Neonatal amygdala volumes, procedural pain and the association with social-emotional development in children born very preterm.

Publisher: Springer-Verlag Country of Publication: Germany NLM ID: 101282001 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1863-2661 (Electronic) Linking ISSN: 18632653 NLM ISO Abbreviation: Brain Struct Funct Subsets: MEDLINE

Original Publication: Berlin : Springer-Verlag, c2007-

Amygdala*/diagnostic imaging ; Amygdala*/pathology ; Magnetic Resonance Imaging* ; Infant, Extremely Premature*/growth & development ; Pain, Procedural*; Humans ; Male ; Female ; Infant, Newborn ; Child, Preschool ; Emotions/physiology ; Prospective Studies ; Child Development/physiology ; Social Behavior ; Gestational Age

Very preterm birth (< 32 weeks' gestational age) is associated with later social and emotional impairments, which may result from enhanced vulnerability of the limbic system during this period of heightened vulnerability. Evidence suggests that early procedural pain may be a key moderator of early brain networks. In a prospective cohort study, neonates born very preterm (< 30 weeks' gestation) underwent MRI scanning at term-equivalent age (TEA) and clinical data were collected (mechanical ventilation, analgesics, sedatives). Procedural pain was operationalized as the number of skin breaking procedures. Amygdala volumes were automatically extracted. The Strengths and Difficulties questionnaire was used to assess social-emotional outcomes at 5 years of age (mean age 67.5 months). General linear models were employed to examine the association between neonatal amygdala volumes and social-emotional outcomes and the timing and amount of procedural pain exposure (early within the first weeks of life to TEA) as a moderator, adjusting for biological sex, gestational age, 5-year assessment age, days of mechanical ventilation and total cerebral volumes. A total of 42 preterm infants participated. Right amygdala volumes at TEA were associated with prosocial behaviour at age 5 (B = -0.010, p = 0.005). Procedural pain was found to moderate the relationship between right amygdala volumes in the neonatal period and conduct problems at 5 years, such that early skin breaking procedures experienced within the first few weeks of life strengthened the association between right amygdala volumes and conduct problems (B = 0.005, p = 0.047). Late skin breaking procedures, experienced near TEA, also strengthened the association between right amygdala volumes and conduct problems (B = 0.004, p = 0.048).
Competing Interests: Declarations. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Ab Aziz CB, Ahmad AH (2006) The role of the thalamus in modulating pain. Malaysian J Med Sciences: MJMS 13(2):11.
Anand KJ (1998) Clinical importance of pain and stress in preterm neonates. Neonatology 73(1):1–9. (PMID: 10.1159/000013953)
Barry TJ, Murray L, Fearon P, Moutsiana C, Johnstone T, Halligan SL (2017) Amygdala volume and hypothalamic-pituitary-adrenal axis reactivity to social stress. Psychoneuroendocrinology 85:96–99. (PMID: 28843903563299910.1016/j.psyneuen.2017.07.487)
Bignall WJR, Mara CA, Stark LJ, Taylor S, Herbst RB, McClure JM, Ammerman RT (2023) Evaluation of the strengths and difficulties Questionnaire for preschoolers in Urban Primary Care. J Child Fam stud, 1–14.
