Posted on February 1, 2024

Nervous System Dysregulation

A New Frontier in Explaining and Treating Chronic Fatigue & Pain

K. Ransom, PhD

Recent research into the causes of chronic pain and fatigue suggests that a dysregulated nervous system may be a key contributor to these conditions. But what exactly throws the nervous system into overdrive? And how can we learn to shift gears so that our bodies come back into balance?


Chronic fatigue and pain are debilitating health problems worldwide, posing a significant burden on societies around the globe. In the United States alone, these conditions impact an estimated 20% of the adult population, or over 65 million people annually (1, 2, 3). Globally, this equates to a staggering 1.6 billion people struggling with persistent pain or fatigue (4).

The financial impact of these conditions on individuals and societies is also astounding. Costs of medical treatments and testing, as well as indirect costs due to missed work, reduced levels of productivity, or increased risk of leaving the labor force altogether, add up to hundreds of billions of dollars annually and exceed that of any other disease category, including cancer and heart disease (5, 6).

Despite their significant worldwide prevalence, both chronic pain and chronic fatigue remain poorly understood. Why does pain sometimes persist – and may even grow stronger – after an acute injury appears to have healed? And why do some patients experience severe fatigue, as well as mental and physical post-exertional malaise, sleep disturbances and cognitive impairment, with no obvious cause?

The enigmatic nature of chronic pain and chronic fatigue syndrome, which is also known as myalgic encephalomyelitis (ME/CFS), unfortunately means that treatments are limited, and often ineffective (7). Because doctors are unclear about what’s causing these conditions, intervention targets have been vague. Patients are often left with managing symptoms as their best way forward. But pain medications can have risks of addiction, and drugs can have difficult side effects. Any side effects must then also be managed. The result for patients? Feeling like this band-aid approach is not exactly working for them.

The lack of a clear answer to the question, “Why is this happening?” not only makes treatment challenging. The mysterious nature of chronic pain and ME/CFS can also be extremely distressing to patients because of the stigma associated with these conditions. On top of symptom discomfort, patients may be faced with family members, friends, and even doctors suggesting that the pain or fatigue is “all in their heads.”

But this situation may now be changing. Recent research offers new hope to chronic pain and fatigue sufferers. Deeper understandings are emerging of a likely key physiological contributor to the chronic pain and immunological activation seen in at least some of these patients. That contributor? A dysregulated nervous system.

What is a dysregulated nervous system?

Nervous system dysregulation, which is defined as an imbalance in the activity of the sympathetic and parasympathetic arms of the autonomic nervous system (ANS), is becoming an important target of research exploring the causes of chronic fatigue and pain management. Studies suggest there may be altered regulation of ANS activity in people experiencing chronic pain and ME/CFS compared to healthy individuals.

Changes in ANS activity observed with ME/CFS patients include reduced heart rate variability, delayed gastric emptying, increased gut permeability, altered thermoregulation, and reduced capacity to recover after exercise (7). A similar dysregulation of the ANS is seen in patients with chronic pain compared to people experiencing pain due to an acute injury (8).

How does the autonomic nervous system work?

Let’s take a look at how the ANS works in the body, and what happens when it becomes dysregulated. Understanding the mechanisms at play can reveal the possible underlying precursors of chronic pain and ME/CFS, and explain why new intervention approaches are transforming how these conditions are treated.

The ANS coordinates the body’s involuntary physiological processes such as metabolism, circulation, respiration, body temperature, digestion, circadian rhythm, and immune response via its two opposing branches: the sympathetic nervous system (SNS), and the parasympathetic nervous system (PNS). When the body is stressed due to some kind of internal or external threat, the sympathetic nervous system fires up and stimulates hormonal signals that contribute to what is known as the “fight, flight, or freeze” response. The body is signaled to shift its energy resources toward fighting off a life threat (“fight”), fleeing from an enemy (“flight”), or shutting down to conserve energy (“freeze”).

