Neuro(b)log For Patients

What Happens in the Brain When Pain Lasts Too Long

Chronic pain is not just a "long version" of acute pain. It is a standalone disease of the nervous system that affects the body, emotions, and thinking. It involves an altered brain state driven by neuroplasticity and the formation of pathological neural networks that maintain pain without any clear tissue damage. Many people feel misunderstood because their pain is not visible at first glance—but very real changes are occurring in the brain at biochemical and cellular levels. The perception of pain is a non-transferable experience, and describing the character and intensity of pain is a difficult task for many patients. 

The Nervous System Becomes Hypersensitive

When pain persists for weeks or months, the nervous system begins to behave differently. This process is called sensitization. Neurons in the brain and spinal cord become hypersensitive, reacting more strongly and quickly than before. The brain and spinal cord amplify painful signals, causing pain to be perceived as much stronger than what would correspond to the actual stimulus (hyperalgesia). Within the spinal cord, specifically in the dorsal horns, glutamatergic activity increases, while the activity of inhibitory GABA and glycine interneurons involved in transmitting various types of information in the central nervous system decreases. Activated support cells of the nervous system, such as microglia and astrocytes, release pro-inflammatory cytokines as mediators that further amplify the pain. These amplified signals travel from the spinal cord to the brain, even long after the danger of tissue damage on the periphery has subsided. Even normal stimuli (touch, cold, movement) can be perceived as painful because the threshold for neuron activation is lowered. This condition is known as allodynia. Nerves "sound the alarm" even when there is nothing left to repair. [1]It is similar to a home alarm system set too sensitively—it triggers even at the slightest disturbance. In essence, a certain pathological learning of pain takes place. 

❤ Emotions and Pain Intertwine

Chronic pain is not just physical. The brain links pain with emotions, fear, and stress. 

• The limbic system—the emotional center—becomes activated. In my articles, I repeatedly mention the ACC (anterior cingulate cortex), a part of the limbic system located above the corpus callosum, which connects pain, emotions, attention, and autonomic nervous system regulation. We can call it the "threat center"...
• Pain becomes exhausting not only physically, but also mentally.
• The fear of pain can amplify the pain even further. 

This does not mean the pain is "all in your head". It means that emotions and pain share the exact same brain circuits. 

🧠 Related Article: When pain becomes chronic, it fundamentally affects your mood and ability to think rationally. Learn how depression alters the architecture of the human mind in the article Depression and Cognitive Functions: How Depression Affects Thinking.

The Brain "Learns" Pain

From birth, the brain exhibits signs of neuroplasticity—it learns new things, but unfortunately, it can also learn pain. Chronic pain alters the structure and function of various brain regions. In the somatosensory cortex, the area representing pain expands, making it very difficult for the patient to localize the exact pain spot. In the prefrontal cortex, these changes lead to impaired pain control, weakening the "rational component" of pain modulation, leaving patients facing a higher risk of anxiety and depressive symptoms. Other areas involved include the insula, which contributes to the heightened emotional experience of pain. 

In a "normal state," the brain can suppress pain to a certain extent using interconnected descending pathways; however, during chronic pain, these pathways weaken or, due to malfunction, can even amplify the pain.

• Repeated painful signals create strong neural pathways.
• The brain begins to expect the pain, triggering it more easily.
• Pain can manifest even without a clear physical cause. 

It is similar to a bad habit—the longer it lasts, the stronger it becomes.

When a Nerve Is Damaged: Neuropathic Pain

This is pain caused by damage or disease affecting the nervous system itself—meaning the nerves, spinal cord, or the brain. It is neither inflammatory nor mechanical pain. It is pain that the nervous system generates on its own because it is damaged or hypersensitive. A damaged nerve shows signs of pathology even at a sub-cellular level, involving changes in the function of cellular ion channels, causing it to generate spontaneous electrical discharges without any external stimulus. 

• The pain can feel burning, electric, stabbing, tingling, or cause numbness, a cold/hot sensation, or the impression of a numb, foreign, swollen limb.
• It appears even without an external stimulus.
• Treatment is usually completely different from standard pain management.