Boggini T, Pozzoli S, Schiavolin P, Erario R, Mosca F, Brambilla P, Fumagalli M (2021) Cumulative procedural pain and brain development in very preterm infants: a systematic review of clinical and preclinical studies. Neurosci Biobehavioral Reviews 123:320–336. (PMID: 10.1016/j.neubiorev.2020.12.016)
Brummelte S, Grunau RE, Chau V, Poskitt KJ, Brant R, Vinall J, Miller SP (2012) Procedural pain and brain development in premature newborns. Ann Neurol 71(3):385–396. (PMID: 22374882376084310.1002/ana.22267)
Carbajal R, Rousset A, Danan C, Coquery S, Nolent P, Ducrocq S, Saizou C, Lapillonne A, Granier M, Durand P, Lenclen R, Coursol A, Hubert P, de Saint Blanquat L, Boe¨lle PY, Annequin D, Cimerman P, Anand KJ, Bre´art G (2008) Epidemiology and treatment of painful procedures in neonates in intensive care units. JAMA 300:60–70. (PMID: 1859404110.1001/jama.300.1.60)
Chau CM, Ranger M, Bichin M, Park MTM, Amaral RS, Chakravarty M, Grunau RE (2019) Hippocampus, amygdala, and thalamus volumes in very preterm children at 8 years: neonatal pain and genetic variation. Front Behav Neurosci 13:51. (PMID: 30941021643397410.3389/fnbeh.2019.00051)
Cheong JL, Burnett AC, Treyvaud K, Spittle AJ (2020) Early environment and long-term outcomes of preterm infants. J Neural Transm 127(1):1–8. (PMID: 3186317210.1007/s00702-019-02121-w)
Cheong JL, Doyle LW, Burnett AC, Lee KJ, Walsh JM, Potter CR, Spittle AJ (2017) Association between moderate and late preterm birth and neurodevelopment and social-emotional development at age 2 years. JAMA Pediatr 171(4):e164805–e164805. (PMID: 2815214410.1001/jamapediatrics.2016.4805)
Cismaru AL, Gui L, Vasung L, Lejeune F, Barisnikov K, Truttmann A, Hüppi PS (2016) Altered Amygdala Development and Fear Processing in Prematurely Born infants. Front Neuroanat 10:55. (PMID: 27242451487028010.3389/fnana.2016.00055)
Cook KM, De Asis-Cruz J, Kim JH, Basu SK, Andescavage N, Murnick J, Limperopoulos C (2023) Experience of early-life pain in premature infants is associated with atypical cerebellar development and later neurodevelopmental deficits. BMC Med 21(1):435. (PMID: 379576511064459910.1186/s12916-023-03141-w)
de Almeida JS, Meskaldji DE, Loukas S, Lordier L, Gui L, Lazeyras F, Hüppi PS (2021) Preterm birth leads to impaired rich-club organization and fronto-paralimbic/limbic structural connectivity in newborns. NeuroImage 225:117440. (PMID: 10.1016/j.neuroimage.2020.117440)
Dean B, Ginnell L, Boardman JP, Fletcher-Watson S (2021) Social cognition following preterm birth: a systematic review. Neurosci Biobehavioral Reviews 124:151–167. (PMID: 10.1016/j.neubiorev.2021.01.006)
De Clifford-Faugère G, Lavallée A, Rioux É, Laporte G, Aita M (2021) Neurodevelopmental outcomes of preterm infants who have experienced procedural pain in the neonatal intensive care unit: a systematic review protocol. JBI Evid Synthesis 19(12):3340–3346. (PMID: 10.11124/JBIES-20-00336)
de Macedo Rodrigues K, Ben-Avi E, Sliva DD, Choe MS, Drottar M, Wang R, Zöllei L (2015) A FreeSurfer-compliant consistent manual segmentation of infant brains spanning the 0–2 year age range. Frontiers in human neuroscience 9:21.
Duerden EG, Grunau RE, Chau V, Groenendaal F, Guo T, Chakravarty MM, Miller SP (2020) Association of early skin breaks and neonatal thalamic maturation: a modifiable risk? Neurology 95(24):e3420–e3427. (PMID: 33087497783665810.1212/WNL.0000000000010953)
Duerden EG, Grunau RE, Guo T, Foong J, Pearson A, Au-Young S, Miller SP (2018) Early procedural pain is associated with regionally-specific alterations in thalamic development in preterm neonates. J Neurosci 38(4):878–886. (PMID: 29255007578396610.1523/JNEUROSCI.0867-17.2017)
Eleftheriou BE, Humphrey T (1972) The development of the human amygdaloid complex. In The Neurobiology of the Amygdala: The Proceedings of a Symposium on the Neurobiology of the Amygdala, Bar Harbor, Maine, June 6–17, 1971 (pp. 21–80). Springer US.
