Maternal fluoxetine exposure alters cortical hemodynamic and calcium response of offspring to somatosensory stimuli

Epidemiological studies have found an increased incidence of neurodevelopmental disorders in populations prenatally exposed to selective serotonin reuptake inhibitors (SSRIs). Optical imaging provides a minimally invasive way to determine if perinatal SSRI exposure has long-term effects on cortical function. Herein we probed the functional neuroimaging effects of perinatal SSRI exposure in a fluoxetine (FLX)-exposed mouse model. While resting-state homotopic contralateral functional connectivity was unperturbed, the evoked cortical response to forepaw stimulation was altered in FLX mice. The stimulated cortex showed decreased activity for FLX versus controls, by both hemodynamic responses [oxyhemoglobin (Hb

Clinical thresholds in pain-related facial activity linked to differences in cortical network activation in neonates

In neonates, a noxious stimulus elicits pain-related facial expression changes and distinct brain activity as measured by electroencephalography, but past research has revealed an inconsistent relationship between these responses. Facial activity is the most commonly used index of neonatal pain in clinical settings, with clinical thresholds determining if analgesia should be provided; however, we do not know if these thresholds are associated with differences in how the neonatal brain processes a noxious stimulus. The objective of this study was to examine whether subclinical vs clinically significant levels of pain-related facial activity are related to differences in the pattern of nociceptive brain activity in preterm and term neonates. We recorded whole-head electroencephalography and video in 78 neonates (0-14 days postnatal age) after a clinically required heel lance. Using an optimal constellation of Neonatal Facial Coding System actions (brow bulge, eye squeeze, and nasolabial furrow), we compared the serial network engagement (microstates) between neonates with and without clinically significant pain behaviour. Results revealed a sequence of nociceptive cortical network activation that was independent of pain-related behavior; however, a separate but interleaved sequence of early activity was related to the magnitude of the immediate behavioural response. Importantly, the degree of pain-related behavior is related to how the brain processes a stimulus and not simply the degree of cortical activation. This suggests that neonates who exhibit clinically significant pain behaviours process the stimulus differently and that neonatal pain-related behaviours reflect just a portion of the overall cortical pain response

Effects of intrauterine exposure to synthetic glucocorticoids on fetal, newborn, and infant hypothalamic-pituitary-adrenal axis function in humans : a systematic review

BACKGROUND: Synthetic glucocorticoids are commonly used in reproductive medicine. Fetal organ systems are highly sensitive to changes in the intrauterine environment, including overexposure to glucocorticoids. Structural and functional alterations resulting from such changes may persist throughout life and have been associated with diverse diseases. One system that could be particularly sensitive to fetal glucocorticoid overexposure is the hypothalamic-pituitary-adrenal (hpa) axis. Many human studies have investigated this possibility, but a systematic review to identify consistent, emergent findings is lacking. METHODS: We systematically review 49 human studies, assessing the effects of intrauterine exposure to synthetic glucocorticoids on fetal, neonate, and infant hpa function. RESULTS: Study quality varied considerably, but the main findings held true after restricting the analyses to higher-quality studies: intrauterine exposure to synthetic glucocorticoids reduces offspring hpa activity under unstimulated conditions after pain but not pharmacological challenge. Although reduced unstimulated hpa function appears to recover within the first 2 wk postpartum, blunted hpa reactivity to pain is likely to persist throughout the first 4 months of life. There is some evidence that the magnitude of the effects is correlated with the total amount of glucocorticoids administered and varies with the time interval between glucocorticoid exposure and hpa assessment. CONCLUSIONS: This systematic review has allowed the demonstration of the way in which intrauterine exposure to various regimens of synthetic glucocorticoids affects various forms of hpa function. As such, it guides future studies in terms of which variables need to be focused on in order to further strengthen the understanding of such therapy, whilst continuing to profit from its clinical benefits

The impact of parental contact upon cortical noxious-related activity in human neonates

