By definition, colicky babies cry for ≥3 hours/day, on ≥3 days/week for ≥3 consecutive weeks, but fortunately, as for noncolicky babies, the cries slowly lessen after a peak at 6 weeks of life and almost stop after month 3 (1). Another particularity of the cries of the first weeks of life is that they concentrate in late afternoon, when colicky babies seem to be overly alert (2). Some authors, therefore, hypothesize that there is a relation between infant colic and the development of the circadian rhythm (3–5).
Close contact between babies and their caregivers is essential for all babies, but what seems to soothe noncolicky babies (eg, hearing their mother's voice, smelling her, being carried or touched) apparently has no impact on severely colicky babies and sometimes even worsens their symptoms. This raises the question whether their sensory processing differs from other babies and how this can be investigated (6,7).
The peak shape of the crying behaviour found in colicky and noncolicky babies, its circadian rhythm, and the fact that they are not soothed by typical sensory stimulation such as being rocked (8) makes it highly possible that despite its name, the prolonged episodes of crying reflect a difference in central nervous system functioning rather than gastrointestinal (GI) dysfunction (9–11).
BRAIN MATURATION AND COLIC
Circadian Rhythm, Sleep, and Colic
All human beings are equipped with time-measuring devices, known as the circadian clock (Fig. 1), that allow them to anticipate daytime and hence to organize their physiology and behaviour in a 24-hour cycle. The main circadian clock that governs the human biological rhythms for the timing of sleep, body temperature, feeding, and melatonin secretion is the suprachiasmatic nucleus (SCN) of the hypothalamus. This endogenous clock is synchronized to day/night changes, thanks to photic information that it receives from the retina and then transmits to cells in other brain regions and peripheral organs via a variety of outputs. As an example, the pineal gland receives circadian information from the SCN of the hypothalamus via norepinephrine, and its downstream hormone melatonin then acts on different targets either directly or via G-protein–coupled membrane receptors.
In humans, the SCN has been detected as early as 18 weeks of gestation (12) and some day–night oscillations seem to be present at the end of gestation, but it is during the first 3 months of life that the circadian system progressively matures and organizes physiological and behavioural activity in a 24-hour cycle (13). The quantity of night sleep versus day sleep and the different wake states depend on these processes. Early in life, crying can be considered as a wake state as active sleep, quiet sleep, awake but drowsy, and quietly alert. As in all maturation processes, there are important individual variations to when a clear day–night cycling is attained (14–18).
A number of authors have noted that infants with infant colic (IC) sleep less than infants without colic (5,19), but most of the articles depend on parental reports, which introduce an important bias: infants who are in bed without fussing or crying are considered asleep by their parents even if they are awake but quiet (20).
St James-Roberts and Peachey have provided insight into the link between crying in the first months and sleep. They analysed data from 2 longitudinal studies including prospectively 610 and 237 healthy newborn babies. Infant crying data were obtained from validated behaviour diaries. The authors concluded that infants with IC are as likely as infants without colic to sleep through the night (ie, not waking their parent[s]) at 12 weeks (20).
A 24-hour sleep polygraphy study was conducted at home by Kirjavainen et al (21) in 24 excessively crying infants and 23 control subjects at age 6 weeks. In addition, parental diaries were kept for 4 days. Although no differences in the total amount of sleep or proportions of sleep stages were observed, excessively crying infants had a relative REM sleep deficiency during the evening hours followed by REM sleep rebound during the following long sleep period. Brand et al (22) found that infants with IC were more likely to exhibit fragmented sleep patterns and elevated cortisol secretion in the morning, an association previously observed only in preschool children and adults. They concluded that it is conceivable that a common pattern linking neuroendocrine activity and sleep–wake regulation emerges early in life.
