OBJECTIVES: Premature birth is associated with a wide range of complications in later life, including structural and functional neurological abnormalities and altered pain sensitivity. We investigated whether during anaesthesia premature-born children display different patterns of background EEG activity and exhibit increased responses to nociceptive stimuli. METHODS: We examined background EEG and time-locked responses to clinical cannulation in 45 children (mean age (±SD) at study: 4.9(±3.0)years) under sevoflurane monoanaesthesia maintained at a steady-state end-tidal concentration of 2.5%. 15 were born prematurely (mean gestational age at birth: 29.2 ± 3.9 weeks) and 30 were age-matched term-born children. RESULTS: Background levels of alpha and beta power were significantly lower in the premature-born children compared to term-born controls (p=0.048). Clinical cannulation evoked a significant increase in delta activity (p=0.032), which was not significantly different between the two groups (p=0.44). CONCLUSIONS: the results indicate that whilst under anaesthesia premature-born children display different patterns of background brain activity compared to term-born children. SIGNIFICANCE: As electrophysiological techniques are increasingly used by anaesthetists to gauge anaesthetic depth, differences in background levels of electrophysiological brain activity between premature and term-born children may be relevant when considering titration of anaesthetic dose.

Various aspects of social behavior are influenced by the highly conserved corticotrophin-releasing factor (CRF) family of peptides and receptors in the mammalian telencephalon. This study has mapped and compared the telencephalic distribution of the CRF receptors, CRF1 and CRF2 , and two of their ligands, CRF and urocortin 3, respectively, in African mole-rat species with diametrically opposed social behavior. Naked mole-rats live in large eusocial colonies that are characterized by exceptional levels of social cohesion, tolerance, and cooperation in burrowing, foraging, defense, and alloparental care for the offspring of the single reproductive female. Cape mole-rats are solitary; they tolerate conspecifics only fleetingly during the breeding season. The telencephalic sites at which the level of CRF1 binding in naked mole-rats exceeds that in Cape mole-rats include the basolateral amygdaloid nucleus, hippocampal CA3 subfield, and dentate gyrus; in contrast, the level is greater in Cape mole-rats in the shell of the nucleus accumbens and medial habenular nucleus. For CRF2 binding, the sites with a greater level in naked mole-rats include the basolateral amygdaloid nucleus and dentate gyrus, but the septohippocampal nucleus, lateral septal nuclei, amygdalostriatal transition area, bed nucleus of the stria terminalis, and medial habenular nucleus display a greater level in Cape mole-rats. The results are discussed with reference to neuroanatomical and behavioral studies of various species, including monogamous and promiscuous voles. By analogy with findings in those species, we speculate that the abundance of CRF1 binding in the nucleus accumbens of Cape mole-rats reflects their lack of affiliative behavior.

Measuring infant pain is complicated by their inability to describe the experience. While nociceptive brain activity, reflex withdrawal and facial grimacing have been characterised, the relationship between these activity patterns has not been examined. As cortical and spinally mediated activity is developmentally regulated, it cannot be assumed that they are predictive of one another in the immature nervous system. Here, using a new experimental paradigm, we characterise the nociceptive-specific brain activity, spinal reflex withdrawal and behavioural activity following graded intensity noxious stimulation and clinical heel lancing in 30 term infants. We show that nociceptive-specific brain activity and nociceptive reflex withdrawal are graded with stimulus intensity (p < 0.001), significantly correlated (r = 0.53, p = 0.001) and elicited at an intensity that does not evoke changes in clinical pain scores (p = 0.55). The strong correlation between reflex withdrawal and nociceptive brain activity suggests that movement of the limb away from a noxious stimulus is a sensitive indication of nociceptive brain activity in term infants. This could underpin the development of new clinical pain assessment measures.

Limited understanding of infant pain has led to its lack of recognition in clinical practice. While the network of brain regions that encode the affective and sensory aspects of adult pain are well described, the brain structures involved in infant nociceptive processing are completely unknown, meaning we cannot infer anything about the nature of the infant pain experience. Using fMRI we identified the network of brain regions that are active following acute noxious stimulation in newborn infants, and compared the activity to that observed in adults. Significant infant brain activity was observed in 18 of the 20 active adult brain regions but not in the infant amygdala or orbitofrontal cortex. Brain regions that encode sensory and affective components of pain are active in infants, suggesting that the infant pain experience closely resembles that seen in adults. This highlights the importance of developing effective pain management strategies in this vulnerable population.