This category includes diabetic (poly)neuropathy, postherpetic neuralgia following shingles, nerve compression in entrapment syndromes (carpal tunnel), radicular syndromes due to herniated discs, nerve damage after trauma or surgery, multiple sclerosis, spinal cord lesions, chemotherapy-induced neuropathy, and others. 

Why Chronic Pain Is So Complex

Chronic pain negatively impacts:

• sleep
• mood
• attention
• memory
• movement
• immunity
• motivation
• emotions

Consequently, it often turns into a vicious cycle—pain leads to stress, and stress amplifies the pain. Chronic stress impacts not only the psyche but also the overall homeostasis of the organism—the intricate balance of all systems within the human body. 

Can the Brain Be "Reprogrammed"?

Yes. Just as the brain learned pain, it can also learn new, healthier patterns. 

Effective approaches include:

• Pain Reprocessing Therapy (PRT)—retraining the brain to respond safely
• Mindfulness and attention training
• Physiotherapy focused on graded loading
• Cognitive-Behavioral Therapy (CBT)
• Neuromodulation techniques (e.g., TENS, brain stimulation)

These methods do not imply that "the pain is just psychological"; instead, they harness the aforementioned neuroplasticity, leveraging the brain's capacity to learn by creating new neural networks and connections. 

PRT (PAIN REPROCESSING THERAPY)

PRT is a modern psychoneurological approach that teaches the brain to stop interpreting harmless bodily signals as a threat. In other words: the brain can be retrained to stop producing pain automatically.It is based on the insight that for a large portion of chronic pain (especially back, neck, headache, and pelvic pain), the primary issue lies not in the tissue, but in the altered processing of pain within the brain. The brain has learned to anticipate pain, so it generates it even in the absence of structural damage. PRT teaches the brain new, safe responses that gradually reduce central sensitization. 

How PRT Works—5 Core Mechanisms

1. Pain Reappraisal
   The patient learns to view pain as a harmless signal, not as a sign of damage. This dampens activity in threat centers (insula, amygdala—the limbic system). 
2. Somatic Exposure
   The patient is gradually exposed to movements or situations that trigger pain but are fundamentally safe. The brain learns: "This is not a threat → I don't need to generate pain." 
3. Calming the Nervous System
   Regulation techniques (breathing, mindfulness, attention management) lower sympathetic activity, reducing pain reactivity.
4. Retraining Brain Predictions
   Chronic pain is largely a prediction error—the brain anticipates pain, and so it creates it. PRT shifts these predictions toward safety. 
5. Processing Emotions
   Emotional stress, suppressed feelings, and the fear of pain reinforce the circuits involved in pain perception. PRT teaches the brain that bodily signals are not dangerous, reducing the emotional amplification of pain. 

What Happens in the Brain During PRT

Evidence from Clinical Trials

The most prominent study was published in 2021 (JAMA Psychiatry):

• Patients with chronic back pain who underwent PRT experienced an average pain reduction of 66%.
• 66% of patients were practically pain-free after therapy.
• fMRI (functional magnetic resonance imaging) demonstrated a significant drop in threat center activity and changes in brain pain networks.

MINDFULNESS AND AND CHRONIC PAIN

Mindfulness for chronic pain is not just "relaxation." It is brain training that alters how the brain processes, predicts, and emotionally evaluates pain. And that is exactly what matters most with chronic pain. 

Mindfulness Reduces Central Sensitization

As explained above, chronic pain is largely a hyper-reactive nervous system. Mindfulness trains the brain to: 

• Stop reacting automatically to every bodily sensation
• Avoid linking physical sensations with immediate threat
• Stop feeding pain with fear and tension

➡ The brain gradually transitions from an "alarm" state back into a "safety" state. 

Attention Training Alters What the Brain Considers Important

The brain does not produce pain because "something is broken," but because it allocates too much attention to the painful signal. Mindfulness teaches you to:

• Shift attention away from pain to neutral bodily sensations
• Disregard automatic catastrophic thoughts
• Perceive pain as one piece of information among many, rather than the dominant signal

➡ Pain loses its "high priority" status within the brain. 

Mindfulness Lowers Activity in the Brain's Threat Centers

Chronic pain is tightly intertwined with: 

• The amygdala (fear)
• The insula (perception of internal bodily signals)
• The ACC center (the emotional dimension of pain)

Mindfulness has been proven to decrease baseline activity in these specific areas. ➡ The brain stops evaluating pain as an immediate danger. 