Quickly recruiting the body’s systems in this way is an adaptive stress response that ensures survival during acute emergencies. If you encounter an unfriendly bear in the forest, for example, your fight, flight or freeze response might just save your life. Your blood pressure and heart rate increase, your blood flows to muscles and organs, and your elevated breathing increases your oxygen intake. All of these autonomic changes coordinated by your SNS may be critically necessary for your escape.

After the immediate threat is over – the bear is long gone and you are safe and sound – the parasympathetic nervous system (the “rest and digest” branch of the ANS) then kicks in to calm the body down, returning all systems to a normal baseline. Your blood pressure, heart rate, and breathing rate decrease based on signals from your PNS, and you breathe a sigh of relief.

When the nervous system goes awry

Sometimes, however, the post-threat calming process doesn’t happen as expected. For some patients struggling with chronic pain, the body’s ANS continues to be activated well after the “threat” of tissue injury or other pain source is resolved.

This extended overactivation of nerves creates a condition in the nervous system known as central sensitization. During central sensitization, the body becomes increasingly sensitive to stimuli. Neurons signaling pain actually increase their response to the same stimuli over time. That is, the pain becomes more painful. Neurons may also develop spontaneous activity in response to non-painful stimuli. For example, the pain may spread to other body parts, or may involve increased sensitization to the point that even a light touch becomes excruciating (9). Sensitivity to other external stimuli such as light, sound or chemical substances can also be part of the picture.

Likewise, in some patients struggling with ME/CFS, an initiating event such as a viral infection is experienced, and the patient suffers fatigue, malaise, and body aches that are attributed to the body’s normal immune response to the infection. However, concern grows when the fatigue and other symptoms continue well after the infection is no longer active. Clinical observations and research of ME/CFS patients suggest that central sensitization may also be the mechanism underlying the chronic immunological and autonomic activation seen in at least some of these patients (10). Due to either overactivity of the SNS or insufficient PNS regulation, the ANS does not appear to return to its normal baseline.

But what causes this extended dysregulation of the nervous system? Why do chronic pain and ME/CFS patients continue to suffer over a longer term, when other patients are able to recover from acute threat with no ongoing health issues at all?

How the limbic system is involved

Research is beginning to reveal a potential culprit behind the nervous system dysregulation observed in at least some forms of chronic pain and fatigue: An impaired or imbalanced “threat detection” function, deep in the limbic structures of the brain.

The limbic system is a group of midbrain structures that includes the amygdala, hippocampus, hypothalamus, prefrontal cortical areas, and others. Current understanding of these structures suggest that they are responsible for coordinating our behavioral and emotional responses related to the processing of stress, motivation, and memory (11).

Interaction of limbic brain structures

Let’s take a look at how the limbic structures interact by imagining them as actors in a play.

A greatly simplified picture of limbic system processes would spotlight the amygdala as the star player on the stage, lighting up with the feelings of pleasure, fear, anxiety, and anger in response to environmental stimuli. In this limbic scene, the amygdala interacts with its co-star, the hippocampus, processor of our memories. Together, the two structures interactively act out the process of attaching emotional meanings to our experiences and filing them into memory, so that we will be primed to avoid fearful threats or approach pleasurable treats in the world around us.

A third important figure, the brain’s prefrontal cortex, watches from the wings and modulates or controls what the amygdala and hippocampus are doing onstage, like a director providing instructions to the play’s actors.

Cued by the interactions of the director and two actors in the spotlight, a cascade of hormones involved in a complex known as the hypothalamic–pituitary–adrenal (HPA) axis then takes the stage to dance and sing. This group of messengers – which includes the hormones corticotropin releasing hormone (CRH), cortisol, and others – scatters to all directions, coordinating and conveying limbic instructions to other brain areas. Various hormonal messages are sent back to inform amygdala-hippocampus interactions, and on to the ANS for orchestration of appropriate SNS, PNS, and other bodily responses including the modulation of cellular activity affecting the immune system (12).

