PARIS SCIENCES & LETTRES (PSL)
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How can we know whether premature babies feel pain?

In recent decades, scientific advances have shaken most of our knowledge about premature babies. A better understanding of epigenetic phenomena has allowed us to identify the long-term impact of what they experience in their first weeks of life and, in particular, of pain. But how is this pain to be identified, how is it to be measured, when the signals that transmit the pain are not yet being processed by the brain?

16
January 2018
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lire en français
Executive Summary

Neonatal medicine has progressed a great deal since the 1960s, and some of these advances have opened up very different representations from those we had before. Pain is now known to have long-term effects on the development of the central nervous system. This also affects longevity. What happens in the first few weeks of a premature baby's life can therefore have a long-term impact. In premature babies, even at 35 weeks, the pain control system is completely immature: the nerve signals are sent, but they are not treated in the brain. Premature babies cannot therefore fully perceive, let alone express, their pain. Measuring this pain is therefore crucial. The incubator of the future will include thermal cameras capable of detecting the signals associated with it.

Paris Innovation Review – Among many other projects, you are working on the incubator of the future. Is this a simple matter of technology?

François Jouen – No, of course not, because the essential element in an incubator is the baby. Now, the motivation behind work on the incubator of the future is, in the first place, the fact that neonatal medicine has made a lot of progress since the 1960s and these advances are leading to representations that are very different than those we had previously.

One of the problems on which we are working at the moment is how to measure pain in premature babies. It is an important point, even a crucial one. What is at issue here is not merely wellbeing. We now know that pain has long-term effects on the development of the central nervous system. And this also has an impact on longevity. Repeated painful stress results in a decrease in the size of the babies’ telomeres – the small pieces of DNA located on the chromosomes. Now, the shorter your telomeres are, the shorter is your life expectancy as well. The length of the telomeres is an indicator of the possible longevity of an individual. We are speaking here of epigenetic phenomena: environmental effects can modify how the gene gets expressed.

Without going into the details, what transpires in the first weeks of the life of a premature baby can thus have very long-term effects.

It is with these issues in mind that pediatricians asked us to work on measuring pain. They currently use systems based on behavioral reactions of an emotional type: systems that work well starting from 35 weeks, when the baby gives a virtually complete response, but not on a baby who was born at 29 weeks. At 35 weeks, when we prick the heel with a needle, we observe motor reactions: furrowing of the brow, squinting, amplification of the naso-labial folds, opening of the mouth, etc.  But the lower the age, the less motor reaction there is, and there is none in a premature baby of 25 weeks.

Pain is a construct of the brain.

Pain is a construct of the brain. There are receptors, but it is the brain that is going to process the information. The systems that transmit nerve impulses appear extremely early in embryonic development. There is discussion in the literature, but around 12 to 20 weeks, the nervous system is already transmitting nociceptive impulses to the brain. The latter is simply not yet able to process this information. In premature babies, including at 35 weeks, the system for controlling pain is totally immature. In us, the interneurons will limit the transmission of nerve impulses at the peripheral level. But this system of regulation does not work in premature babies.

Now, as for the pain “signal,” it is indeed sent by the nervous system. Firstly, these children have hyperalgesia, and, secondly, they are going to experience painful events almost constantly as part of their care: for example, their skin is very immature. Even just to wash a baby is painful for the child. As a consequence, opioid derivatives are going to be used that are administered almost non-stop: to such an extent that when you have children that have spent several weeks in intensive care, you have to have them undergo a sort of detox treatment when they are discharged.

Let us come back to the question of pain. How can it be measured, when it does not yet exist as such at the level of the brain?

To respond to this question, I had a simple, but somewhat risky, idea, which has given rise to a project financed by the National Research Agency (ANR). I am trained as a psycho-physiologist, and I took up a point that we were taught during our studies: when you study the localization of the central nervous system, the nociceptive pathways (the transmission of pain) and the thermal pathways are nearly the same. Why not use a thermal imaging camera? Originally, we wanted to develop an ad hoc camera together with engineers; but, in the end, we gave up the idea, because it is complicated and expensive. We found a small camera manufactured by German engineers in a company that develops technical products. The camera has interesting characteristics both with respect to the thermal aspect and by virtue of its size: 4 x 4 cm, which is ideal for putting in an incubator.

By introducing this camera in an incubator, one is going to obtain thermal images that can be processed. We have devised algorithms for retrieving the face of the baby and for not getting the hand of the nurse when she intervenes in the incubator, etc.  The system is not yet sufficiently developed to be patentable. We are in the process of setting up a start-up with a student of Ecole Normale Supérieure - PSL, and we might integrate certain elements of this project into it.

The image processing is supplemented by mathematical approaches. By using different systems of image processing and classification, we are able to identify when the babies are experiencing painful states in 98% of the cases: including among those born at 25 weeks.  We still need to quantify these states. For that, we need indicators that allow us to construct gradients.

Heat is not the only indicator: at the same time, we record the heart rate, the rate of respiration, etc. But the thermal element has a great deal to teach us and certain aspects have been well documented. There have been studies in veterinary medicine on horses in Normandy, because there are large breeding facilities and important economic stakes can sometimes be involved in the good health of a thoroughbred.  Human medicine has also worked on these questions. What do we learn from all these studies? When there is a painful situation, we observe an asymmetry of thermal gradients on each bodily emission. This asymmetry is easy to detect and it allows us, for example, to measure pain in patients suffering from cerebral palsy. These are children who, in general, are in a painful state all the time and who have difficulty expressing their pain: when they are lying down, you take their temperature at the level of the soles of their feet and if there is a differential, there is pain. (When you are in a state of equilibrium, there is no difference.)