It Teaches the Brain to Distinguish Between "Pain" and "Suffering"

Pain = a bodily signal | Suffering = the brain's emotional reaction to that signal 

Mindfulness decouples these two distinct layers: 

• The raw physical pain may remain present
• But the brain stops adding layers of fear, tension, and catastrophizing

➡ The patient experiences significantly less suffering, even if the baseline pain does not completely vanish. Mindfulness Alters Brain PredictionsChronic pain is largely a prediction error—the brain anticipates pain, and so it generates it. [1]Mindfulness:

• Slows down automatic predictive loops
• Teaches the brain to react to the actual current state of the body, not to expectations
• Reduces anticipatory anxiety

➡ The brain stops "forecasting" pain.

Neuroplasticity: The Brain Physically Changes

Long-term mindfulness practice structurally leads to: 

• Thickening of the prefrontal cortex (enhanced pain regulation)
• Sinking volume of the amygdala (less fear reactivity)
• Structural adjustments in the insula (more realistic body perception)
• Reduced rumination—the patient dwells far less on the pain

➡ The brain becomes structurally less pain-prone. 

PHYSIOTHERAPY AND CHRONIC PAIN

Physiotherapy focused on graded loading in chronic pain management. Chronic pain is not just an issue within local tissues. It is an altered state of the nervous system, where the brain: 

• Overestimates potential threat
• Predicts pain even during entirely safe movements
• Generates protective muscle guarding and tension
• Sustains pain even after the tissue has fully healed

Graded loading is a method designed to teach the brain that movement is fundamentally safe, thereby suppressing pain activation.

How Graded Loading Rewires the Brain

Rewriting Brain Predictions

In chronic pain, the brain frequently anticipates pain, which causes it to generate it. When a patient repeatedly performs safe, controlled movements, the brain updates its baseline prediction: "This movement is not a threat → I do not need to produce pain." 

Reducing Kinesiophobia (Fear of Movement)

Fear of pain stands as one of the strongest predictors of chronification. Graded loading:

• Shatters the debilitating cycle of fear → avoidance → deconditioning → more pain
• Reassures the patient that moving is entirely safe
• Reduces hypervigilance toward subtle bodily sensations

➡ The brain stops responding with an emergency alarm.

Dampening Central Sensitization

Repeated safe movements Structurally:

• Decrease hyper-activation in the insula and ACC
• Bolster inhibitory descending control from the prefrontal cortex
• Normalize corrupted somatosensory maps
• Restrain over-activation of the sympathetic nervous system

➡ The entire nervous system becomes fundamentally less hypersensitive. 

Increasing Physical Capacity Without Overloading

Tissue tolerance is systematically built up:

• Improved muscular strength
• Heightened endurance
• Better motor coordination
• Dissolution of chronic protective muscle guarding

➡ The physical body grows more resilient and far less reactive. 

What Graded Loading Looks Like in Practice

Establishing the Baseline
The physiotherapist determines a workload level that the patient can complete without a significant flare-up (e.g., 5–10 minutes of walking, 3 squats, or a 2-minute hold).

Progressive Increments
The load is increased by small, pre-determined steps, independent of daily pain fluctuations. For instance:

• +10% time duration
• +1 repetition
• +1 kg of resistance
• +1 minute of steady walking

Focusing on Safety, Not Pure Performance: The primary goal is not to "push through the pain," but rather to train the brain to respond calmly and safely. Exposure to Feared Movements: For example: forward bending, rotation, running, or lifting objects.
➡ The brain learns that these movements do not represent a threat. 

Calming the Nervous System
This incorporates: breathwork, mindfulness, attention management, and direct pain education.
➡ The brain learns to stop triggering the emergency alarm. 

What the Research Says

Graded activity and graded exposure successfully reduce pain intensities, structural disability, and kinesiophobia.
The overall effect is exponentially stronger when combined with pain neuroscience education and mindfulness.
These changes are visible on fMRI (functional magnetic resonance imaging) scans—showing noticeably less active threat centers and significantly more active prefrontal regulation. 