BACKGROUND: Neonates display strong behavioural, physiological and cortical responses to tissue-damaging procedures. Parental contact can successfully regulate general behavioural and physiological reactivity of the infant, but it is not known whether it can influence noxious-related activity in the brain. Brain activity is highly dependent upon maternal presence in animal models, and therefore this could be an important contextual factor in human infant pain-related brain activity. METHODS: Global topographic analysis was used to identify the presence and inter-group differences in noxious-related activity in three separate parental contexts. EEG was recorded during a clinically required heel lance in three age and sex-matched groups of neonates (a) while held by a parent in skin-to-skin (n = 9), (b) while held by a parent with clothing (n = 9) or (c) not held at all, but in individualized care (n = 9). RESULTS: The lance elicited a sequence of 4-5 event-related potentials (ERPs), including the noxious ERP (nERP), which was smallest for infants held skin-to-skin and largest for infants held with clothing (p=0.016). The nERP was then followed by additional and divergent long-latency ERPs (> 750 ms post-lance), not previously described, in each of the groups, suggesting the engagement of different higher level cortical processes depending on parental contact. CONCLUSIONS: These results show the importance of considering contextual factors in determining infant brain activity and reveal the powerful influence of parental contact upon noxious-related activity across the developing human brain. SIGNIFICANCE: This observational study found that the way in which the neonatal brain processes a noxious stimulus is altered by the type of contact the infant has with their mother. Specifically, being held in skin-to-skin reduces the magnitude of noxious-related cortical activity. This work has also shown that different neural mechanisms are engaged depending on the mother/infant context, suggesting maternal contact can change how a baby's brain processes a noxious stimulus

Encoding of mechanical nociception differs in the adult and infant brain

Newborn human infants display robust pain behaviour and specific cortical activity following noxious skin stimulation, but it is not known whether brain processing of nociceptive information differs in infants and adults. Imaging studies have emphasised the overlap between infant and adult brain connectome architecture, but electrophysiological analysis of infant brain nociceptive networks can provide further understanding of the functional postnatal development of pain perception. Here we hypothesise that the human infant brain encodes noxious information with different neuronal patterns compared to adults. To test this we compared EEG responses to the same time-locked noxious skin lance in infants aged 0-19 days (n = 18, clinically required) and adults aged 23-48 years (n = 21). Time-frequency analysis revealed that while some features of adult nociceptive network activity are present in infants at longer latencies, including beta-gamma oscillations, infants display a distinct, long latency, noxious evoked 18-fold energy increase in the fast delta band (2-4 Hz) that is absent in adults. The differences in activity between infants and adults have a widespread topographic distribution across the brain. These data support our hypothesis and indicate important postnatal changes in the encoding of mechanical pain in the human brain

Developmental Mechanisms of CPSP: Clinical Observations and Translational Laboratory Evaluations

Understanding mechanisms that underly the transition from acute to chronic pain and identifying potential targets for preventing or minimizing this progression have specific relevance for chronic postsurgical pain (CPSP). Though it is clear that multiple psychosocial, family, and environmental factors may influence CPSP, this review will focus on parallels between clinical observations and translational laboratory studies investigating the acute and long-term effects of surgical injury on nociceptive pathways. This includes data related to alterations in sensitivity at different points along nociceptive pathways from the periphery to the brain; age- and sex-dependent mechanisms underlying the transition from acute to persistent pain; potential targets for preventive interventions; and the impact of prior surgical injury. Ongoing preclinical studies evaluating age- and sex-dependent mechanisms will also inform comparative efficacy and preclinical safety assessments of potential preventive pharmacological interventions aimed at reducing the risk of CPSP. In future clinical studies, more detailed and longitudinal peri-operative phenotyping with patient- and parent-reported chronic pain core outcomes, alongside more specialized evaluations of somatosensory function, modulation, and circuitry, may enhance understanding of individual variability in postsurgical pain trajectories and improve recognition and management of CPSP

Olfaction scaffolds the developing human from neonate to adolescent and beyond

The impact of the olfactory sense is regularly apparent across development. The foetus is bathed in amniotic fluid that conveys the mother’s chemical ecology. Transnatal olfactory continuity between the odours of amniotic fluid and milk assists in the transition to nursing. At the same time, odours emanating from the mammary areas provoke appetitive responses in newborns. Odours experienced from the mother’s diet during breastfeeding, and from practices such as pre-mastication, may assist in the dietary transition at weaning. In parallel, infants are attracted to and recognise their mother’s odours; later, children are able to recognise other kin and peers based on their odours. Familiar odours, such as those of the mother, regulate the child’s emotions, and scaffold perception and learning through non-olfactory senses. During adolescence, individuals become more sensitive to some bodily odours, while the timing of adolescence itself has been speculated to draw from the chemical ecology of the family unit. Odours learnt early in life and within the family niche continue to influence preferences as mate choice becomes relevant. Olfaction thus appears significant in turning on, sustaining and, in cases when mother odour is altered, disturbing adaptive reciprocity between offspring and caregiver during the multiple transitions of development between birth and adolescence

Toward personalized medicine for pharmacological interventions in neonates using vital signs