Fernández de Gamarra-Oca L, Lucas-Jiménez O, Ontañón JM, Loureiro-Gonzalez B, Peña J, Ibarretxe-Bilbao N, Zubiaurre-Elorza L (2024) Amygdala structure and function and its associations with social-emotional outcomes in a low-risk preterm sample. Brain Struct Function, 1–12.
Fitzgerald M (2005) The development of nociceptive circuits. Nat Rev Neurosci 6(7):507–520. (PMID: 1599572210.1038/nrn1701)
Fitzgerald M (2013) Central nociceptive pathways and descending modulation. Oxford Textbook of Paediatric Pain, pp 74–81.
Fitzgerald M (2021) The development of central nociceptive processing and descending modulation of pain. Oxford Textbook of Pediatric Pain, p 72.
Fitzgerald M, Walker SM (2009) Infant pain management: a developmental neurobiological approach. Nat Clin Pract Neurol 5(1):35–50. (PMID: 1912978910.1038/ncpneuro0984)
Fowler CH, Bogdan R, Gaffrey MS (2021) Stress-induced cortisol response is associated with right amygdala volume in early childhood. Neurobiol Stress 14:100329. (PMID: 33997154810262110.1016/j.ynstr.2021.100329)
Gee DG, Gabard-Durnam LJ, Flannery J, Goff B, Humphreys KL, Telzer E, Tottenham N (2013) Early developmental emergence of human amygdala–prefrontal connectivity after maternal deprivation. Proceedings of the National Academy of Sciences, 110(39), 15638–15643.
Giannakoulopoulos X, Teixeira J, Fisk N, Glover V (1999) Human fetal and maternal noradrenaline responses to invasive procedures. Pediatr Res 45(4):494–499. (PMID: 1020314010.1203/00006450-199904010-00007)
Gilchrist CP, Thompson DK, Kelly CE, Beare R, Adamson C, Dhollander T, Anderson PJ (2022) The structural connectome and internalizing and externalizing symptoms at 7 and 13 years in individuals born very preterm and full term. Biol Psychiatry: Cogn Neurosci Neuroimaging 7(4):424–434. (PMID: 34655805)
Goodman R (1997) The strengths and difficulties questionnaire: a research note. Child Psychology & Psychiatry & Allied Disciplines 38(5):581–586. https://doi.org/10.1111/j.1469-7610.1997.tb01545.x.
Goodman A, Goodman R (2009) Strengths and difficulties questionnaire as a dimensional measure of child mental health. J Am Acad Child Adolesc Psychiatry 48(4):400–403. (PMID: 1924238310.1097/CHI.0b013e3181985068)
Grunau RE (2013) Neonatal pain in very preterm infants: long-term effects on brain, neurodevelopment and pain reactivity. Rambam Maimonides Med J 4:e0025. https://doi.org/10.5041/RMMJ.10132. (PMID: 10.5041/RMMJ.10132242281683820298)
Grunau RE, Whitfield MF, Petrie-Thomas J, Synnes AR, Cepeda IL, Keidar A, Johannesen D (2009) Neonatal pain, parenting stress and interaction, in relation to cognitive and motor development at 8 and 18 months in preterm infants. Pain 143(1–2):138–146. (PMID: 19307058283679310.1016/j.pain.2009.02.014)
Guadagno A, Belliveau C, Mechawar N, Walker CD (2021) Effects of early life stress on the developing basolateral amygdala-prefrontal cortex circuit: the emerging role of local inhibition and perineuronal nets. Front Hum Neurosci 15:669120. (PMID: 34512291842662810.3389/fnhum.2021.669120)
Guillot M, Guo T, Ufkes S, Schneider J, Synnes A, Chau V, Miller SP (2020) Mechanical ventilation duration, brainstem development, and neurodevelopment in children born preterm: a prospective cohort study. J Pediatr 226:87–95. (PMID: 3245411510.1016/j.jpeds.2020.05.039)
Holland D, Chang L, Ernst TM, Curran M, Buchthal SD, Alicata D, Dale AM (2014) Structural growth trajectories and rates of change in the first 3 months of infant brain development. JAMA Neurol 71(10):1266–1274. (PMID: 25111045494015710.1001/jamaneurol.2014.1638)
Iglesias JE, Sabuncu MR (2015) Multi-atlas segmentation of biomedical images: a survey. Medical image analysis 24(1):205–219.
