1 INTRODUCTION

(Hermann Handwerker)

This obituary for Erik Torejörk has been dedicated by some of his friends and pupils. It shall reflect our memories of different periods of the rich scientific life of this brilliant and warm-hearted scientist (Figure 1).

Erik Torebjörk, 1939–2021

Erik Torebjörk's scientific life has mainly been dedicated to human nociceptors, that is, the subgroup of peripheral nerve fibres dedicated to mediating the sensations of pain and itch following damaging stimuli. Fifty years ago, when Torebjörk started his work, this concept was still somewhat controversial, and in particular, nothing was known about nociceptors in human nerves. The young Erik Torebjörk, together with Rolf Hallin, inserted microelectrodes into their own skin nerves proving the existence and physiological features of human C-nociceptors. When they tried in 1970 to publish their pioneering work in Nature, the paper was rejected with the laconic comment that it is impossible to record from C-fibres. Erik and his colleague were so upset about this brusque rejection that they decided to publish their findings in a series of papers in ‘Acta Societatis Medicorum’ of their home university of Uppsala. The first publication in an internationally better known scholarly journal appeared subsequently by another group having learned the method from Erik.

He started his scientific career in the lab of Karl-Erik Hagbarth who had, together with Å. Vallbo, developed the technique of recording from single human nerve fibres with percutaneously inserted electrodes. This technique was called ‘microneurography’ to distinguish it from the electroneurography used by neurologists but also from the animal recordings from split nerve strands. At a time when no one spoke of ‘translational research’—the term was not even invented—, this was an important bridge between basic science on animals and clinical research. Around 1970, Karl-Erik Hagbarth's lab was immensely fertile. Hagbarth himself together with Å. Vallbo studied mainly myelinated muscle afferents and cutaneous mechanosensors. Gunnar Wallin who had joined the group concentrated on recordings of sympathetic efferents and in parallel, Erik Stalberg developed the method of single motor unit recordings. Erik Torbjörk was the youngest in this group of prominent researchers. He became the pioneer of human C-fibre recordings for studying peripheral pain mechanisms.

Erik got his education in medicine at the Karolinska Institute 1959–61 and at the University of Umea 1961–67. He started his postgraduate work in Hagbarth's group in Uppsala 1968 and his PhD thesis, accepted in 1974, was rewarded with the highest grade possible. He was appointed consultant in Clinical Neurophysiology at the University Hospital of Uppsala 1974–81 and became Associate Professor of Clinical Neurophysiology. In 1988, he was awarded with a personal chair as Professor of Clinical Pain Research.

During his scientific career he became part time visiting professor at important medical schools abroad: In the United States, at the Department of Anesthesiology, Yale University, for collaboration with Robert LaMotte (1980–81) and at the Dartmouth Medical School, Hanover, New Hampshire, and at the University of Wisconsin, Madison, for collaboration with Jose Ochoa (1981–86). He was visiting Professor in Norway at the University of Bergen (1996–99), for collaboration with Rolf Moe-Nielssen and Elisabeth Ljunggren. He was also visiting Professor in Germany at the FAU Erlangen, for collaboration with Hermann Handwerker and coworkers (1993 and following years).

Among the many scientific prices and honours he received was the Max Planck Prize of the German Humboldt Foundation, 1995, for the collaboration with the Erlangen group.

He was founding member of the International Association for the Study of Pain (IASP) and the Scandinavian Association for the study of pain, the chapter of IASP.

In the late 1980s, I once had a discussion with Erik about C-fibre nociceptors in human skin nerves and the fascinating possibility to record nerve signals together with the reports of the subjects of their sensations. We were puzzled by some mismatches and speculated if our recording procedures probably could bias our experimental results. While probing the nerve with a microelectrode we used to search for single units by slightly squeezing skin folds in the search for receptive fields. This search method induced a bias in favour of mechanically excitable afferent fibres. Erik mentioned a spike collision technique he had used in the beginning of his research and called ‘falling leaf’. We decided to adapt this technique and to improve it with the advanced methods of computer-assisted recordings, which were meanwhile available. This would allow us to identify also C-fibres, which were activated by other stimuli, but not mechanically. This discussion lead to a cooperation of our groups, which is still alive among our scholars now in Oslo and Mannheim. We were able to identify new groups of nociceptor units. Martin Schmelz in his contribution to this obituary illuminates this period.