Circadian Hormones and Colic
Melatonin is secreted by the pineal gland in a circadian pattern, with the highest amounts released during the night. Melatonin is involved in many regulatory processes, such as in sleep regulation, mood regulation, and regulation of immune responses (23,24). Cohen et al (25) found in 94 healthy 2- to 4-month-olds that those exclusively breast-fed had a significantly lower incidence of colic attacks, lower severity of irritability attacks, and a trend towards longer nocturnal sleep duration. They also showed that breast milk (nocturnal) contains substantial melatonin levels, whereas artificial formulae do not. They concluded that breast-feeding is associated with reduced irritability/colic and a tendency towards longer nocturnal sleep. The authors speculated that melatonin, which is supplied to the infant via breast milk, may play a role in improving sleep and reducing colic in breast-fed infants as compared with formula-fed infants. Another study further highlighted that melatonin levels in breast milk vary by the time of the day and are influenced by maternal mood (26).
The hypothalamic–pituitary–adrenal axis is a major homeostatic system that is activated in response to stress. The endpoint of the hypothalamic–pituitary–adrenal axis activation in humans is the release of the glucocorticosteroid cortisol (27). Cortisol not only is the body's response to stress but it also plays an important role in awakening with a high morning cortisol level.
In a population of 20 two-month-olds with IC and 20 without, White et al (5) found that during physical examination, infants with IC cried twice as much, cried more intensely, and were more inconsolable than were the control infants. Despite these behavioural differences, heart rate, vagal tone, and cortisol measures were not different for the 2 groups. A major difference between the 2 groups was nevertheless found insofar as that no circadian rhythm of the cortisol secretion was found in 2-month-olds with IC, whereas the control group showed clear daily variations in their saliva cortisol levels.
COLIC AND SENSORY PROCESSING
At birth, the sensory experiences of olfaction, taste, touch, posture, sound, and sight activate and reinforce specific neural pathways in the developing brain. Early experiences from birth and during the first months of life influence how sensory information is represented in the brain and shape perceptual and behavioural development. Several studies suggest that excessive crying in the early developmental stages could be a result of this major neurobehavioral reorganization that occurs during the same period (10,28).
Understanding perceptual and behavioural development during the perinatal period is essential because individual difference in crying behaviours could be an early difference in an infant's ability to regulate its responses to everyday stimuli and explain why some infants cry longer once they start and are not soothed by typical calming stimuli (8).
The following sections present different sensory stimuli such as olfaction, taste, and touch and the behaviour-regulatory processes involved in the action of soothing crying babies. In addition, the possible effects of stress and maternal mood on IC are discussed.
Olfaction and Taste
During foetal sensory development, the chemosensory (olfaction and taste) system is one of the earliest systems to develop in the human brain in parallel with the tactile/somatosensory system. These sensory systems are thus important for later development.
Olfaction is an important sensory modality for the developing infant, guiding and modulating behaviours before other sensory systems have matured. Immediately after delivery it allows, for example, the newborn to locate the nipple (29,30).
Olfactory receptor neurons are located in the olfactory epithelium in the nasal cavity, and their axons, the olfactory nerves, pass through the cribriform plate to the olfactory bulbs on the ventral part of the frontal lobe. The primary olfactory sulci appear at 16 weeks of gestation, become deeper and detectable with foetal magnetic resonance imaging at approximately 28 to 30 weeks. The olfactory bulbs mature during the same period (31,32) (Fig. 2[32a–c]) and have been identified by magnetic resonance imaging studies in premature babies at 32 weeks (33,34). There is evidence from animal studies of the ability to discriminate odours in utero, indicating a well-established prenatal olfactory function (35,36).
The first olfactory activity begins in utero, with odorant substances present in the amniotic fluid; the foetus becomes familiar with chemical information in intrauterine life. The mother's diet influences these prenatal experiences and the preferences of the newborn after birth via flavours transmitted through the amniotic fluid (37).
The odour of amniotic fluid has a calming effect on the crying behaviour of newborns and can be implicated in the mediation of infants’ early behaviours (38). This is supported by a randomized controlled trial of 44 full-term newborns, in which the authors describe that crying and grimacing during a minor painful procedure are reduced by a familiar odour (39).
The chemosensory system includes both the olfactory and gustatory systems, which are closely interconnected, especially during intrauterine life. The foetus ingests volatile odorant molecules present in the amniotic fluid, which are released into the back of the nasal cavity and reach olfactory receptors; thus, they can be detected by taste as well as smell. The newborn responds to the 4 distinct taste sensations of sweet, salty, sour, and bitter.
