Background & Aims
Pain perception relies on coordinated activity across a widespread network of brain regions, which together are responsible for the encoding of its sensory, affective and cognitive components (1,2). For these areas to work together and ultimately lead to the experience of pain, there must be an established framework of local and cross-cortical connections which can be engaged when required: the pain connectome (3). The infant brain is strongly activated by noxious events from at least the beginning of the third gestational trimester (4,5), but it also undergoes rapid changes over this period (6,7). We therefore hypothesised that the pain connectome, and consequently how infants experience pain, go through extensive organisational changes over this developmental period. We aimed to assess the functional availability of the connections forming this network at different stages of development comparing them to the mature network in adults.
Methods
Resting-state fMRI data from the dHCP (372 infants, 26-42 weeks post-menstrual age, PMA) (8) and from the HCP (98 individuals, 22-35 years old) (9) were used.
A pain connectome atlas, based on regions consistently engaged in adult pain, was adapted for neonates starting from a neonatal version of the automated anatomical labelling atlas (10) to 12 include pain-related regions of interest (ROIs). Functional connectivity between pairs of ROIs was assessed with Pearson’s partial correlation and values were normalized to adult connectivity to reflect degree of maturation of the connections. The presence/absence of connections was determined by comparing these values to a reference connection which is established early in development (thalamus-S1 at 26-31 weeks PMA). Linear regression was used to assess developmental trends of connection presence and strength within the sensory, affective, and cognitive subnetworks of the pain connectome and two-way ANOVA was used to compare subnetworks
Results
Functional connectivity within the pain connectome increases over the equivalent of the third gestational trimester with a significant increase in both the percentage of functional connections present and strength, with 50% and 46% of the variance explained by PMA. Subnetwork analysis identified non-uniform development in the sensory, affective, and cognitive subnetworks. Before 34 weeks PMA, the proportion and strength of connections were significantly lower than in adults for all subnetworks. After 34 weeks PMA: (i) the sensory subnetwork surpassed the others, reaching and exceeding adult levels from 34-36 weeks PMA; (ii) development of the affective subnetwork lagged behind reaching adult levels only at 36-38 weeks PMA and (iii) the cognitive subnetwork did not reach adult levels by full term equivalent age. At term age, connectivity within each subnetwork still did not have its mature configuration with 20-70% of connections stronger and 10-40% weaker than adults.
Conclusions
Resting functional connections within the pain connectome are altered compared to controls in various pain conditions (11–14) and the strength of these connections is often directly related to the pain intensity (12,14), suggesting that for normal pain processing the pain connectome must be functionally intact even at rest. Our results suggest that the different components of pain processing, and consequently of pain experience, change rapidly over the period equivalent to the third gestational trimester and are still immature at the time of normal birth. The overconnectivity of the sensory subnetwork implies poor localization of pain sources and hypersensitivity, the lack of maturation of the affective subnetwork indicates an inability to encoding pain quality and unpleasantness. Finally, as the cognitive subnetwork is largely unconnected, neonates may not have conscious awareness or cognitive control of a noxious stimulus even at term.
References
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Presenting Author
Lorenzo Fabrizi
Poster Authors
Dr Lorenzo Fabrizi, PhD
PhD
Department of Neuroscience, Physiology and Pharmacology, University College London
Lead Author
Dafnis Batalle
PhD
King's College London
Lead Author
Dr Judith Meek
PhD
Neonatal Unit, Elizabeth Garrett Anderson Wing, University College London Hopital NHS Trust
Lead Author
David Edwards
PhD
King's College London
Lead Author
Maria Fitzgerald
University College London
Lead Author
Laura Jones
University College London
Lead Author
Tomoki Arichi
King's College London
Lead Author
Topics
- Pain Imaging