(ORDO NEWS) — There is such a well-known neurophysiological experiment: two small pieces of metal, about a centimeter in length, are applied to neighboring areas of the skin.
One piece is cold (20 degrees), the other is warm (40 degrees). What will the subject feel: warm or cold? Neither: he will feel pain. Let’s talk about where it comes from.
From the point of view of sensitive neurons, pain is an impact that threatens the existence of cells. There are three types of nociceptors (pain receptors) in humans:
- Mechanical react to too much stretching or excessive pressure. Moreover, the impact can be both external and internal – both a needle prick and bladder tension will be a cause for alarm.
- Temperature react to temperatures below 15 degrees Celsius and above 45 (the discovery of one of these receptors in 2021 was awarded the Nobel Prize, our text “Award for well-being” is about this).
- Chemicals respond to exposure to dangerous chemicals like acids.
The signal from the excited receptors goes to the center of pain – a cluster of neurons that permeates the posterior horns of the spinal cord from top to bottom. This center is directly connected with two parts of the brain.
One path from the center of pain goes to the limbic system, which is responsible for our emotions – and when the signal reaches it, we experience pain. The other path stretches into the neocortex, into the zones responsible for the body schema, so the brain determines where it hurts.
This is how the pain signal travels through the nervous system
The task of the pain center is to “decide” on the basis of the signals coming to it from the receptors whether to hurt – that is, to send the appropriate signal to the brain or not. He takes the decision as follows: if the strength of the input signals exceeds the threshold of his excitability, then the center generates a pain impulse.
The pain center receives signals not only from pain receptors. Tactile and temperature receptors also pull their fibers to it. True, they have less “strength”: a signal given to the pain input will easily cause excitation in the center, while normal tactile stimuli do not normally lead to this.
In addition, so that the pain center does not constantly panic, the pain system also sends signals to it. Fibers from the raphe nuclei and the periaqueductal gray matter, which are located in the brain stem, come to the center of pain.
They transmit their signals through the mediators serotonin, enkephalins and endorphins. The latter belong to the class of endogenous opioids – therefore, artificial analogues of these neurotransmitters are the strongest painkillers and drugs, such as opium, morphine or heroin.
The pain centers of the spinal cord are only the lowest (however, the most studied, especially from a molecular point of view) level of the so-called pain matrix.
The upper ones are already in the brain: among them are the reticular formation, the thalamus, the periaqueductal gray matter, the insula, the cingulate gyrus, and the somatosensory cortex.
There is a hierarchy between them (although not quite linear), that is, senior structures can either block signals “from below” or give them a further move.
It turns out that the pain that we feel from an injection or a hot iron is a signal that has been verified several times, refined and endorsed by a dozen instances within the nervous system.
Pain in nothing
The complex hierarchy of the pain matrix is designed to cut off unnecessary stimuli and not raise the alarm over trifles.
That is why, for example, we do not feel how our internal organs are constantly contracting, stretching and pressing on each other. But sometimes the system fails: then even a slight prick with a needle responds with unbearable pain. This condition is called hyperalgesia.
It also happens that a deliberately non-painful stimulus, like stroking with a cotton swab, causes pain. This is allodynia.
In both cases – and also in the story with hot and cold metal plates above – the same mechanism works. The cause of pain here is not in the receptors, but in the information processing center, so the mechanism is called central sensitization.
Sensitization is an increase in the sensitivity of neurons in some part of the brain. In other words, the threshold of excitability decreases: neurons that make a “decision about pain” are more easily excited. And the reasons for this sensitivity may be different.
Hyperalgesia and allodynia are different forms of abnormal response to a stimulus
Several neurons in the center of pain may “break” or simply several synapses through which a pain signal comes to these neurons.
Sometimes this breakdown is congenital: a mutation in a gene leads to the incorrect formation of the corresponding protein (for example, a cell receptor), and therefore the synapse does not work properly. In this case, a person from birth is predisposed to causeless pain.
Sometimes this breakdown is provoked by some kind of toxin. For example, in an experiment, scientists can sensitize pain neurons in the spinal cord of a rat by injecting formalin under the skin.
But more often than not, neurons become too sensitive because they are constantly bombarded with pain signals for hours or days on end.
Continuous stimulation changes gene expression in neurons, and cells begin to overproduce ion channel and receptor proteins – both for pain signals (like TRPV1) and in order to continue to adjust to the intensity of impulses (the NMDA receptor is responsible for this).