Johns CB, Lacadie C, Vohr B, Ment LR, Scheinost D (2019) Amygdala functional connectivity is associated with social impairments in preterm born young adults. NeuroImage: Clin 21:101626. (PMID: 3054568810.1016/j.nicl.2018.101626)
Klimes-Dougan B, Eberly LE, Schreiner MW, Kurkiewicz P, Houri A, Schlesinger A, Cullen KR (2014) Multilevel assessment of the neurobiological threat system in depressed adolescents: interplay between the limbic system and hypothalamic–pituitary–adrenal axis. Dev Psychopathol 26(4pt2):1321–1335. (PMID: 25422964438570710.1017/S0954579414001059)
Kostović I (2020) The enigmatic fetal subplate compartment forms an early tangential cortical nexus and provides the framework for construction of cortical connectivity. Prog Neurobiol 194:101883. (PMID: 3265931810.1016/j.pneurobio.2020.101883)
Lammertink F, Benders MJ, Hermans EJ, Tataranno ML, Dudink J, Vinkers CH, van den Heuvel MP (2022) Vulnerability of the neonatal connectome following postnatal stress. J Neurosci 42(48):8948–8959. (PMID: 36376077973282710.1523/JNEUROSCI.0176-22.2022)
LeDoux J (2003) The emotional brain, fear, and the amygdala. Cell Mol Neurobiol 23:727–738. (PMID: 1451402710.1023/A:1025048802629)
LeDoux JE (2012) Evolution of human emotion: a view through fear. Prog Brain Res 195:431–442. (PMID: 22230640360091410.1016/B978-0-444-53860-4.00021-0)
Liverani MC, Loukas S, Gui L, Pittet MP, Pereira M, Truttmann AC, Borradori-Tolsa C (2023) Behavioral outcome of very preterm children at 5 years of age: prognostic utility of brain tissue volumes at term‐equivalent‐age, perinatal, and environmental factors. Brain Behav 13(2):e2818. (PMID: 36639960992783410.1002/brb3.2818)
Lucas-Jiménez O, Ontañón JM, Loureiro-Gonzalez B, Peña J, Ibarretxe-Bilbao N, García-Guerrero MA, Zubiaurre-Elorza L (2024) Amygdala structure and function and its associations with social-emotional outcomes in a low-risk preterm sample. Brain Structure & Function.
Meltzer H, Gatward R, Goodman R, Ford T (2003) Mental health of children and adolescents in Great Britain. Int Rev Psychiatry 15(1–2):185–187. (PMID: 1274533110.1080/0954026021000046155)
Mueller M, Thompson B, Poppe T, Alsweiler J, Gamble G, Jiang Y, Leung M, Tottman AC, Wouldes T, Harding JE, Duerden EG (2022) PIANO Study Group. Amygdala subnuclei volumes, functional connectivity, and social-emotional outcomes in children born very preterm. Cereb Cortex Commun 3(3):tgac028. https://doi.org/10.1093/texcom/tgac028 . PMID: 35990310; PMCID: PMC9383265.
Nikolić I, Kostović I (1986) Development of the lateral amygdaloid nucleus in the human fetus: transient presence of discrete cytoarchitectonic units. Anat Embryol 174:355–360. (PMID: 10.1007/BF00698785)
Nolvi S, Tuulari JJ, Pelto J, Bridgett DJ, Eskola E, Lehtola SJ, Karlsson H (2021) Neonatal amygdala volumes and the development of self-regulation from early infancy to toddlerhood. Neuropsychology 35(3):285. (PMID: 3397066210.1037/neu0000724)
O’Rahilly RR, Fabiola M (2006) The embryonic human brain: an atlas of developmental stages. Wiley.