Cognitive-Behavioral Therapy for Chronic Pain

Cognitive-Behavioral Therapy (CBT) stands as one of the most thoroughly researched and effective approaches for chronic pain management. It does not treat pain as an imaginary "psychological issue," but rather as a complex neurobiological state that is heavily influenced by how the brain evaluates, predicts, and regulates incoming somatic signals. 

Shifting the Relationship Between Thoughts, Emotions, and Pain

Chronic pain is powerfully driven by:

• Catastrophizing ("Something is structurally wrong with me")
• Hypervigilance (obsessive scanning of bodily sensations)
• Kinesiophobia (fear of movement)
• Negative baseline expectations

CBT trains the brain to identify and rewrite these malicious loops, leading to a direct down-regulation of threat centers located within the limbic system. 

Dismantling Catastrophizing—The Engine of Chronic Pain

Catastrophizing is the absolute strongest predictor of:

• Heightened pain intensity
• Functional disability
• Long-term chronification

CBT systematically teaches:

• Objective, realistic evaluation of bodily signals
• Decoupling raw physical sensations from catastrophic mental scenarios
• Replacing automated panic thoughts with adaptive alternatives

➡ The brain stops amplifying and broadcasting the pain signal.

Breaking Through Kinesiophobia (Fear of Movement)

Fear of pain causes avoidance behaviors, which breed muscle deconditioning, leading directly to a higher pain load. CBT shatters this destructive cycle through: 

• Gradual exposure to movement
• Deconstructing outdated beliefs about bodily tissue damage
• Cultivating strong self-efficacy

➡ The brain relearns that movement is fundamentally safe. 

Shifting Attention—From Hypervigilance to Cognitive Flexibility

Durable chronic pain frequently forces a patient into:

• Obsessive bodily scanning and monitoring
• Constant attentional focus locked onto pain
• Pervasive anticipatory anxiety

CBT explicitly trains:

• Conscious redirection of attentional assets
• Mindful awareness devoid of immediate emotional judgment
• The mental capacity to gently "let the pain be"

➡ Pain systematically loses its absolute priority status inside the brain. 

Boosting Self-Efficacy and Active Control Over Pain

The patient realizes they can directly influence their pain state, ceasing to be merely a passive victim of chronic pain. By mastering cognitive tools, they learn to modulate pain through targeted activation of the prefrontal cortex. 

Enhancing Stress Regulation and the Autonomic Nervous System

Chronic pain syndromes are consistently linked with: 

• An over-activated sympathetic branch
• Elevated baseline muscle tension
• Severely fractured sleep architecture

CBT deploys:

• Therapeutic breathing techniques
• Systematic relaxation training
• Integrated mindfulness components

➡ The central nervous system successfully steps out of chronic "fight or flight" mode. 

Neurobiological Advancements Verified by Scientific Data

fMRI research clearly indicates that CBT: 

• Lowers metabolic activity in the insula, ACC, and amygdala
• Elevates functional output in the prefrontal cortex
• Normalizes warped somatosensory maps
• Decreases over-activation in the default mode network (fewer rumination cycles)

➡ The brain fundamentally learns to stop generating pain.

What Clinical Trials Indicate

CBT for chronic pain conditions:

• Lowers subjective pain score intensity by 20–40%
• Substantially diminishes overall functional disability
• Measurably upgrades overall quality of life
• Reduces daily reliance on pharmaceutical analgesics
• Delivers long-term lasting effects spanning months to years

It is officially recommended in all major international guidelines (NICE, CDC, EFIC). 

NEUROMODULATION TECHNIQUES IN CHRONIC PAIN MANAGEMENT

Neuromodulation methods represent one of the most critical frontiers in modern chronic pain treatment. Rather than merely masking symptoms, they directly interface with the nervous system, which is actively generating, maintaining, or amplifying the pain.

Peripheral Neuromodulation—TENS and Related Modalities

• TENS stands as the most widely deployed neuromodulation tool in clinical outpatient practices. 

How It Works:

• It activates thick Aβ sensory fibers, which directly inhibit pain transmission within the dorsal horn of the spinal cord (Gate Control Theory).
• It triggers the systemic release of endogenous endorphins and enkephalins.
• Regular use helps down-regulate central sensitization over time. 