Vital signs, such as heart rate and oxygen saturation, are continuously monitored for infants in neonatal care units. Pharmacological interventions can alter an infant's vital signs, either as an intended effect or as a side effect, and consequently could provide an approach to explore the wide variability in pharmacodynamics across infants and could be used to develop models to predict outcome (efficacy or adverse effects) in an individual infant. This will enable doses to be tailored according to the individual, shifting the balance toward efficacy and away from the adverse effects of a drug. Pharmacological analgesics are frequently not given in part due to the risk of adverse effects, yet this exposes infants to the short- and long-term effects of painful procedures. Personalized analgesic dosing will be an important step forward in providing safer effective pain relief in infants. The aim of this paper was to describe a framework to develop predictive models of drug outcome from analysis of vital signs data, focusing on analgesics as a representative example. This framework investigates changes in vital signs in response to the analgesic (prior to the painful procedure) and proposes using machine learning to examine if these changes are predictive of outcome-either efficacy (with pain response measured using a multimodal approach, as changes in vital signs alone have limited sensitivity and specificity) or adverse effects. The framework could be applied to both preterm and term infants in neonatal care units, as well as older children. Sharing vital signs data are proposed as a means to achieve this aim and bring personalized medicine rapidly to the forefront in neonatology

Neonatal Pain-Related Stress and NFKBIA Genotype Are Associated with Altered Cortisol Levels in Preterm Boys at School Age

Neonatal pain-related stress is associated with elevated salivary cortisol levels to age 18 months in children born very preterm, compared to full-term, suggesting early programming effects. Importantly, interactions between immune/inflammatory and neuroendocrine systems may underlie programming effects. We examined whether cortisol changes persist to school age, and if common genetic variants in the promoter region of the NFKBIA gene involved in regulation of immune and inflammatory responses, modify the association between early experience and later life stress as indexed by hair cortisol levels, which provide an integrated index of endogenous HPA axis activity. Cortisol was assayed in hair samples from 128 children (83 born preterm ≤ 32 weeks gestation and 45 born full-term) without major sensory, motor or cognitive impairments at age 7 years. We found that hair cortisol levels were lower in preterm compared to term-born children. Downregulation of the HPA axis in preterm children without major impairment, seen years after neonatal stress terminated, suggests persistent alteration of stress system programming. Importantly, the etiology was gender-specific such that in preterm boys but not girls, specifically those with the minor allele for NFKBIA rs2233409, lower hair cortisol was associated with greater neonatal pain (number of skin-breaking procedures from birth to term), independent of medical confounders. Moreover, the minor allele (CT or TT) of NFKBIA rs2233409 was associated with higher secretion of inflammatory cytokines, supporting the hypothesis that neonatal pain-related stress may act as a proinflammatory stimulus that induces long-term immune cell activation. These findings are the first evidence that a long-term association between early pain-related stress and cortisol may be mediated by a genetic variants that regulate the activity of NF-κB, suggesting possible involvement of stress/inflammatory mechanisms in HPA programming in boys born very preterm

To Eat or Not To Eat: Contributions of Dorsal Hippocampal Neurons and Memory to Meal Onset

There is extensive research regarding the neural mechanisms that control satiety and meal termination; in contrast, there is very limited understanding of how the central nervous system regulates meal onset and thus the duration of the postprandial intermeal interval (ppIMI) and meal frequency. Based on emerging evidence, we hypothesize that dorsal hippocampal neurons, which are critical for episodic memory, form a memory of a meal and inhibit meal onset during the ppIMI. To test whether hippocampal neurons form a memory of a meal, we first determined that ingesting sucrose or isopreferred concentrations of the non-caloric sweetener saccharin increased the expression of the plasticity-related immediate early gene activity-regulated cytoskeleton-associated protein (Arc) in dorsal CA1 hippocampal (dCA1) neurons in Sprague-Dawley rats. Furthermore, repeated exposure to the sucrose meal attenuated the ability of the sucrose to induce Arc expression. Together, these data indicate that orosensory stimulation produced by a sweet taste is sufficient to induce synaptic plasticity in dCA1 neurons in an experience-dependent manner. Second, we showed that reversibly inactivating dorsal hippocampal neurons with infusions of the GABAA agonist muscimol after the end of a sucrose meal accelerated the onset of the next meal, indicating that dorsal hippocampal neurons inhibit meal onset. Lastly, using a clinically-relevant animal model of early life inflammatory injury, we found that neonatal injury (1) impairs hippocampal-dependent memory, (2) decreases the ppIMI and increases sucrose intake, (3) increases body mass, (4) attenuates sucrose-induced Arc expression in dCA1 neurons, and that (5) blocking inflammatory pain with morphine at the time of injury reverses the effects of injury on memory, energy intake and Arc expression. Collectively, the findings of this dissertation support the overarching hypothesis that dorsal hippocampal neurons inhibit meal onset during the ppIMI and suggest that dorsal hippocampal dysfunction may contribute to the development and/or maintenance of diet-induced obesity