The sucrose taste is known to produce a calming effect (40) and this provides a measure of the ability to regulate distress in already-crying infants. In a randomised controlled trial of 2 groups of 19 infants with and without IC, the authors demonstrated that the regulatory effects of sucrose taste are reduced in infants with IC (41). Infants with IC were less effectively calmed by the sucrose taste than infants without IC and were less able to regulate crying once it started.
There are different hypotheses for the pain-reducing effect of sweet-tasting solutions; one is the endogenous opioid system. Opioid receptors and their endogenous ligands (enkephalins, endorphins, and dynorphins) have an effect in the central nervous system in mediating pain and stress via a decrease in the release of excitatory neurotransmitters involved in pain pathways (42). Endogenous ligands and their opioid receptors appear early in foetal life—as early as 10 weeks in the human spinal cord (43)—but important changes in pain pathways occur only postnatally. The mechanisms underlying the calming effect of sucrose taste are not fully understood, and the lack of this effect in IC may imply an altered endogenous opoid system, but this needs to be further studied.
Tactile Stimulation and Colic
The somatosensory system is involved in proprioception, characterisation and localisation of touch, stroking, pain, and all motor action involving the body. Somatosensory information enters the cerebral cortex via the thalamus and through the dorsal column in the spinal cord from peripheral receptors.
Both human and animal studies have demonstrated that the peripheral sensory processing becomes functional early in foetal life (44). Sensory systems have different receptive degrees before structural and functional maturity.
In utero, foetal motility, maternal movement, and uterine pressure activate muscular proprioception receptors. In humans, the sensory structures that develop first (from the 7th week of gestation) are the peripheral receptors in the perioral area of the face. Peripheral afferent inputs from the skin to the spinal cord develop around the 20th week of gestation. The spinothalamic connections are already present at this time. The first thalamocortical connections reach the cortex at approximately 25 gestational weeks and these connections then influence sensory responses (44–48). Studies on preterm babies have shown that electrocortical response to sensory stimuli can be observed from 25 weeks’ gestational age onward (49,50) (Fig. 2). Thus, the first sensory experiences and cortical processes become possible around 26 weeks’ gestation, when the thalamocortical connections begin to grow (45,51).
Gentle touching is one of the privileged means of communication between parents and their young baby. Close contact between babies and their caregivers certainly diminishes the number of hours of crying in the first months of life (52–54), but its impact on colicky babies is controversial. What seems to soothe noncolicky babies (being carried or touched) seems to have no impact on the extreme cryers and sometimes even worsens their symptoms, as though these babies have a lower threshold for pain (6,7,55). A difference in the maturation of somatosensory processing could underlie these differences. Here again, further studies are needed to demonstrate it.
Temperament, Stress, and Colic
Temperamental differences may be observed early in life. Stable individual differences in behaviour, reactivity, and self-regulation are attributable to innate biological factors.
The neurobiological model of temperament in adults is associated with different brain structures such as the anterior cingulate cortex, the prefrontal and orbitofrontal cortex, the nucleus accumbens, the amygdala, and the hippocampus. These networks underlie different behavioural functions, affective regulation, and impulse and emotion control in different dimensions of temperament (56,57). Schwartz et al (58) have explored the relation between infant temperament at 4 months of age and its effect on brain structure in adulthood. Their results suggest that regional differences in the thickness of the adult orbitofrontal and ventromedial prefrontal cerebral cortices are predicted by temperamental differences observed during the first months of life.
The hypothesis that colic is an early manifestation of a difficult temperament has not been supported by a prospective longitudinal study in which the authors found no differences in temperament in the 2 groups studied (59).
Numerous animal studies have looked at the brain and behavioural effects in offspring after repeated maternal stress during pregnancy. The studies suggest that the prenatal environment may produce long-term biological and behavioural disorders in offspring (60–62). For example, in the Coe et al study (60), prenatal stress (early and late in pregnancy) was found to provoke structural changes in the hippocampus of the offspring and the inhibition of neurogenesis in the dentate gyrus. These changes were associated with behavioural profiles, suggesting altered emotionality.