When It Helps:

• Musculoskeletal pain
• Neuropathic pain states
• Postoperative pain management
• General spinal, neck, and joint pain

Why It Excels in Chronic Pain:

TENS does not train the brain to permanently shut down pain, but it dampens the incoming signal volume reaching central structures, leaving the brain with less "raw material" to construct pain predictions. 

• Spinal Cord Neuromodulation—Spinal Cord Stimulation (SCS)
  Surgically implanted electrodes deliver precise stimulation to the posterior columns of the spinal cord. 

Mechanism:

• Direct inhibition of nociceptive pathways in the dorsal horns
• Activation of endogenous descending inhibitory pathways
• Reshaping functional connectivity between the cord and cortical pain networks

Clinical Indications:

• FBSS (Failed Back Surgery Syndrome)
• Intractable radiculopathy
• CRPS (Complex Regional Pain Syndrome)
• Severe peripheral neuropathies
• Chronic ischemic pain conditions

Therapeutic Effect:

SCS stands out as one of the most powerful interventions available for refractory neuropathic pain states. 

Brain neuromodulation – non-invasive brain stimulation

rTMS – repetitive transcranial magnetic stimulation
Magnetic pulses stimulate specific areas of the brain, most commonly M1 (motor cortex).

Mechanism:

• modulation of cortical excitability
• activation of descending inhibitory pathways
• decreased activity of the insula and ACC
• altered functional connectivity of the DMN

Indications:

• neuropathic pain
• fibromyalgia
• central post-stroke pain
• pain following spinal cord injury

¨

tDCS – Transcranial direct current stimulation
A weak electrical current alters the excitability of neurons.

Mechanism:

• enhancement of prefrontal pain control
• reduction of emotional amplification of pain
• influence on neuroplasticity

Indications:

• fibromyalgia
• chronic back pain
• neuropathic pain

Invasive brain neuromodulation

• DBS – deep brain stimulation

Used only for extremely refractory pain; target structures include the periaqueductal gray, periventricular gray matter, or thalamus. The mechanism involves influencing endogenous opioid systems and thalamocortical circuits that convey pain information to deep brain structures.

High-inductive pulsed magnetotherapy
Sometimes designated by the abbreviations HITS, rPMS, or super-inductive therapy, it generates powerful magnetic pulses that penetrate deep into tissues and directly depolarize nerve fibers.

Why it is classified as neuromodulation:

• affects peripheral nerves (altered excitability)
• affects spinal circuits (inhibition of nociception, facilitation of motor functions)
• alters cortical excitability (similarly to rTMS, but less targeted)
• reduces central sensitization
• modulates descending inhibitory pathways

➡️ The mechanism is clearly neuromodulatory – it alters the activity of the nervous system.

Clinical applications:

• chronic back pain
• neuropathic pain
• myofascial pain
• spasticity
• postoperative pain

Efficacy in musculoskeletal pain
Most studies focus on:

• lower back pain
• cervical spine
• shoulder
• myofascial pain
• postoperative pain

Results:

• significant reduction in pain compared to placebo
• improvement in function
• the effect often persists for weeks to months
• better results in acute/subacute conditions, but efficacy is also shown in chronic pain

➡️ For musculoskeletal pain, the evidence is moderate to strong.

Efficacy in neuropathic pain
Studies in radiculopathy, diabetic neuropathy, postoperative neuropathic pain.
CRPS (Complex Regional Pain Syndrome) – limited but promising results.

Results:

• reduction of neuropathic pain (burning sensations, electric shocks)
• improvement in sensitivity
• reduction of allodynia

➡️ The evidence is moderate but growing. The results are superior to classical low-frequency magnetotherapy!

Effects on muscle tone and motor function
rPMS is also utilized in neurology for:

• spasticity after stroke
• spasticity in cerebral palsy
• Parkinson's disease
• multiple sclerosis

Results:

• reduction of spasticity (measured by MAS)
• improvement in motor control
• improvement in gait and limb function

➡️ The evidence is moderate but consistent.