Our cooperation was strongly stimulated by our friendship and the extraordinary hospitality of Erik and his wife Birgitta, which is pictured in the following reports. When we cooperated at Uppsala, Erik had offered us generously to stay in his summerhouse at Mälaren and we could use his second car for commuting from the summerhouse to the department in the university hospital. My coworkers Martin Schmelz, Clemens Forster and Barbara Namer enjoyed the hospitality of the idyllic house at the lake. Erik is now buried nearby in the churchyard of Ytternäs Kyrka, which we always passed on our way.

I will always be grateful for Erik's deep friendship.

2 FROM POST-DOC TO LONG-LASTING COLLABORATION AND FRIENDSHIP

(Ellen Jørum)

My first meeting with Erik was in the beginning of the 1980s as a PhD student at the Institute of Neurophysiology at the University of Oslo. Following a seminar at the institute, he invited me to work with him in Uppsala. The stay in Uppsala was postponed until I had finished my PhD experiments. In 1987, I stayed at Erik's laboratory for several months, and also during several shorter stays in the period 1988-1990 (during my training as a neurologist at the National Hospital in Oslo). Finally, I had the opportunity of learning the technique of microneurography. Although technically difficult, it was fascinating. I still remember my first C-fibre recording like ‘the rising of the sun’. Microneurography was definitely the method I wished to work with! I had the chance of working with Lars Lundberg, Lis Karin Wahren also with use of quantitative sensory testing. But microneurography was the star, as used for the study of the peripheral projections of nociceptive unmyelinated axons in the human peroneal nerve and also in a study of effects of different pulse patterns on magnitude of pain by intraneural stimulation. For a lecture before my PhD dissertation in 1988, I chose the theme ‘Pain research with microneurography’; in other words, the work of Erik. He smiled when I told him and gave me all the slides. He also showed me how he kept track of all his ongoing projects, listed on sheets of papers on the back of the door to his office.

In spite of full clinical work first as a neurologist, then as a clinical neurophysiologist, the dream of an own laboratory for microneurography never faded. The technique had in the period of my clinical work and Erik's collaboration with Hermann Handwerker made headway, and it was no longer possible for one single person to perform the experiments as I had learned. I met Erik again in the late 1990s, at a meeting where we both gave talks on neuropathic pain. I ended my talk saying that we did not know the exact mechanisms in these patients. Erik approached me after the meeting and said: ‘Ellen, we have to do something about this’. We decided to revive our previous collaboration and discussed with which patients we should start. The choice was erythromelalgia (EM) (before the finding of the classical EM being mediated by a Nav 1.7 gene mutation). My PhD student Kristin Ørstavik went to Uppsala, where she collaborated with Erik, Hermann and others of the group. This was our first microneurography study on patients, with principally important findings of sensitization and spontaneous activity in Cmi fibres. It was followed by a study of patients with painful diabetic neuropathy. We were extremely careful not to harm patients and did not choose patients with high-intensity pain. Although the findings were interesting, we were disappointed since the spontaneous firing in CMi fibres did not exceed spontaneous activity in healthy elderly.

After Erik's retirement, microneurography recordings continued at the National hospital in Oslo, still in collaboration with Erik and Hermann, and also in collaboration with Martin Schmelz, Barbara Namer and Roland Schmidt who came to Oslo for some weeks each year for recordings on patients with peripheral neuropathic pain, first and foremost small fibre neuropathy and CRPS. We later returned to EM with various gene mutations in Na-channels.

I am extremely grateful for the collaboration with Erik and will honour him as the eminent researcher and the gentleman he was.

3 MY OFFERING TO THE MEMORY OF A LOVELY MAN

(Wolfgang Schady)

I first met Erik Torebjork in Professor Jose Ochoa's laboratory at Dartmouth Medical School in New Hampshire. They had embarked on a fruitful collaboration from two different backgrounds, namely the anatomical descriptive and the physiological study of the peripheral sensory nervous system. The introduction of microneurography in alert humans by Åke Vallbo and Karl Erik Hagbarth a few years earlier was a milestone that launched the career of many an aspiring neuroscientist. Erik chose C fibres as his predominant field of study, combining microneurography with intraneural microstimulation (a technique that he and Jose Ochoa developed jointly) to analyse the elements responsible for the perception of pain. When he offered me the opportunity to work towards a doctoral thesis in his department I accepted without hesitation. At that time, Uppsala was the world capital of microneurography. Karl Erik Hagbarth in proprioception, Gunnar Wallin in the sympathetic system and Erik Torebjork in pain sealed the reputation of this extraordinary department, further enhanced by Erik Stalberg's ground-breaking work in single-fibre electromyography. To work in such a setting was a young researcher's dream. Unlike the current perception of the role of science in clinical departments, the guiding principle then was that science was the first priority.