In comparing these different results in animal studies, the influence of maternal mood or stress during pregnancy in humans is of great interest. Different studies explain that maternal psychobiologic states can have a programming influence on the developing foetus and thus on behavioural regulation, including infants’ crying behaviour. For example, a prospective longitudinal study of 86 mothers demonstrated that prenatal life stress is associated with infant crying/fussing in the first 6 months postpartum (63). In addition, third-trimester prenatal stress was associated with higher infant cortisol reactivity to stressful events in a nonclinical population of 173 mother–infants dyads in a prospective longitudinal study (64). During pregnancy, maternal self-efficacy (the personality resources of a mother and her beliefs about her capacity to manage stressful situations) moderates the postpartum effect of prenatal stress on infants’ crying/fussing, as shown in a prospective study on 120 mother–infant dyads (65). In contrast, an observational study on 88 mother–infant dyads from a general population demonstrated that mothers’ postpartum moods were associated with longer crying/fussing duration but that third-trimester emotional distress was not related to infant crying/fussing or to motor activity.
In infants, cortisol levels after stressful events change in the first 6 months of life and psychological stressors vary cortisol levels, with an increase in poststressor cortisol only in certain individuals (66). Young infants show considerable cortisol reaction in response to physical stressors. With aging, this response decreases in magnitude (for an extensive review of cortisol reactivity in infants, see reference (67)).
Individual Differences in Sensory Processing Versus Regulatory Disorder
After birth, infants interact with the external world and need to regulate their responses to sensory stimulation. They begin to develop their self-regulatory capacity, including the ability to regulate ongoing behaviour and maintain attention.
Crying, feeding, and sleeping problems have been related to regulatory problems during infancy. Sensory and regulatory problems may manifest as hypersensitivity to sensations, resulting in irritability to sensory stimulation and intolerance to change. The reactivity and regulation of response refer to individual differences in how intensely infants respond to a given amount of stimulation (68). These regulatory difficulties may be an underlying factor that perpetuates infant crying and are sometimes referred to as the regulatory disorder of infancy (behavioural disturbances in feeding, sleeping, motor activity, state control, self-calming, affect, and poor sensory processing) (69,70).
Infants with IC are more responsive and can manifest increased reactivity, but they also have a diminished regulatory capacity. Based on several controlled studies, Barr proposed a difference among responsivity, reactivity, and regulation to describe the transient responsivity hypothesis of colic syndrome (28). Responsivity is referred to as the type of response (positive/smiling or negative/crying) and the dynamics of the response (quality, intensity, and timing of the response). Reactivity is reflected in the threshold, intensity, and time of onset, and regulation is reflected in the duration or rate of recovery of response. This view is well supported by the fact that infants with IC cry longer and more often than typical infants and that they are more difficult to soothe once crying has started. Effective crying regulators or calming manoeuvers (eg, carrying, sucrose taste) in typical infants are not effective in infants with IC. IC also seems to involve a regulatory capacity problem rather than simply be a reactivity disorder.
There is a difference between IC lasting only the first 1 to 3 months of life (transient IC) and excessive crying that lasts beyond the first 3 months of life. It seems that transient IC does not affect cognitive development. Only excessive, uncontrolled crying that continues beyond 3 months is associated with an increased risk of cognitive problems, including lower IQ scores, poor motor abilities, and attention-deficit/hyperactivity problems (71–75).
If, in addition to excessive crying, multiple other regulatory problems (eg, feeding, sleeping difficulties) occur after age 5 months, the likelihood for other neurodevelopmental and psychosocial abnormalities is high. For example, extremely preterm birth, foetal abnormalities, family adversity, and psychosocial stress factors were associated with multiple regulatory problems in infants such as excessive crying and feeding and sleeping difficulties as reported in a prospective longitudinal study based on 5093 infants in Germany (76).
HYPOTHESES AND FURTHER RESEARCH
At birth, newborns are equipped with basic connections involved in pain processing, but major maturation and organisation of their pain control networks occur later (44,77,78). Maturational differences in pain network maturation could, therefore, be related to the specific pattern of sensitivity and regulation observed in crying and colicky infants, which occurs during the first weeks of life.
