https://doi.org/10.36866/pn.126.42

Professor Maria Fitzgerald
Professor of Developmental Neurobiology at University College London (UCL), UK

Maria Fitzgerald is an Honorary Member of The Society and a world leader on the neurobiological processes involved in the development of pain pathways. Maria reflects on the papers that have most influenced her career.

I am a Professor of Developmental Neurobiology at University College London (UCL), UK. My research has focused upon the development of touch and pain pathways in the peripheral and central nervous system, from late foetal life to adolescence. I was drawn to Physiological Sciences as my first degree because I knew that I wanted to study biological processes in living animals but also knew that I did not want to be a doctor.

After a very enjoyable PhD in the Physiology department at UCL (with Bruce Lynn) recording from individual nociceptors, I accepted a postdoc position with Patrick Wall, the father of pain physiology. He was an amazing mentor and an inspirational scientist; through him I developed a passion for understanding pain in infants and children that remains today.

Wall PD (1960). Cord cells responding to touch, damage, and temperature of skin. Journal of Neurophysiology 23, 197-210. doi: 10.1152/jn.1960.23.2.197.
This classic paper had a great influence on my (and others’) understanding of sensory processing in the spinal cord. The senses of touch and pain were classically described in terms of simple lines of information from the skin (via primary afferents) up to the spinal cord dorsal horn and subsequently on up to the brain, with specific “lines” for each modality. Wall showed in this paper that although spinal cord neurons detect the characteristics of sensations, the circuitry in which they operate is not fixed and can be “gated” by controlling peripheral sensory nerve inputs. It formed the basis of his famous “gate theory of pain” and taught me a very important lesson – be prepared to think beyond the accepted scientific dogma.

Woolf CJ (1983). Evidence for a central component of post-injury pain hypersensitivity. Nature 306(5944), 686-688. doi: 10.1038/306686a0.
This deceptively simple paper provided the first clear evidence that spinal cord circuits actively enhance and spread pain beyond a site of injury. It demonstrated that nociceptive signals from an injury site generate “central sensitisation” within dorsal horn circuitry, leading to the enhanced and widespread pain. Central sensitisation meant that pain could be maintained even when the original nociceptive input was silenced with local anaesthetics. This elegant study led me to understand the importance of the central nervous system in generating pain, independent of an injury.

Owens ME, Todt EH (1984). Pain in infancy: Neonatal reaction to a heel lance. Pain 20(1), 77-86. doi: 10.1016/0304-3959(84)90813-3.
I had always been interested in developmental physiology and had begun to ask questions about how nociceptors and spinal cord circuits ever developed to process pain in the first place. Reading this paper made me realise how important this question was in humans – in other words, that this scientific question had real-life impact. The paper shows significant increases in heart rate and crying follow a tissue-damaging stimulus in human infants and suggests that, contrary to received wisdom at the time, infants experience pain and that pain in infants can be reliably measured in clinical settings. This pioneering paper stimulated me to begin research on human infant pain in collaboration with colleagues at University College London Hospital, alongside my ongoing lab experiments.

Johansen JP, Fields HL (2004). Glutamatergic activation of anterior cingulate cortex produces an aversive teaching signal. Nature Neuroscience 7(4), 398-403. doi:10.1038/nn1207.
This paper introduced to me to the concept that noxious stimuli do not simply cause pain, but also have motivational power and can support associative learning. The study shows the role of neural circuitry in the anterior cingulate cortex (ACC) in the affective response to noxious stimuli and the motivational properties of conditioned stimuli that predict noxious stimulation. Using conditioned place aversion in rats, the authors showed that ACC neuronal activity is necessary and sufficient for noxious stimuli to produce an aversive teaching signal. This exciting paper made me realise that, despite my love of spinal cord pain circuits, it was time to move into the brain to really understand pain experience.

Duerden EG, Grunau RE, Guo T et al. (2018). Early procedural pain is associated with regionally-specific alterations in thalamic development in preterm infants. Journal of Neuroscience 38(4), 878-886. doi: 10.1523/JNEUROSCI.0867-17.2017.
My lab was building evidence that early life pain does not only cause suffering but, at critical stages of development, may cause longer-term changes in connections within the developing spinal cord and brain. This paper provided convincing evidence of this in humans. It shows that early exposure to repetitive procedural pain in very preterm neonates disrupts the development of regions involved in somatosensory processing, leading to poor functional outcomes. Specifically, early pain is associated with thalamic volume loss in the territory of the somatosensory thalamus and is accompanied by disruptions in thalamic metabolic growth and thalamocortical pathway maturation, associated with cognitive and motor outcome at 3 years corrected age. The data convinced me that it was indeed important to understand the underlying physiology of this vulnerability to early pain.

These five papers summarise my overall research philosophy. Be brave – science moves on, so open your mind to new ideas and evidence and be prepared to change the focus or direction of your research. And make sure that your laboratory work has relevance to the human condition.