity: It's crucial to engage in all activities that trigger your PEM, but do so mindfully and within your limits. The aim is to gently re-associate these activities with positive or neutral feelings, not to push yourself to the point of relapse. Think of it as slowly rewiring the circuits in your nervous system so that activity is no longer interpreted as a trigger for the immune response. For example, if you used to go to the gym three times a week, but now you can't without getting PEM, then keep going to the gym three times a week, but only for a couple of minutes. This way you are reconditioning your body to the gym without triggering your PEM. Then gradually increase the time you spend at the gym.
Relapses are Part of Recovery: You can't control every aspect of your activity level. Life happens! Focus on what you can control and let go of the rest. When you experience a relapse, see it as an opportunity to recondition your body by adjusting how you respond to it. Each time, strive to remain calmer and less stressed than before.
The Only Way to Go Fast Is to Go Slow: Reconditioning takes time. You're retraining your nervous system and immune system, which requires consistent effort and patience. Much like desensitization therapy for allergies, which often takes years, progress is gradual and non-linear. Your initial focus should be on practicing indifference to your symptoms rather than trying to eliminate them. By cultivating a neutral response to discomfort, you'll begin to weaken the conditioned association, paving the way for lasting recovery.
Learn from Recovery Stories: Explore anecdotal evidence in the form of recovery stories on YouTube and other platforms. Notice the common threads that run through them. Many individuals who claim to have recovered from CFS describe unknowingly aspects of GET and CBT as part of their recovery, even if they don't label them as such. Look for the underlying principles these individuals applied, like pacing, gradually increasing activity, and reframing their thoughts and beliefs about their condition.
You are not special: You are like one of Robert Ader's rats that has been conditioned to an immune response. And thus, you can be unconditioned in the same way. The process is simple, but difficult. It's simple because it's a basic conditioning mechanism, but it's difficult because it requires time, patience, and consistency. Unlike Ader's rats, you live in a complex environment with many variables you can't control. However, by focusing on what you can control, you can gradually and relentlessly decondition your body and regain your health step by step.
Your Symptoms Are Real: Don't fight against your symptoms. Once your immune response has been triggered, there's no point in pushing through. Instead, accept and adapt your daily activities to accommodate your symptoms. Have a plan in place for relaxation, but even during a relapse also include some activities that trigger your PEM. Engage in these activities symbolically for a short while just for the sake of practicing indifference towards your symptoms. This way you are also reconditioning your body to these activities while having a relapse.
Do not follow any rigid prescription: The ultimate goal of recovery is to essentially forget about this illness and live your life as if you never had it. This doesn't mean following a rigid prescription of CBT or GET. However, it's crucial to temporarily acknowledge the reality of your condition. Avoid the trap of denying the syndrome or pushing yourself beyond your limits. Once you are recovered you can push yourself as much as you want, but for now, less is more.
Share Your Story: Once you've recovered, share your experience! The stories of those who have overcome CFS are often underrepresented as discussed earlier.