Perception of pain requires peripheral receptors and their connection to the spinal cord, spinothalamic and thalamocortical connections, and activation of somatosensory cortex. Pain is not only a simple sensory process but also a homeostatic emotion similar to hunger, thirst, temperature, itching, and visceral distension. The human feeling of pain generates an emotion in addition to a sensation (nociception); thus, pain perception includes other cerebral regions such as the insula, the anterior cingulate cortex, and the brainstem (79,80).
Throughout foetal life, the peripheral and central networks of pain perception are developing. The insular and differentiating cortices develop early in the foetus. These become morphologically observable from 18 gestational weeks onward (34,81) (Fig. 2). The neuroanatomical pathways necessary for processing pain are functional at 23 weeks of gestation, a period in which the thalamocortical connectivity is being established (47,48,82,83) (Fig. 2). Using electroencephalogram surface recordings, Fabrizi et al suggested that the human brain may discriminate touch from pain only after 35 to 37 weeks of gestation (84).
γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. GABAergic neurons are widely distributed in the central nervous system, including regions of the spinal cord and supraspinal sites involved in pain processing. GABA acts as an excitatory neurotransmitter early in development, and an important developmental switch in inhibitory-GABAergic control occurs during the postnatal period (after 3 weeks of age in rats) (85). These inhibitory pathways grow during these first weeks of life via an important increase in GABAergic control. If the establishment of inhibitory pathways in humans also occurs only postnatally, it may contribute to the pattern of crying during the first months of life and the hypersensitivity of newborns, which occurs during the same period (10) and decreases thereafter.
Excessive crying in babies could be an infant analogue to hyperalgesia and allodynia in adults. These 2 processes refer to differential pain threshold, pain perception, and duration of response after painful stimuli.
The mechanisms involved in pain conduction and sensory processes also involve melatonin and serotonin, 2 hormones also found in the gastrointestinal (GI) tract. These hormones may participate in the regulation of GI motility and sensitivity. Melatonin is involved in many regulatory processes, such as sleep, mood, reproduction, and immune responses (23,24) and plays a role in sensitivity (86) and in pain conduction (87). A disturbed melatonin level or a positive response to melatonin treatment was described in different chronic pain disorders, in which no pathological findings underlie the pain felt by patients, suggesting its role in the brain over reactivity to usually nonpainful stimuli (88–90). Serotonin levels are higher in colicky babies than in controls, as demonstrated by Kurtoglu et al (91); thus, serotonin may affect IC by affecting GI motility, pain conduction, and pain sensation, but this is only a hypothesis and needs further studies.
Many studies demonstrate that IC is tightly linked to early brain maturation processes. More longitudinal studies and studies linking brain structure and brain function, possible with advanced neuroimaging tools (92), will provide a better understanding of the maturation of brain networks and how they are influenced by environmental stimuli.
1. Wessel MA, Cobb JC, Jackson EB, et al. Paroxysmal fussing in infancy, sometimes called colic. Pediatrics
2. Savino F. Focus on infantile colic. Acta Paediatr
3. Jenni OG, LeBourgeois MK. Understanding sleep-wake behavior and sleep disorders in children: the value of a model. Curr Opin Psychiatry
4. Kumral A, Tuzun F, Yesilirmak D, et al. Circadian genes: mystery underlying the physiopathology of infantile colic. Med Hypotheses
5. White BP, Gunnar MR, Larson MC, et al. Behavioral and physiological responsivity, sleep, and patterns of daily cortisol production in infants with and without colic. Child Dev
6. Huhtala V, Lehtonen L, Heinonen R, et al. Infant massage compared with crib vibrator in the treatment of colicky infants. Pediatrics