Mechanisms confirmed by studies
Studies show that rPMS:

• depolarizes peripheral nerves
• modulates spinal reflex circuits
• reduces the activity of nociceptive pathways
• increases descending pain inhibition
• alters cortical excitability (similarly to rTMS, but less targeted)
• reduces central sensitization

➡️ This is why rPMS is classified among neuromodulatory techniques.

How strong is the overall evidence?

Strong evidence:

• back pain
• cervical spine pain
• myofascial pain
• spasticity

Moderate evidence:

• neuropathic pain
• postoperative pain
• functional improvement after injuries

Weaker evidence: CRPS, headaches, fibromyalgia

Safety of high-inductive pulsed magnetotherapy:
Studies confirm that this is a safe and well-tolerated physical therapy method:

• very good safety profile
• minimal side effects
• occasional fatigue, muscle soreness, transient increase in pain
• no serious complications

⭐ Take the first step toward a life with less pain.
Modern magnetotherapy Salus Talent A helps relieve chronic pain and support tissue regeneration.👉 Book magnetotherapy

How neuromodulation changes the brain in chronic pain

All techniques share common effects:

• ↓ activity of the insula (perception of bodily signals)
• ↓ activity of the ACC (emotional component of pain)
• ↓ activity of the amygdala (fear of pain)
• ↑ activity of the prefrontal cortex (cognitive control)
• ↑ descending pain inhibition
• ↓ central sensitization
• normalization of somatosensory maps

➡️ The brain learns to produce and amplify pain less.

What studies say

• TENS: effective for many types of pain, minimal risks.
• rTMS: strong evidence for neuropathic pain and fibromyalgia.
• tDCS: moderate evidence, good tolerance.
• SCS: one of the most effective methods for refractory neuropathic pain.
• DBS: reserved for extreme cases.
• High-inductive pulsed magnetotherapy (rPMS): see above.

Neuromodulatory techniques directly affect the nervous system — from the periphery to the cerebral cortex — thereby reducing pain, central sensitization, and the emotional component of pain.

Are you suffering from chronic spinal pain? Trigeminal neuralgia or polyneuropathy?
👉 Book an examination.

In conclusion

Chronic pain is real, complex, and exhausting. It is not your fault. And you are not alone. Chronic pain occurs when the nervous system switches into a state of hypersensitivity, brain circuits alter, and the pain begins to maintain itself for no reason.If pain lasts longer than three months or worsens, it is important to consult a physician or a pain specialist – an algesiologist (typically a pain management center or clinic). They can help find a combination of approaches to provide relief. In my practice, I very frequently encounter chronic pain, not only in patients with spinal diseases but also in other conditions accompanied by chronic pain. One of the options for pharmacological treatment is the prescription of medical cannabis.

MUDr. Petra Mištríková, MBA

FAQ

References:

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Zhimin Huang, Ying Wang, Yongxing Yan, Ying Liu, Jielin Chen, Huili Liu, Jie Li, Zhongming Gao, Xianwei Che, Identifying neural circuitry abnormalities in neuropathic pain with transcranial magnetic stimulation and electroencephalogram co-registration, Neurotherapeutics, Volume 22, Issue 2, 2025, e00496, ISSN 1878-7479, https://doi.org/10.1016/j.neurot.2024.e00496. https://www.sciencedirect.com/science/article/pii/S1878747924001831

Iwatsuki K, Hoshiyama M, Yoshida A, Uemura JI, Hoshino A, Morikawa I, Nakagawa Y, Hirata H. Chronic pain-related cortical neural activity in patients with complex regional pain syndrome. IBRO Neurosci Rep. 2021 May 13;10:208-215. doi: 10.1016/j.ibneur.2021.05.001. PMID: 34095892; PMCID: PMC8167223.

Delon-Martin C, Lefaucheur J, Hodaj E ...Neural Correlates of Pain-Autonomic Coupling in Patients With Complex Regional Pain Syndrome Treated by Repetitive Transcranial Magnetic Stimulation of the Motor CortexNeuromodulation, 2023; 27, 188-199

Zhu Z, Xie L, Mao Y, Fan Y, Huang C, Zhu Z and Song N (2026) The effect of different transcranial magnetic stimulation protocols on pain scores in patients with neuropathic pain: a systematic review and meta-analysis. Front. Psychiatry 17:1822963. doi: 10.3389/fpsyt.2026.1822963

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