Limbic system imbalances

In the brains of at least some patients struggling with chronic pain and ME/CFS, the hormonal interaction of limbic system structures appears to become imbalanced. (11, 13). Sometime during or after the initial work of assessing an immediate threat and assigning it to memory, something goes awry. The threat detection system gets stuck on “high alert.”

Even though our understanding of limbic system impairment is currently fuzzy at best, researchers now believe that in some chronic pain and fatigue cases, chronic illness may arise as a function of differences in the complex interaction of perception, arousal, cognition, and emotions taking place in a dysregulated limbic system (11).

Most importantly, new treatments that target limbic brain structures are emerging to help chronic pain and fatigue sufferers. Patients who previously relied on band-aid approaches such as pain medications now have new options to pursue. The new interventions are targeted to address the underlying causes of some types of chronic pain and fatigue by introducing plasticity changes into brain circuits responsible for threat detection and alert. The aim: To calm and retrain an overactive limbic system.

But before we delve into these exciting new treatment approaches, it is important to first consider other chronic illnesses that have been identified as potentially related to limbic system dysregulation, and specifically to impairments in the threat detection function of the brain. Some patients struggling with these illnesses may also benefit from the new treatment frontier we are now entering.

Trauma and the limbic system

One of these potentially related chronic conditions is actually a behavioral health illness. As a Clinical Psychologist, I work with many people who are struggling with acute and chronic traumatic stress symptoms. My interest in limbic system dysregulation began primarily in understanding how the brain’s threat detection system is involved with behavioral health conditions such as posttraumatic stress disorder (PTSD).

As with chronic pain and fatigue, PTSD patients can usually point to an initiating event – in this case, an emotionally traumatic experience – that occurred prior to the appearance of their symptoms. In the acute unfolding of an emotionally traumatic event, such a stress response can be adaptive and necessary. Recall the bear in the forest! But for PTSD patients, after the imminent environmental danger subsides, the brain continues to chronically respond to neutral stimuli as if the danger is still present. PTSD sufferers experience the bear threatening them again and again in the course of their everyday lives.

What’s more, each time the threat is reexperienced, the stress response can become more and more exaggerated. The body can get stuck in a vicious circle of threat and response (14) that some have dubbed a limbic system trauma loop. Each time the threat is reexperienced, the memory of the trauma is reexamined and stored anew, and it may become associated with mental imagery, secondary emotional reactions (such as fear of the fear) and other experiences (15). The result? The trauma memory may deepen and intensify over time.

Once this happens, all subsequent experiences of threat can be altered. Getting stuck in a limbic system trauma loop means that future trauma loops are more likely to be triggered. That’s because changes to brain plasticity via the expression of various hormones can predispose the individual to react with greater dysregulation when subsequently exposed to experiences of stressful stimuli (16).

Specific brain structures involved in PTSD

Research has begun to detail the specific limbic structures involved in PTSD. One study, for example, provides very clear information on the causal contribution of specific limbic areas to PTSD symptoms. This study examined a group of Vietnam War veterans who suffered both a physically traumatic brain injury (suffered through head trauma in combat) as well as emotionally traumatic events on the battlefield (17).

The researchers observed that while most of the veterans experienced PTSD symptoms at a rate expected for this population (40%), in the groups of veterans with physical brain lesions in the ventromedial prefrontal cortex, significantly fewer (18%) experienced PTSD symptoms. Remarkably, the group with amygdala lesions (0%) did not develop PTSD at all (17). It’s clear from this and other studies that the amygdala in particular is implicated in PTSD.

Other central sensitization syndromes

PTSD is one example of a chronic illness that may be related to impairments in the brain’s limbic system, as is now suspected for at least some chronic pain and fatigue cases. Other conditions which may be similarly related include multiple chemical sensitivities, fibromyalgia, migraine headaches, and irritable bowel syndrome (18, 19). It is becoming clearer that limbic system trauma loops may be initiated not just by emotionally overwhelming traumatic events, but also by overwhelming exposures to chemicals, environmental toxins, and pathogens.

