Neuroscience, immunity, memory, and new perspectives for understanding a form of suffering that is still too often misunderstood.
It’s almost noon, and the traffic light is about to turn green. At the edge of the sidewalk, a small crowd waits absently: some are looking at their phones, some are talking, and others have already leaned forward, ready to go. A woman stands slightly behind the others, not far enough back to be noticed. She brings one hand to her opposite arm, as if by chance, then shifts her position slightly.
Her legs feel heavy, her back aches, her shoulders burn, and even the fabric of her jacket seems to weigh more today. The little green man appears. Everyone starts walking. She does, too. Watching her, no one would imagine that putting one foot in front of the other requires attention, precision, and a silent negotiation with her own body. It is perhaps precisely here—in the almost imperceptible space that separates what a person feels from what others can see—that fibromyalgia becomes difficult to describe.
There are diseases that immediately show a sign. A fracture appears on an X-ray, a wound has recognizable edges, and many inflammatory processes alter measurable parameters.
Fibromyalgia, on the other hand, presents medicine with a more complex reality: concrete symptoms—sometimes profoundly disabling—for which conventional tests do not necessarily reveal a lesion capable of explaining, on its own, the intensity of the suffering.
Widespread pain may be accompanied by persistent fatigue, stiffness, non-restorative sleep, and cognitive difficulties. Some people describe being unable to recall a common word, losing their train of thought, or having to make an unexpected effort to stay focused. This is the condition that many patients call “fibro fog”: a sort of cognitive fog that can linger throughout the day alongside fatigue.
For a long time, the absence of an obvious lesion fostered a misconception that was difficult to dispel. When no organic cause commensurate with the symptoms could be identified, it became easy to shift the explanation to psychological factors. As if what medical tools could not reveal were necessarily a figment of the imagination.
Contemporary neuroscience has gradually overcome this dichotomy. Pain is not a snapshot of damage, nor is it a message that passively travels from the tissues to the brain. It is a sensory and emotional experience constructed through complex biological systems, in which information from the periphery is processed, amplified, or inhibited along the spinal cord and within brain networks. Sleep, attention, past experiences, expectations, and the perception of safety or threat also contribute to modulating these processes.
The reality of suffering, therefore, does not depend on the existence of a visible injury. It is within this framework that the concept of nociplastic pain is situated, adopted by the International Association for the Study of Pain as a third mechanistic descriptor alongside nociceptive and neuropathic pain. It refers to pain arising from altered nociception without clear evidence of tissue damage capable of explaining the activation of peripheral nociceptors, nor of a lesion or disease of the somatosensory system sufficient to justify it.
Fibromyalgia is one of the primary contexts in which this model is studied, although different mechanisms may coexist in the same individual.
We can imagine—with the caution that every metaphor requires—a sophisticated alarm system. Under normal conditions, the signal intensifies in the face of a threat and subsides when the danger disappears.
In some forms of persistent pain, however, parts of the protective system may become more reactive: the threshold changes, pressure that is usually tolerable may become painful, and a stimulus that was already unpleasant may be perceived with greater intensity.
This is not a “fictitious” alarm. It is the regulatory system that has altered its response.
In fibromyalgia, some people report heightened sensitivity to noise, light, odors, or temperature changes. Research on nociplastic pain is delving deeper into the interaction between sensory processing, amplification mechanisms, and the nervous system’s ability to modulate stimuli.
In recent years, the focus has expanded beyond the brain. A review published in 2026 by the Pain Study Group of the Italian Society of Rheumatology describes fibromyalgia as a complex and heterogeneous condition in which, alongside central mechanisms, autonomic regulation, immune and neuroendocrine processes, metabolism, and genetic predisposition are being studied.
This is an important shift because the actual body is far less fragmented than the categories through which we are accustomed to describing it. The nervous system, the immune system, and the endocrine system communicate continuously via hormones, neurotransmitters, cytokines, and other mediators. neuroimmunomodulation studies precisely this dialogue.