7. Barr RG, McMullan SJ, Spiess H, et al. Carrying as colic “therapy”: a randomized controlled trial. Pediatrics
8. Barr RG, Paterson JA, MacMartin LM, et al. Prolonged and unsoothable crying bouts in infants with and without colic. J Dev Behav Pediatr
9. Kanabar D, Randhawa M, Clayton P. Improvement of symptoms in infant colic following reduction of lactose load with lactase. J Hum Nutr Diet
10. Barr RG. Changing our understanding of infant colic. Arch Pediatr Adolesc Med
11. Juberg DR, Alfano K, Coughlin RJ, et al. An observational study of object mouthing behavior by young children. Pediatrics
12. Reppert SM, Weaver DR, Rivkees SA, et al. Putative melatonin receptors in a human biological clock. Science
13. Rivkees SA. Developing circadian rhythmicity in infants. Pediatr Endocrinol Rev
14. Ardura J, Gutierrez R, Andres J, et al. Emergence and evolution of the circadian rhythm of melatonin in children. Horm Res
15. Sadeh A. Sleep and melatonin in infants: a preliminary study. Sleep
16. McGraw K, Hoffmann R, Harker C, et al. The development of circadian rhythms in a human infant. Sleep
17. Sivan Y, Laudon M, Tauman R, et al. Melatonin production in healthy infants: evidence for seasonal variations. Pediatr Res
18. Kennaway DJ, Goble FC, Stamp GE. Factors influencing the development of melatonin rhythmicity in humans. J Clin Endocrinol Metab
19. James-Roberts IS, Conroy S, Hurry J. Links between infant crying and sleep-waking at six weeks of age. Early Hum Dev
20. St James-Roberts I, Peachey E. Distinguishing infant prolonged crying from sleep-waking problems. Arch Dis Child
21. Kirjavainen J, Lehtonen L, Kirjavainen T, et al. Sleep of excessively crying infants: a 24-hour ambulatory sleep polygraphy study. Pediatrics
22. Brand S, Furlano R, Sidler M, et al. “Oh, baby, please don’t cry!”: in infants suffering from infantile colic hypothalamic-pituitary-adrenocortical axis activity is related to poor sleep and increased crying intensity. Neuropsychobiology
23. Brzezinski A. Melatonin in humans. N Engl J Med
24. Brzezinski A, Vangel MG, Wurtman RJ, et al. Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Med Rev
25. Cohen EA, Hadash A, Shehadeh N, et al. Breastfeeding may improve nocturnal sleep and reduce infantile colic: potential role of breast milk melatonin. Eur J Pediatr
26. Kimata H. Laughter elevates the levels of breast-milk melatonin. J Psychosom Res
27. Jacobson L. Hypothalamic-pituitary-adrenocortical axis regulation. Endocrinol Metab Clin North Am
28. Barr RG. Colic and crying syndromes in infants. Pediatrics
1998; 102 (5 Suppl E):1282–1286.
29. Winberg J, Porter RH. Olfaction and human neonatal behaviour: clinical implications. Acta Paediatr
30. Romantshik O, Porter RH, Tillmann V, et al. Preliminary evidence of a sensitive period for olfactory learning by human newborns. Acta Paediatr
31. Chi JG, Dooling EC, Gilles FH. Gyral development of the human brain. Ann Neurol
32. Azoulay R, Fallet-Bianco C, Garel C, et al. MRI of the olfactory bulbs and sulci in human fetuses. Pediatr Radiol
de Graaf-Peters VB, Hadders-Algra M. Ontogeny of the human central nervous system: what is happening when? Early Hum Dev
Lodygensky GA, Vasung L, Sizonenko SV, et al. Neuroimaging of cortical development and brain connectivity in human newborns and animal models. J Anat
Huttenlocher PR, Dabholkar AS. Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol
33. Dubois J, Dehaene-Lambertz G, Mangin JF, et al. [Brain development of infant and MRI by diffusion tensor imaging]. Neurophysiol Clin
34. Dubois J, Benders M, Cachia A, et al. Mapping the early cortical folding process in the preterm newborn brain. Cereb Cortex
35. Smotherman WP, Robinson SR, Ronca AE, et al. Heart rate response of the rat fetus and neonate to a chemosensory stimulus. Physiol Behav
36. Schaal B, Orgeur P, Lecanuet JP, et al. [Nasal chemoreception in utero: preliminary experiences in fetal sheep]. C R Acad Sci III
37. Schaal B, Marlier L, Soussignan R. Human foetuses learn odours from their pregnant mother's diet. Chem Senses
38. Varendi H, Christensson K, Porter RH, et al. Soothing effect of amniotic fluid smell in newborn infants. Early Hum Dev