When I began working in Erik's laboratory in early 1982 I soon realised that I had fallen in the warm embrace of a mentor who was committed to ensure my welfare well beyond the call of duty. A stressed investigator was not, in his view, going to find inspiration in his work, so he made sure that the house he rented for me and my family was satisfactory, that an appropriate school for the children was found and that our finances were in good order. He even provided a car. We began to recruit students as experimental subjects in our proposed study of the projections of sensory fibres in the median nerve. The work environment was excellent, and the subjects graciously put up with my linguistic deficiencies. It was typical that the statistics tutor switched from Swedish to English on the day I joined the class. Erik oversaw my work, but I was given the freedom to pursue avenues I thought might be productive. We ended up mapping the territories of scores of mechanoreceptive afferents as well as whole fascicles, confirming the interlacing patterns that Sydney Sunderland had earlier mapped anatomically.

Throughout this time, until the completion of my thesis, Erik was like a guardian angel. He was, of course, engaged in many other projects, but he never failed to provide support when it was needed. He shared his doctorands' enthusiasms and found platforms for the presentation of their work. His lovely house by the lake at Ytter Nas was unfailingly available to his collaborators. He was warm and gentle, and I never heard him raise his voice. When I returned to the United Kingdom on completion of my thesis we kept in frequent touch, and it was an honour to have him stay with us both in London and in Madrid. He regretted, he told me, that I had pursued a clinical career rather than remaining in the world of science, but in this regard, I think he misjudged my abilities. For me, he was a role model, not least as a human being. Sadly, Parkinson's disease robbed him of his mobility but, true to character, he showed proverbial serenity during his illness, ably supported by his wife Birgitta. It is good that his last place of rest should be in the small churchyard at Ytter Nas, looking down on the lake that was the scene of so many joyful moments.

4 FRUITFUL COLLABORATION AT UPPSALA AND YALE

(Robert LaMotte)

I first met Erik at the 2nd International Symposium on Skin Senses in Tallahassee, Florida, June, 1978, He gave an exciting presentation of his use of percutaneous nerve recording to characterize the functional properties of C-polymodal nociceptors in awake humans. At that time, my new laboratory in the Dept. of Anesthesiology at Yale was investigating peripheral mechanisms of hyperalgesia (increased sensitivity) to painful heat within the area of a mild burn injury. Our approach was to combine psychophysics in humans with electrophysiological recordings from teased nerve fibres in anesthetized monkeys. Our implicit assumption was that nociceptors had similar signalling properties in monkeys and humans. Erik was instrumental in the design and implementation of a plan to dispense with this assumption and measure both pain ratings and nociceptor discharges in the awake human. Through his guidance, we gained approval to do microneurography in my lab at Yale and obtain funding from the Swedish Medical Research Council and I from my NIH grant. The experiments were rather heroic. But Erik's considerable patience and skills as a clinical neurophysiologist made them feasible: A subject's ratings of pain and evoked action potentials in a single C-polymodal nociceptive nerve fibre in the common peroneal nerve were simultaneously recorded in response to heat stimuli of different temperatures delivered before and periodically after a mild burn. Among our discoveries from Erik's recordings from humans and our recordings from monkeys in our lab (1981–82) and in collaboration with postdoctoral associates Charlie (C.J.) Robinson and Hans (J.G.) Thalhammer was that C-mechanoheat (polymodal) nociceptors in human and monkey were nearly identical in their capacities to encode the temperature of painful heat stimuli and exhibited a time course of changes in heat sensitivity that accounted for the time course of changes in pain sensitivity during the development of ‘primary’ hyperalgesia within the area of the burn injury. Erik's pioneering work furthered our understanding of pain signalling in humans and also provided support for translational studies of nociceptive pathways in nonhuman primates

Erik was very attentive and kind. While visiting, he asked our young daughters what gift he might buy them to which they replied ‘goldfish’! He went with them to the pet store where they picked three out. One of these fish lived for 15 years!