A systematic review published in 2026 in Brain, Behavior, and Immunity analyzed eighteen studies on possible central neuroimmune alterations in fibromyalgia. Despite considerable methodological heterogeneity, converging evidence emerged regarding glial and neurometabolic changes in certain brain regions, along with alterations in proteins involved in immune signaling.
This is an interesting finding, but it does not prove the existence of a single “fibromyalgia neuroinflammation.” Rather, it suggests that the relationship between neural activity and immunity may represent one component of a much more complex pathophysiology.
A meta-analysis published in July 2026 in BMC Rheumatology, which pooled eighteen observational studies and 1,605 participants, found differences in certain inflammatory biomarkers between people with fibromyalgia and healthy controls. The authors themselves, however, highlight the variability of the results: currently, there is no single inflammatory biomarker capable of diagnosing the syndrome.
The peripheral nervous system is also receiving increasing attention. A 2025 review compiled studies conducted using skin biopsy and corneal confocal microscopy, detecting signs of alterations in small nerve fibers in approximately half of the people with fibromyalgia examined.
However, it is necessary to avoid an improper equivalence: fibromyalgia and small-fiber neuropathy are not the same condition. The significance of these findings is not yet fully understood, and their presence in only a subset of individuals raises a particularly interesting question: biologically distinct subgroups may exist within the same diagnosis.
Perhaps the future of research lies precisely here—not merely in asking what “the cause” of fibromyalgia is, but in trying to understand which mechanisms prevail in the individual sitting before the doctor.
Two individuals may share the same diagnosis yet experience very different clinical presentations. In one, widespread tenderness may dominate; in another, exhaustion. Some suffer primarily from fragmented sleep, while others struggle with cognitive difficulties or symptoms related to autonomic regulation. Recognizing this diversity does not make the disease any less well-defined; rather, it allows us to observe it with greater precision.
In this context, a delicate word inevitably arises:stress.
Using it requires care, because for years phrases like “it’s just stress” have been used to dismiss what could not be explained.
From a biological standpoint, stress is not the same as being nervous. It is an adaptive response of the entire organism, involving the hypothalamic-pituitary-adrenal axis, the autonomic nervous system, metabolism, immunity, and sleep. Research is investigating what happens when this activation becomes intense or persistent and the mechanisms responsible for recovery lose some of their flexibility.
In fibromyalgia, alterations in the autonomic and neuroendocrine systems involved in the stress response have been described, though not uniformly.
Stating this does not equate to attributing the cause of fibromyalgia to stress. It means recognizing that what happens in life can interact with biology through real mechanisms, without reducing the complexity of the disease to a psychological explanation.
The same rigor is necessary when discussing trauma. A systematic review published in 2025 in Psychiatry Research found an association between fibromyalgia and post-traumatic stress disorder (PTSD) and, in some of the literature reviewed, more severe symptoms in people with PTSD. The authors emphasize, however, that the prevalence of cross-sectional studies prevents the establishment of a simple cause-and-effect relationship.
Not all people with fibromyalgia have experienced trauma, just as a traumatic experience does not inevitably lead to the syndrome. It would be incorrect to replace the old organic reductionism with a psychological one.
The interesting finding is another: an experience perceived as threatening can alter the systems that regulate memory, attention, arousal, and the autonomic response. The brain learns, makes predictions, and prepares the body to react to what has previously posed a danger.
In this sense, the body also participates in learning. Not because it “stores trauma in the muscles,” nor because pain is the symbolic expression of a conflict, but because memory, expectation, bodily perception, and threat-regulation systems belong to biological networks in constant communication.
Sleep also plays an essential role. When it becomes fragmented or non-restorative, it can diminish the body’s ability to modulate painful stimuli. This creates a vicious cycle that is difficult to break: pain disrupts rest; a poor night’s sleep exacerbates fatigue and sensitivity; exhaustion limits movement; and the fear of worsening the condition can lead to constantly monitoring every sensation.
Little by little, the disease thus risks taking over not only the body but also the space meant for living.