And the more “receivers” for the signal on the neuron membrane, the easier it reacts to it, that is, the more excitable it becomes. And such an attack of hypersensitivity can happen to a neuron at any level of the pain matrix, either in the spinal cord or in the brain.
Another reason for sensitization may not be a point breakdown, but a violation in the very structure of the neural circuit. For example, if the pain inhibition system does not work, which normally suppresses the activity of pain centers.
The less inhibitory signals the pain center receives, the easier it is excited – which means that the weaker pain impulse gets a chance to slip through it upward, into consciousness. Something similar happens during drug withdrawal: inveterate “users” have their own pain control system is unnecessary and ceases to produce opioids.
When the drug in the body ends, there is no one to block the extra impulses – and the person begins to feel pain even from the internal organs, which he normally never experienced.
Approximately according to this principle, pain arises from two metal plates of different temperatures (this is called a thermal grill illusion).
Grill illusion plate, temperature measured with an infrared camera. A – hot stimulus, B – cold stimulus, C – mixture of stimuli, D – control stimulus
Imagine for a start that only a cold plate is applied to the skin. Cold simultaneously excites both ordinary cold receptors and pain receptors. Signals from them go to the brain along two parallel paths.
The non-pain signal comes to the insula (a small area of the cortex approximately in the region of the temple), the pain signal comes to the cingulate gyrus (an extensive area of the cortex that runs from the front to the back of the head).
But there is one caveat: the insula is connected to the cingulate gyrus by inhibitory fibers, and when it is excited, we do not feel any pain.
But now there are two plates: cold and warm. The signals of cold and heat meet at the level of the spinal cord and cancel each other out. Therefore, the brain does not receive any temperature signal, and the islet is not excited.
But the pain pathway works, as before, stimulating the cingulate gyrus, and there is no one to slow it down. That’s where the pain comes from.
Phantom pains are arranged in a similar way – when a person has pain, for example, an amputated arm. Along with the loss of a hand, the body also loses signals from its non-painful receptors, tactile and temperature.
The pain center lacks inhibitory signals, and it becomes much easier to excite it. As a result, phantom pains can appear not only in those who have lost any part of the body, but also in people who were completely born without one or another limb.
In this sense, it is not so important whether the arm or leg is in place, it is only important whether the center of pain in the spinal cord is in place, and whether there is someone to slow it down in time.
Not everyone has to face the grill illusion in life, but the pain “out of nowhere” is a much more common phenomenon. According to some estimates, up to 40 percent of people on the planet suffer from chronic pain.
There may be more, but doctors tend to underestimate the strength of the sensations in such patients because the apparent cause, even if there is one, is usually clearly out of proportion to the degree of their complaints. To make this diagnosis, one has to find a way to measure its strength.
Relying on the words of the patients themselves is inconvenient, and various mechanical tests come to the rescue.
For example, a patient is tested with vibration, temperature stimuli, and electrical impulses of varying frequencies, and assesses not only how he describes his feelings, but also non-verbal responses, such as how much he withdraws his hand.
Such a quantitative sensory test determines hyperalgesia and allodynia, which are just characteristic of central sensitization, as well as their severity.
Quantitative Sensory Test Kit: Patients are asked to rate the degree of pain of each stimulus and describe what kind of pain they are experiencing
There is another common way to assess chronic pain, which is called the conditional pain modulation method. It is based on the fact that one painful stimulus can activate the inhibitory centers of the nervous system and thereby weaken another stimulus.
Therefore, you can apply a heated iron stick to the patient’s skin and ask him to evaluate how much this exposure relieves the chronic pain that he feels. The hotter the rod is needed for such anesthesia, the stronger the inhibition is needed for the pain centers and, consequently, the higher their excitability.
In some patients, chronic pain cannot be alleviated in this way at all, because the inhibitory connections of the pain centers are broken. But even if the doctors are convinced that the patient is really in pain, finding a breakdown in the pain signaling system is not easy.
It is believed that most often chronic pain occurs on the basis of ordinary pain, which does not go away for a long time. A striking and common example is osteoarthritis, a joint disease associated with the destruction of cartilage tissue.
Frequent pain impulses lower the threshold of excitability of the pain center, and he begins to worry about any movement of the limb. And although the damage, it would seem, is obvious, the pain is often incommensurable with the pathological process that causes it.