Porter FL, Wolf CM, Miller JP (1999) Procedural pain in newborn infants: the influence of intensity and development. Pediatrics 104(1):e13–e13. (PMID: 1039029910.1542/peds.104.1.e13)
Ranger M, Grunau RE (2014) Early repetitive pain in preterm infants in relation to the developing brain. Pain Manage 4(1):57–67. (PMID: 10.2217/pmt.13.61)
Rogers CE, Anderson PJ, Thompson DK, Kidokoro H, Wallendorf M, Treyvaud K, Inder TE (2012) Regional cerebral development at term relates to school-age social–emotional development in very preterm children. J Am Acad Child Adolesc Psychiatry 51(2):181–191. (PMID: 22265364341118710.1016/j.jaac.2011.11.009)
Rogers CE, Sylvester CM, Mintz C, Kenley JK, Shimony JS, Barch DM, Smyser CD (2017) Neonatal amygdala functional connectivity at rest in healthy and preterm infants and early internalizing symptoms. J Am Acad Child Adolesc Psychiatry 56(2):157–166. (PMID: 2811706210.1016/j.jaac.2016.11.005)
Rolls ET (2015) Limbic systems for emotion and for memory, but no single limbic system. cortex, 62, 119–157.
Scheinost D, Kwon SH, Lacadie C, Sze G, Sinha R, Constable RT, Ment LR (2016) Prenatal stress alters amygdala functional connectivity in preterm neonates. NeuroImage: Clin 12:381–388. (PMID: 2762213410.1016/j.nicl.2016.08.010)
Schmitz-Koep B, Zimmermann J, Menegaux A, Nuttall R, Bäuml JG, Schneider SC, Sorg C (2021a) Decreased amygdala volume in adults after premature birth. Sci Rep 11(1):5403. (PMID: 33686187797087910.1038/s41598-021-84906-2)
Schmitz-Koep B, Zimmermann J, Menegaux A, Nuttall R, Bäuml JG, Schneider SC, Sorg C (2021b) Within amygdala: basolateral parts are selectively impaired in premature-born adults. NeuroImage: Clin 31:102780. (PMID: 3439114010.1016/j.nicl.2021.102780)
Schneider J, Duerden EG, Guo T, Ng K, Hagmann P, Graz MB, Miller SP (2018) Procedural pain and oral glucose in preterm neonates: brain development and sex-specific effects. Pain 159(3):515–525. (PMID: 2920018010.1097/j.pain.0000000000001123)
Seguin D, Pac S, Wang J, Nicolson R, Martinez-Trujillo J, Duerden EG (2021) Amygdala subnuclei development in adolescents with autism spectrum disorder: Association with social communication and repetitive behaviors. Brain Behav, 11(8), e2299.
Setzer M, Ulfig N (1999) Differential expression of calbindin and calretinin in the human fetal amygdala. Microsc Res Tech 46(1):1–17. https://doi.org/10.1002/(SICI)1097-0029(19990701)46:13.0.CO;2-P.
Slater L, Asmerom Y, Boskovic DS, Bahjri K, Plank MS, Angeles KR, Angeles DM (2012) Procedural pain and oxidative stress in premature neonates. J pain 13(6):590–597. (PMID: 22543043336703310.1016/j.jpain.2012.03.010)
Slater R, Fabrizi L, Worley A, Meek J, Boyd S, Fitzgerald M (2010) Premature infants display increased noxious-evoked neuronal activity in the brain compared to healthy age-matched term-born infants. NeuroImage 52(2):583–589. (PMID: 2043885510.1016/j.neuroimage.2010.04.253)
Smith GC, Gutovich J, Smyser C, Pineda R, Newnham C, Tjoeng TH, Inder T (2011) Neonatal intensive care unit stress is associated with brain development in preterm infants. Ann Neurol 70(4):541–549. (PMID: 21976396462747310.1002/ana.22545)
Stone LL, Otten R, Engels RC, Vermulst AA, Janssens JM (2010) Psychometric properties of the parent and teacher versions of the strengths and difficulties questionnaire for 4-to 12-year-olds: a review. Clin Child Fam Psychol Rev 13:254–274. (PMID: 20589428291968410.1007/s10567-010-0071-2)
Tortora D, Severino M, Di Biase C, Malova M, Parodi A, Minghetti D, Ramenghi LA (2019) Early pain exposure influences functional brain connectivity in very preterm neonates. Front NeuroSci 13:899. (PMID: 31507370671647610.3389/fnins.2019.00899)
Uematsu A, Matsui M, Tanaka C, Takahashi T, Noguchi K, Suzuki M, Nishijo H (2012) Developmental trajectories of amygdala and hippocampus from infancy to early adulthood in healthy individuals.