For premature babies, we focused on the face. This is for two reasons: the first reason is that the children have hypothermia. Hence, they are dressed and one cannot undress them to measure temperature over the whole body. The second reason is that I read a paper some thirty years ago, which was published by a Japanese team that had done a nice experiment.  It is known that, culturally, the Japanese express very little emotion. In the experiment, one made people listen to a soundtrack with traumatic situations (a bit like in a horror film) and the subjects did not budge one iota. But if you placed a thermal imaging camera at the level of their faces, you could see that they were reacting. Hence, the idea of focusing on the face.

In order to choose the right parameters, we measured a lot of different things. The most interesting indicator is the variation between the thermal minimum and the thermal maximum obtained. The typical example is a very simple medical procedure. A venipuncture is done in the wrist and the thermal differences can be seen: the needle going in hurts, but not the venipuncture. This is relatively stable from one individual to another. It is the most reliable indicator and it has oscillating properties that are a little different.

Whatever the indicators chosen, such a measure is, by definition, relative. Is it not, then, necessary to concentrate on the variations in one and the same subject?

Yes, of course. What is interesting here is to do time-frequency: to obtain a measure of energy as a function of time.

To do this, various mathematical tools are used. The most common is Fourier's spectral analysis. A temporal series is a signal that evolves as a function of time, and these signals have a periodic function. Fourier's decomposition is a decomposition of the signal into a series of periods in such a way as to extract the basic frequency and the harmonics from them. It is frequently used in acoustics or for images. It is a very good tool, except for the fact that it reduces everything to a single measure: it does not take into account the modification of the frequential content of the response over time. By contrast, in using what are called time-frequency algorithms – based, for example, on the wavelets of Haar – we are able to reconstruct the energy representation of the signal as a function of time. One is going to be able to use this idea to have a system of automatic identification of painful states. This is what we are in the process of doing with a student of the École Normale Supérieure - PSL who will be contributing his mathematical skills to the project.

Is work also being done with clinical teams: both to gather their experiences and to test modifications in forms of care, for example?

Yes. For example, we are working with three hospital facilities: one in Caen, and Necker and Trousseau in Paris. All these facilities are very attentive to the care they give to babies.  And we have learned a lot on the subject over the course of time. When I started, at the end of the 1970s, babies in incubators were exposed to light 24 hours a day. This has two consequences: the first is that the visual system of the premature baby is ahead of its level of development. So, the exposure to light is not optimal. Toward the end of the pregnancy, the baby sees in the uterus, but the uterus serves as a protective filter. This is very important, because the visual experience that the baby is going to have in utero allows for the stabilization of the neural networks that will be used when the baby is born.  And the second consequence is that if you put children under neon lights 24 hours a day, there is no opportunity for the alternation wakefulness/sleep to be constructed. There has been a lot of interest in this. Articles were published, and nowadays it has entered into the practice of pediatric units: they put covering systems over the incubators.

This is an avenue to be pursued for the incubator of the future: it will not only be capable of perceiving and measuring pain; it will also allow the light environment to be managed in a much more precise fashion. The technologies mobilized can come from very different sectors: we are working with the department of mechatronics of Mines ParisTech - PSL. Together with the Saint-Gobain group, they have developed innovative windows for the automobile industry, which become opaque when you press on them.

The incubator of the future, you see, incorporates technology, but also clinical knowledge, biology, anatomy, mathematics... With, at the heart of it all, an attention to what is human: to a fragile humanity, which has not yet achieved speech, which has not even achieved consciousness of pain.

The new attention being paid to pain, and to what transpires in premature babies, bears on societal issues.

Certainly. Representations are evolving. Pain in the little baby has always been denied. Up until the beginning of the 1970s, cardiac surgery on premature babies could be done without anesthesia. Not out of cruelty or indifference, but because the physiological model that we had at the time said that there was no transmission of nerve impulses. It was thought that to feel pain, there has to be thalamo-cortical connection: a connection between a sub-cortical structure – an integrative structure and transmission path for sensory and motor impulses – and the cortex, which has an integrative function.

For a change in approach, we had to wait until the 1990s and findings coming out of the neurosciences. Studies on the newborn, the premature baby and the embryo demonstrated the early existence, in the development of the embryo, of a system of consciousness of having a body in space. The thalamic precursors, in particular, appear extremely early on: the thalamo-cortical connections get established in utero starting at 12 weeks.

It is interesting to think about this from a societal point of view: In France and numerous other countries, 14 weeks is the legal age-limit for interrupting a pregnancy. On the basis of these discoveries, one wonders if it is not necessary to lower it a bit. But this raises other problems: notably, that of the detection of a pregnancy, of the time required for making a decision... These are sensitive points: there is no question of forgetting that the right to an abortion was an important societal achievement and that it has to be possible to exercise a right in practice, if it is not to remain a dead letter. But, on the other hand, we cannot rationally consider issues without taking into account how knowledge has evolved.  In order to be able to treat these questions dispassionately, the wisest course is, firstly, to bring about dialogue between the disciplines. A symposium on “Law and Consciousness” was recently organized by our research group at the Cité des Sciences. The aim was to bring about a discussion between jurists and scholars on a sensitive question: When does one become a legal subject? And what constitutes a legal subject? A single discipline cannot answer this question. But it cannot avoid the debate.

François Jouen
Senior Researcher, Human and Articial Cognition lab, EPHE - PSL