I was very fortunate to have a subsequent collaboration with Erik in the mid to late 1980s, this time taking place in his laboratory in the Dept. of Clinical Neurophysiology at University Hospital, in Uppsala. This time our focus was on the ‘secondary’ hyperalgesia to tactile and pricking mechanical stimulation of the skin that can develop in uninjured skin surrounding the site of a localized injury. Instead of an actual injury our lab had used an intradermal injection of capsaicin (algesic agent in hot peppers). Psychophysical data from humans and electrophysiological recordings from nociceptive neurons in monkey supported the hypothesis that the area of secondary hyperalgesia is due to the sensitization of mechanosensitive neurons in the spinal dorsal horn and not peripheral sensory neurons. Erik devised a clever experiment that provided direct evidence for this in human subjects during percutaneous nerve fibre recording. With Lars Lundberg, a doctoral student, it was found that intraneural electrical stimuli that evoked a pain-free sensation of touch referred to a small area on the skin was accompanied by pain when this area became hyperalgesic after a remote injection of capsaicin. The pain disappeared as the area of hyperalgesia receded. This touch evoked pain was present even when the skin was then anesthetized consistent with enhanced central neuronal excitability.

During my first visit to Uppsala in 1985, a beautiful fall turned into bitter cold in December. But Erik and Birgitta kindly included me in entertaining activities such as a visit to the opera and cross-country skiing. Unlike me, Erik was well suited to the cold; I envied the elegant and warm hat he wore, (“rat hat” because it was from the fur of a rodent in northern Sweden where his family had a farm). My last period of collaboration occurred several years later, in August of 1988. This time I was accompanied by my family. Erik and Birgitta generously allowed us the use of their country house by the lake and even the use of a car which made it easy to get to the lab and back. Over the years since then, I saw Erik on occasion though not often enough. But I will never forget the happy and productive days we had together (Figure 2).

Erik with his wife Birgitta in discussion with Michaela Kress from Innsbruck

5 CHASING ‘SILENT’ NOCICEPTORS BY MICRONEUROGRAPHY IN UPPSALA

(Martin Schmelz)

Starting my career in pain research I was fortunate to be part of German-Swedish research project lead by Erik Torebjörk in Uppsala and Hermann Handwerker in Erlangen investigating ‘silent’ nociceptors by microneurography (i.e. mechanically unexcitable n.). For me, this was a uniquely successful research setting as we not only found ‘silent’ nociceptors in humans and could sensitize them, but unexpectedly, we found different slowing patterns of C-fibre classes implying class-specific encoding properties. Moreover, we recorded more spontaneously active silent nociceptors in painful versus non-painful neuropathy and by chance stumbled on histamine sensitive pruriceptors. In fact, our control experiments were designed to test histamine outside the innervation territory and to our surprise, we found responses in units with extraordinarily large innervation territories. Erik was not only amazingly sharp in his analysis and suggestions for deviations from the intended protocol but also created an inspiring atmosphere that invited all members of the group for their ideas and contributions. There is a current discussion about the importance of communication on an equal footing to facilitate the start of young scientists—looking back to the mid-90s this was exactly what I was experiencing by the leadership of Erik and Hermann. I am thankful for the extended and highly instructive conceptual discussions that have shaped my idea of what scientific work means and why it is that special.

Beyond learning clinical and neurophysiologic concepts, I am thankful for his example and education not only in patience, frustration tolerance, accuracy and diligence in the experimental work and analysis but also in thoroughness and stringency of writing. Erik told me one of the most instructive stories characterizing political aspects in scientific publishing by telling me the story of his first failure to publish in Nature (retold by Hermann in the introduction to this obituary). The idea of speaking truth to seemingly established concepts has not lost its relevance over time, it rather has gained importance in times of frenzy rush for publications.

From my perspective, the most defining aspect of Erik's personality was the combination of remarkable dedication and enthusiasm with distinct sobriety and stoicism. This was true not only for the scientific exchange but also for social interaction and human attitude. His hospitality and generosity were fabulous and steadfast even when challenged by my exuberant use of the open fireplace in his summer house scenically located at lake Mälar and for which my handling posed a certain risk. I will always remember with great pleasure the evening discussions after the experiments at this fireplace with some red wine Hermann brought from Germany and research periods when my family could join me in the summer house with the kids playing at the lake.

Beyond my introduction into science, I was also introduced to after dinner speeches in Erik's and Birgitta's cozy home: In contrast to what I had expected from such distinguished experts or ‘big shots’ in the field, I was impressed by the cordiality and friendship that emanated from the private meetings of Erik and Hermann and that even included young newcomers like me. I am convinced that it is such standards in science and beyond that are essential for real progress.