Symptoms of a dysregulated nervous system

Patients struggling with chronic pain, ME/CFS, or the other conditions with a central sensitization profile, often experience symptoms of ANS dysregulation. Depending on the particular health challenge, these symptoms can include:

  • Headaches, dizziness, and lightheadedness
  • Irregular heartbeat
  • Rashes and skin issues
  • Nausea, indigestion, and general stomach upset
  • Upper respiratory discomfort and/or breathing problems
  • Allergy-like symptoms such as runny eyes, sneezing, and sore throat
  • Arthralgia or unexplained joint pain
  • Intense fatigue
  • Brain fog, lack of concentration, and memory difficulties
  • Feelings of depression and anxiety
  • Significant mood disruption and mood swings

Treatments for regulating the nervous system

The good news is that the brain can change. The neuroplasticity of brain circuits makes it possible to actually influence change in neural pathways over time. Various interventions have been observed to result in structural and functional brain differences which can be measured using magnetic resonance imaging and other techniques (20, 21, 22). And just as some stroke and head injury patients are able to retrain their brains to overcome impairments (21, 23, 24), it appears to be also possible to introduce plasticity changes that relax and balance the brain and nervous system.

Research supporting neuroplasticity-based interventions in stroke and brain injury patients has a long history. Studies have shown that by engaging in physical rehabilitation and even mental rehearsal protocols, patients recovering from stroke and brain injuries are able to encourage their brains to start making new connections. Lost movement and language capacities can be slowly regained (25, 26).

Similarly, there is a growing body of research supporting the idea that interventions can help patients with symptoms of nervous system dysregulation by influencing neuroplastic changes in the brain.

The use of mindfulness meditation, yoga, tai chi, and other mind-body approaches has been observed to influence brain changes (27). Various forms of psychotherapy including cognitive-behavioral therapies, eye movement desensitization and reprocessing (EMDR) and others, have also shown to have positive neuroplastic effects in the treatment of PTSD and other behavioral health conditions (28). And stimulation of the vagus nerve through electrical stimulation and other means (29) has shown promising results in the treatment of chronic pain and other disorders.

As a result of new developments in our understanding of how nervous system dysregulation can be remodeled over time, innovative non-pharmaceutical treatments for chronic pain and fatigue are emerging. Brain retraining programs employing cognitive, emotional, and behavioral rehearsal such as the Dynamic Neural Retraining System (DNRS) have shown preliminary promise as a means of rebalancing the limbic system and easing symptoms of chronic fatigue, chronic pain, and other disorders characterized by nervous system dysregulation (30). Interventions such as DNRS give patients a means of taking powerful individual action to contribute to their own health and healing, and target the underlying contributors to these conditions. Brain retraining interventions that target the nervous system can augment existing medical treatments and help patients feel increased self-efficacy in coping with, and making a difference in, their chronic conditions.


We are still early in this new frontier, and much still needs to be done in terms of clinical observation and rigorous research based on randomized controlled trials to deepen our understanding of various intervention approaches. Studies must have sample sizes sufficient to support statistical significance, and wherever possible they must use biomarkers of neuroplasticity or brain imaging to clearly show neurophysiological effects.

But regardless of the work yet to be done, the promise of plasticity-based interventions for the treatment of chronic pain and fatigue is nevertheless compelling. Treatments that encourage limbic system rebalancing have resulted in real progress for many patients. Considering the millions of people suffering from these and other chronic central sensitization conditions worldwide, the hope of a new approach is important and worthy of considerable research investment (31). The potential is there for brain retraining to give chronic fatigue and pain patients – as well as those struggling with other central sensitization disorders involving maladaptive plasticities – a means of regaining some control over their physical well-being, which is a profound development indeed.


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