39. Goubet N, Strasbaugh K, Chesney J. Familiarity breeds content? Soothing effect of a familiar odor on full-term newborns. J Dev Behav Pediatr
40. Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst Rev
41. Barr RG, Young SN, Wright JH, et al. Differential calming responses to sucrose taste in crying infants with and without colic. Pediatrics
42. Marsh DF, Hatch DJ, Fitzgerald M. Opioid systems and the newborn. Br J Anaesth
43. Charnay Y, Paulin C, Dray F, et al. Distribution of enkephalin in human fetus and infant spinal cord: an immunofluorescence study. J Comp Neurol
44. Fitzgerald M. The development of nociceptive circuits. Nat Rev Neurosci
45. Vanhatalo S, van NO. Fetal pain? Brain Dev
46. Fitzgerald M. Development of pain mechanisms. Br Med Bull
47. Kostovic I, Rakic P. Developmental history of the transient subplate zone in the visual and somatosensory cortex of the macaque monkey and human brain. J Comp Neurol
48. Kostovic I, Judas M. The development of the subplate and thalamocortical connections in the human foetal brain. Acta Paediatr
49. Taylor MJ, Boor R, Ekert PG. Preterm maturation of the somatosensory evoked potential. Electroencephalogr Clin Neurophysiol
50. Vanhatalo S, Lauronen L. Neonatal SEP—back to bedside with basic science. Semin Fetal Neonatal Med
51. Erberich SG, Panigrahy A, Friedlich P, et al. Somatosensory lateralization in the newborn brain. Neuroimage
52. Underdown A, Barlow J, Chung V, et al. Massage intervention for promoting mental and physical health in infants aged under six months. Cochrane Database Syst Rev
53. St James-Roberts I, Alvarez M, Csipke E, et al. Infant crying and sleeping in London, Copenhagen and when parents adopt a “proximal” form of care. Pediatrics
54. Moore ER, Anderson GC, Bergman N. Early skin-to-skin contact for mothers and their healthy newborn infants. Cochrane Database Syst Rev
55. St James-Roberts I, Conroy S, Wilsher K. Clinical, developmental and social aspects of infant crying and colic. Early Dev Parent
56. Whittle S, Allen NB, Lubman DI, et al. The neurobiological basis of temperament: towards a better understanding of psychopathology. Neurosci Biobehav Rev
57. Perlman SB, Pelphrey KA. Regulatory brain development: balancing emotion and cognition. Soc Neurosci
58. Schwartz CE, Kunwar PS, Greve DN, et al. Structural differences in adult orbital and ventromedial prefrontal cortex predicted by infant temperament at 4 months of age. Arch Gen Psychiatry
59. Lehtonen L, Korhonen T, Korvenranta H. Temperament and sleeping patterns in colicky infants during the first year of life. J Dev Behav Pediatr
60. Coe CL, Kramer M, Czeh B, et al. Prenatal stress diminishes neurogenesis in the dentate gyrus of juvenile rhesus monkeys. Biol Psychiatry
61. Berger MA, Barros VG, Sarchi MI, et al. Long-term effects of prenatal stress on dopamine and glutamate receptors in adult rat brain. Neurochem Res
62. Day JC, Koehl M, Deroche V, et al. Prenatal stress enhances stress- and corticotropin-releasing factor-induced stimulation of hippocampal acetylcholine release in adult rats. J Neurosci
63. Wurmser H, Rieger M, Domogalla C, et al. Association between life stress during pregnancy and infant crying in the first six months postpartum: a prospective longitudinal study. Early Hum Dev
64. Tollenaar MS, Beijers R, Jansen J, et al. Maternal prenatal stress and cortisol reactivity to stressors in human infants. Stress
65. Bolten MI, Fink NS, Stadler C. Maternal self-efficacy reduces the impact of prenatal stress on infant's crying behavior. J Pediatr
66. Miller AR, Barr RG, Eaton WO. Crying and motor behavior of six-week-old infants and postpartum maternal mood. Pediatrics
67. Jansen J, Beijers R, Riksen-Walraven M, et al. Cortisol reactivity in young infants. Psychoneuroendocrinology
68. St James-Roberts I, Goodwin J, Peter B, et al. Individual differences in responsivity to a neurobehavioural examination predict crying patterns of 1-week-old infants at home. Dev Med Child Neurol
69. Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood: Revised Edition (DC:0-3R)
. Washington, DC: ZERO TO THREE Press; 2005.
