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Very preterm human neonates are exposed to numerous invasive procedures as part of life-saving care. Evidence suggests that repetitive neonatal procedural pain precedes long-term alterations in brain development. However, to date the link between pain and brain development has limited temporal and anatomic specificity. We hypothesized that early exposure to painful stimuli during a period of rapid brain development, before pain modulatory systems reach maturity, will predict pronounced changes in thalamic development, and thereby cognitive and motor function. In a prospective cohort study, 155 very preterm neonates (82 males, 73 females) born 24-32 weeks' gestation underwent two MRIs at median postmenstrual ages 32 and 40 weeks that included structural, metabolic, and diffusion imaging. Detailed day-by-day clinical data were collected. Cognitive and motor abilities were assessed at 3 years, corrected age. The association of early (skin breaks, birth-Scan 1) and late pain (skin breaks, Scans 1-2) with thalamic volumes and N -acetylaspartate (NAA)/choline (Cho), and fractional anisotropy of white-matter pathways was assessed. Early pain was associated with slower thalamic macrostructural growth, most pronounced in extremely premature neonates. Deformation-based morphometry analyses confirmed early pain-related volume losses were localized to somatosensory regions. In extremely preterm neonates early pain was associated with decreased thalamic NAA/Cho and microstructural alterations in thalamocortical pathways. Thalamic growth was in turn related to cognitive and motor outcomes. We observed regionally-specific alterations in the lateral thalamus and thalamocortical pathways in extremely preterm neonates exposed to more procedural pain. Findings suggest a sensitive period leading to lasting alterations in somatosensory-system development. SIGNIFICANCE STATEMENT Early exposure to repetitive procedural pain in very preterm neonates may disrupt the development of regions involved in somatosensory processing, leading to poor functional outcomes. We demonstrate that early pain is associated with thalamic volume loss in the territory of the somatosensory thalamus and is accompanied by disruptions thalamic metabolic growth and thalamocortical pathway maturation, particularly in extremely preterm neonates. Thalamic growth was associated with cognitive and motor outcome at 3 years corrected age. Findings provide evidence for a developmentally sensitive period whereby subcortical structures in young neonates may be most vulnerable to procedural pain. Furthermore, results suggest that the thalamus may play a key role underlying the association between neonatal pain and poor neurodevelopmental outcomes in these high-risk neonates., (Copyright © 2018 the authors 0270-6474/18/380879-09$15.00/0.)

During a delayed period in a delayed-response task, prefrontal cortical neurons show a change in neuronal firing rate that is dependent on a functional mesocortical dopamine input. This change in firing rate has been attributed to be part of the cellular processes underlying working memory. However, it is unclear what neural mechanisms activate mesocortical dopamine neurons to provide an optimal level of dopamine to modulate the firing of the medial prefrontal cortical (mPFC) neurons. This study examined the possibility of whether mPFC neurons that project to the ventral tegmental area (VTA) might activate the ascending mesocortical dopamine neurons. To determine the locations of the mPFC-->VTA neurons, cholera toxin subunit B was microinjected into the VTA. Retrogradely labeled mPFC neurons mainly reside in the deep lamina V and VI. In vivo single unit recording in urethane-anesthetized rats were also used to determine the responses of some of these neurons to burst-patterned stimulation of the VTA. Single-pulse stimulation (1 Hz) of the VTA antidromically activated burst firing mPFC-->VTA neurons. In response to burst-patterned stimulation of the VTA, which mimicked burst firing of VTA dopamine neurons (4-10 pulses at 10-15 Hz cycled at 0.5-3 Hz), the temporal structure of spontaneous burst firing patterns of these neurons but not their mean firing rate were changed. However, the mean firing rate of the non-VTA projecting neurons (i.e., no antidromic response to VTA stimulations) was either increased or decreased by similar burst-patterned stimulation of the VTA. These data suggest that burst-patterned stimulation of the ascending VTA-->mPFC or putative mesocortical dopamine neurons might have released dopamine and/or other neuromodulators to modulate the temporal code, rather than the rate code, of mPFC-->VTA neurons. Medial PFC neurons that project elsewhere (e.g., nucleus accumbens or mediodorsal thalamus) may mediate the sustained firing rate changes during, e.g., short-term working memory., (Copyright 1999 Wiley-Liss, Inc.)