For this reason, the most widely accepted therapeutic strategies do not focus on a single target. The EULAR recommendations identify adapted physical activity as the therapeutic intervention with the strongest evidence among those evaluated, incorporating it into a progressive pathway that begins with education and prioritizes non-pharmacological options, before tailoring interventions to individual needs.
More recently, in 2025, the Neuropathic Pain Working Group of the Italian Society of Neurology reaffirmed the need for a multimodal approach capable of integrating pharmacological and non-pharmacological strategies.
Talking about exercise doesn’t mean telling an exhausted person that they should simply move more. For those who have learned to associate excessive exertion with worsening symptoms, starting over means gradually regaining confidence in their own body, respecting its capabilities without turning them into immutable limitations.
Psychotherapy can also play an important role, but not because it aims to convince the person that their pain is psychological. Living with a persistent condition for a long time inevitably changes one’s relationship with oneself, with movement, with others, and with the future. Fear of worsening symptoms, avoidance, hypervigilance, mood disorders, or social withdrawal can become a second form of suffering alongside the physical pain.
When the patient’s medical history includes traumatic experiences that are still highly distressing or a post-traumatic stress disorder, EMDR (Eye Movement Desensitization and Reprocessing) may also be considered. However, its use in fibromyalgia is still an area of ongoing research.
A randomized trial published in 2024 involved 79 participants and compared standard of care with the same treatment combined with EMDR; the study found improvements in various measures related to pain, fibromyalgia symptoms, depression, sleep, and traumatic stress.
A 2025 systematic review on chronic pain, which included nine studies—seven of which were randomized—considers EMDR promising but highlights the heterogeneity of the available research and the fact that it is not yet a routine practice for pain management.
This distinction is crucial. EMDR should not be recommended based on the assumption that every case of fibromyalgia must involve underlying trauma, but rather when a person’s history actually reveals traumatic memories or post-traumatic symptoms that warrant specific treatment.
Clinical hypnosis is also generating interest. Far removed from the sensationalized portrayals with which it is often associated, it uses focused attention, imagination, and therapeutic suggestion to modulate perceptual experience without depriving the person of their capacity for choice. A meta-analysis of randomized studies had already pointed to possible benefits. In 2024, a further controlled trial involving 49 participants observed, after eight sessions, improvements in certain measures related to pain, sleep, psychological health, and quality of life. These are interesting findings, not promises.
And this is perhaps the most respectful stance medicine can take: welcoming what emerges without turning every new finding into a definitive solution.
The future of fibromyalgia may depend less on the search for a one-size-fits-all treatment and more on the ability to understand each individual’s unique profile. For some, regaining sleep will be a priority; for others, gradually rebuilding mobility. In some cases, it will be necessary to address the consequences of trauma or a co-occurring mood disorder; in others, to investigate neurological or autonomic symptoms.
Medicine becomes more precise when it stops expecting people to be alike simply because they share the same diagnosis.
Finally, there remains something that no biomarker can ever replace: being believed.
Those who live with an invisible condition for a long time often learn to justify themselves. Because they can’t go out today if they went out to dinner yesterday. Because they can be in pain and smile at the same time. Because one morning they work almost normally and the next they feel drained. Because they manage to cross a street and no one can imagine how much energy it cost them. This variability is easily mistaken for inconsistency. The absence of visible signs is taken to mean the absence of suffering.
Listening doesn’t mean giving up scientific rigor. It means applying it to the fullest, accepting that what we still can’t measure perfectly doesn’t cease to exist just because of that.
It’s almost noon. A few blocks away, another traffic light turns green. People start moving all at once. The woman waits a fraction of a second, then begins to cross. Maybe her legs hurt less today. Maybe not. The light starts flashing, and the others speed up.
She continues at her own pace. One step, then another. She reaches the other side and steps onto the sidewalk. No one turns around. No one knows what those few meters meant. The city keeps moving. And perhaps this is exactly what those living with fibromyalgia want: not to be forced to prove constantly what they’re feeling and to be able to return, one day, to performing an ordinary action without having to measure every step.
Crossing a street. Just that.