70. Degangi GA, Porges SW, Sickel RZ. Four-year follow-up of a sample of regulatory disordered infants. Infant Ment Health
71. Rao MR, Brenner RA, Schisterman EF, et al. Long term cognitive development in children with prolonged crying. Arch Dis Child
72. Wolke D, Rizzo P, Woods S. Persistent infant crying and hyperactivity problems in middle childhood. Pediatrics
73. Wolke D, Schmid G, Schreier A, et al. Crying and feeding problems in infancy and cognitive outcome in preschool children born at risk: a prospective population study. J Dev Behav Pediatr
74. Hemmi MH, Wolke D, Schneider S. Associations between problems with crying, sleeping and/or feeding in infancy and long-term behavioural outcomes in childhood: a meta-analysis. Arch Dis Child
75. Schmid G, Schreier A, Meyer R, et al. A prospective study on the persistence of infant crying, sleeping and feeding problems and preschool behaviour. Acta Paediatr
76. Schmid G, Schreier A, Meyer R, et al. Predictors of crying, feeding and sleeping problems: a prospective study. Child Care Health Dev
77. Fitzgerald M, Jennings E. The postnatal development of spinal sensory processing. Proc Natl Acad Sci U S A
78. Beggs S, Torsney C, Drew LJ, et al. The postnatal reorganization of primary afferent input and dorsal horn cell receptive fields in the rat spinal cord is an activity-dependent process. Eur J Neurosci
79. Craig AD. A new view of pain as a homeostatic emotion. Trends Neurosci
80. Peyron R, Laurent B, Garcia-Larrea L. Functional imaging of brain responses to pain. A review and meta-analysis. Neurophysiol Clin
81. Afif A, Bouvier R, Buenerd A, et al. Development of the human fetal insular cortex: study of the gyration from 13 to 28 gestational weeks. Brain Struct Funct
82. Slater R, Worley A, Fabrizi L, et al. Evoked potentials generated by noxious stimulation in the human infant brain. Eur J Pain
83. Derbyshire SW. Can fetuses feel pain? BMJ
84. Fabrizi L, Slater R, Worley A, et al. A shift in sensory processing that enables the developing human brain to discriminate touch from pain. Curr Biol
85. Hathway GJ, Koch S, Low L, et al. The changing balance of brainstem-spinal cord modulation of pain processing over the first weeks of rat postnatal life. J Physiol
2009; 587 (Pt 12):2927–2935.
86. Thor PJ, Krolczyk G, Gil K, et al. Melatonin and serotonin effects on gastrointestinal motility. J Physiol Pharmacol
2007; 58 (Suppl 6):97–103.
87. Ambriz-Tututi M, Rocha-Gonzalez HI, Cruz SL, et al. Melatonin: a hormone that modulates pain. Life Sci
88. Gagnier JJ. The therapeutic potential of melatonin in migraines and other headache types. Altern Med Rev
2001; 6 4:383–389.
89. Saha L, Malhotra S, Rana S, et al. A preliminary study of melatonin in irritable bowel syndrome. J Clin Gastroenterol
2007; 41 1:29–32.
90. Korszun A, Sackett-Lundeen L, Papadopoulos E, et al. Melatonin levels in women with fibromyalgia and chronic fatigue syndrome. J Rheumatol
1999; 26 12:2675–2680.
91. Kurtoglu S, Uzum K, Hallac IK, et al. 5-Hydroxy-3-indole acetic acid levels in infantile colic: is serotoninergic tonus responsible for this problem? Acta Paediatr
1997; 86 7:764–765.
92. Ment LR, Hirtz D, Huppi PS. Imaging biomarkers of outcome in the developing preterm brain. Lancet Neurol
2009; 8 11:1042–1055.