In these patients, areas of the brain associated with the perception of pain and the generation of emotions, fMRI shows excessive arousal. And for some, pain persists even after the damaged joint has been replaced with an artificial one – although it would seem that there is nothing more to hurt.
It also happens that the pain arises literally from scratch – as with fibromyalgia, which affects two to eight percent of people on Earth. This disease has many other signs: sleep problems, fatigue and depression, but the main one is muscle and bone pain throughout the body, usually symmetrical.
At the same time, doctors do not find any inflammatory processes, so fibromyalgia was previously considered a mental disorder.
But now it turns out that patients with fibromyalgia do indeed have decreased neuronal thresholds in the areas of the brain responsible for the perception of pain, and on fMRI they show excessive arousal. Moreover, NMDA receptors, which cause neurons to respond more acutely to pain, have been shown to malfunction in this disease.
Where the cause is and where the effect is is unclear, but it is clear that the problem is not only in individual neurons.
Scientists also found systemic disorders in patients – in the work of structures that are associated with inhibition of pain centers. And this also applies to arthrosis, and fibromyalgia, and phantom pain, and other diseases associated with central sensitization – and there are more than a dozen of them, including postoperative pain and migraine.
But from the fact that we find the causes of causeless pain one after another, it does not become clearer how to treat it.
How to calm the phantom
In the case of ordinary pain, everything is approximately clear. It is enough to remove the source of pain – say, to heal the wound on the finger – and the problem is solved. If this does not help, you can slow down the pain centers, for example, with the help of opioids.
But their effectiveness against chronic pain is not too high. Since chronic pain is a failure in the system, and even a very complex system, in order to get rid of it, you need to force the system to fix itself.
You can go through the human pain system and force it to slow down the pain matrix. Various psychological techniques such as hypnosis and meditation rely on this. They are designed to stimulate the areas of the cortex that are responsible for emotions – so that they suppress the activity of underlying structures.
Indeed, in experiments with hypnosis and meditation, the subjects changed the activity of the thalamus, insula, and cingulate gyrus, according to fMRI and EEG.
At the same time, hypnosis has shown high efficiency in the treatment of chronic pain: up to 30 percent for chronic pain with spinal injuries and up to 60 percent for phantom pain.
Another way to beat chronic pain is to shift the attention of the nervous system to something else. This is probably how non-invasive brain stimulation can work. There are two main methods: micropolarization and magnetic transcranial stimulation.
The essence of both lies in the fact that a weak alternating current acts on the brain, which makes it possible to lower or increase the activation thresholds of neurons in the stimulated areas. Studies have shown that such methods are quite effective in relieving some types of chronic pain, although the improvements were short-term.
Interestingly, stimulation and reduction of excitability thresholds in the neurons of the motor cortex, that is, the area that is responsible for movement, showed the greatest effectiveness against pain. Apparently, in this case, the system is distracted by an unexpected signal and forgets that
Finally, you can try to teach the system to calm itself. This is how the neurofeedback technique, one of the types of biofeedback, works.
This method is based on the assumption that a person cannot control his physiological state and the work of internal organs, since he does not have objective information about all this. But if such information is provided to him, for example, in a playful way, then he can learn to control his physiology.
Here is an example that is actively used in the training of athletes or in the rehabilitation of patients. They are put to play a computer game – racing, where the car goes faster, the slower the player’s heart beats.
At first, the player, of course, does not know what to do, and the machine turns out to be completely uncontrollable, but gradually, from session to session, he feels more and more control over it and, therefore, learns to control the work of his heart to some extent.
EEG data from a 59-year-old patient with chronic groin pain before (top) and after (bottom) neurofeedback therapy. The color shows the difference between cortical activity and control
The same can be applied to patients with chronic pain. In this case, the electrical activity of the brain or, much less frequently, fMRI is considered an objective physiological criterion.
Doctors are trying to achieve such a picture on the electroencephalogram, which is considered a sign of a calm and relaxed state. There are still few works on the effectiveness of this method, although they report some positive results.
But even here difficulties arise: neuroscientists still have a rather superficial idea of how EEG rhythms are related to specific brain functions and its physiological states.
Therefore, even in those studies where neurofeedback sessions showed a positive clinical effect, the expected pattern of changes in electrical brain activity was not always observed.
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