More than 235,000 children/year in the UK receive general anaesthesia, but it is unknown whether nociceptive stimuli alter cortical brain activity in anaesthetised children. Time-locked electroencephalogram (EEG) responses to experimental tactile stimuli, experimental noxious stimuli, and clinically required cannulation were examined in 51 children (ages 1-12 years) under sevoflurane monoanaesthesia. Based on a pilot study (n=12), we hypothesised that noxious stimulation in children receiving sevoflurane monoanaesthesia would evoke an increase in delta activity. This was tested in an independent sample of children (n=39), where a subset (n=11) had topical local anaesthetic applied prior to stimulation. A novel method of time-locking the stimuli to the EEG recording was developed using an event detection interface and high-speed camera. Clinical cannulation evoked a significant increase (34.2 ± 8.3%) in delta activity (P=0.042), without concomitant changes in heart rate or reflex withdrawal, which was not observed when local anaesthetic was applied (P=0.30). Experimental tactile (P=0.012) and noxious (P=0.0099) stimulation also evoked significant increases in delta activity, but the magnitude of the response was graded with stimulus intensity, with the greatest increase evoked by cannulation. We demonstrate that experimental and clinically essential noxious procedures, undertaken in anaesthetised children, alter the pattern of EEG activity, that this response can be inhibited by local anaesthetic, and that this measure is more sensitive than other physiological indicators of nociception. This technique provides the possibility that sensitivity to noxious stimuli during anaesthesia could be investigated in other clinical populations.

African mole-rats provide a unique taxonomic group for investigating the evolution and neurobiology of sociality. The two species investigated here display extreme differences in social organization and reproductive strategy. Naked mole-rats (NMRs) live in colonies, dominated by a queen and her consorts; most members remain nonreproductive throughout life but cooperate in burrowing, foraging, and caring for pups, for which they are not biological parents (alloparenting). In contrast, Cape mole-rats (CMRs) are solitary and intolerant of conspecifics, except during fleeting seasonal copulation or minimal maternal behavior. Research on other mammals suggests that oxytocin receptors at various telencephalic sites regulate social recognition, monogamous pair bonding, and maternal/allomaternal behavior. Current paradigms in this field derive from monogamous and polygamous species of New World voles, which are evolutionarily remote from Old World mole-rats. The present findings indicate that NMRs exhibit a considerably greater level of oxytocin receptor (OTR) binding than CMRs in the: nucleus accumbens; indusium griseum; central, medial, and cortical amygdaloid nuclei; bed nucleus of the stria terminalis; and CA1 hippocampal subfield. In contrast, OTR binding in the piriform cortex is intense in CMRs but undetectable in NMRs. We speculate that the abundance of OTR binding and oxytocin-neurophysin-immunoreactive processes in the nucleus accumbens of NMRs reflects their sociality, alloparenting behavior, and potential for reproductive attachments. In contrast, the paucity of oxytocin and its receptors at this site in CMRs may reflect a paucity of prosocial behaviors. Whether similarities in OTR expression between eusocial mole-rats and monogamous voles are due to gene conservation or convergent evolution remains to be determined.

Changes in metabolic state, such as those induced by fasting, have profound effects on reproduction. In rats, the time-course over which fasting inhibits luteinising hormone (LH) release is reduced to 48 h by the presence of oestradiol-17beta (E(2)). Hypothalamic kisspeptin plays a key role in mediating the actions of E(2) on gonadotrophin-releasing hormone (GnRH) neurones, and thereby promotes LH release. KiSS-1-expressing neurones are found in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC). Extensive evidence implicates the AVPV in GnRH release and the ARC in energy balance. The latter nucleus also contains neurones that express neuropeptide Y (NPY), an orexigenic peptide implicated in GnRH control. To elucidate the involvement of kisspeptin and/or NPY in hypothalamic responses to fasting, their expression was quantified by in situ hybridisation histochemistry in ovariectomised rats, with or without E(2) replacement, before and after 48 h of fasting. In the presence of E(2), but not in its absence, the fasting suppressed plasma LH. In the AVPV, the low level of KiSS-1 expression found in the absence of E(2) was unaffected by fasting. By contrast, the elevated level found in the presence of E(2) was suppressed by fasting. Independent of E(2), fasting had no effect on KiSS-1 expression in the ARC, but increased NPY expression at that site. The present study has identified the AVPV as a site at which KiSS-1 expression can be influenced by fasting. The results suggest that inhibition of KiSS-1 expression in the AVPV may be a significant factor in restraining the gonadotrophic axis in response to negative energy balance in the presence of oestrogen. The extent to which the concurrent rise in NPY expression in the ARC may contribute to the suppression of LH release by influencing AVPV kisspeptin neurones, directly or indirectly, or by actions independent of kisspeptin, remains to be established.