Ulfig N, Setzer M, Bohl J (1999) Distribution of GAP-43-immunoreactive structures in the human fetal amygdala. Eur J Histochemistry: EJH 43(1):19–28. (PMID: 10340140)
Valeri BO, Holsti L, Linhares MB (2015) Neonatal pain and developmental outcomes in children born preterm: a systematic review. Clin J Pain 31(4):355–362. (PMID: 2486685310.1097/AJP.0000000000000114)
Veinante P, Yalcin I, Barrot M (2013) The amygdala between sensation and affect: a role in pain. J Mol Psychiatr 1:9. (PMID: 10.1186/2049-9256-1-9)
Vinall J, Grunau RE (2014) Impact of repeated procedural pain-related stress in infants born very preterm. Pediatr Res 75(5):584–587. (PMID: 24500615399218910.1038/pr.2014.16)
Vinall J, Miller SP, Synnes AR, Grunau RE (2013) Parent behaviors moderate the relationship between neonatal pain and internalizing behaviors at 18 months corrected age in children born very prematurely. PAIN ^® 154(9):1831–1839. (PMID: 2374807910.1016/j.pain.2013.05.050)
Vyas A, Mitra R, Shankaranarayana Rao BS, Chattarji S (2002) Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci 22:6810–6681. (PMID: 12151561675813010.1523/JNEUROSCI.22-15-06810.2002)
Vyas A, Pillai AG, Chattarji S (2004) Recovery after chronic stress fails to reverse amygdaloid neuronal hypertrophy and enhanced anxiety-like behavior. Neuroscience 128:667–673. https://doi.org/10.1016/j.neuroscience.2004.07.013. (PMID: 10.1016/j.neuroscience.2004.07.01315464275)
Walker SM, Melbourne A, O’Reilly H, Beckmann J, Eaton-Rosen Z, Ourselin S, Marlow N (2018) Somatosensory function and pain in extremely preterm young adults from the UK EPICure cohort: sex-dependent differences and impact of neonatal surgery. Br J Anaesth 121(3):623–635. (PMID: 30115261620011410.1016/j.bja.2018.03.035)
Wood GE, Norris EH, Waters E, Stoldt JT, McEwen BS (2008) Chronic immobilization stress alters aspects of emotionality and associative learning in the rat. Behav Neurosci 122(2):282. (PMID: 1841016810.1037/0735-7044.122.2.282)
Yamamoto T, Toki S, Siegle GJ, Takamura M, Takaishi Y, Yoshimura S, Yamawaki S (2017) Increased amygdala reactivity following early life stress: a potential resilience enhancer role. BMC Psychiatry 17:1–11. (PMID: 10.1186/s12888-017-1201-x)
Zöllei L, Iglesias JE, Ou Y, Grant PE, Fischl B (2020) Infant freesurfer: an automated segmentation and surface extraction pipeline for T1-weighted neuroimaging data of infants 0–2 years. Neuroimage 218:116946.

33CM30-124101 Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

Keywords: Development; Emotional; Prematurity; Procedural pain; Social
Local Abstract: [Publisher, German] Dysregulated growth and maturation of the amygdala in preterm neonates is associated with differences in social functioning in children born preterm, with early life procedural pain moderating these associations. Examination of sensitive windows when the developing brain may be most vulnerable to the adverse effects of procedural pain may inform pain management practices. This is key in the identification of children at risk for social difficulties and can lead to targeted interventions to support social development in this population. [Publisher, French] ● Preterm birth is associated with social-emotional challenges.● Amygdala volumes at term equivalent age were assessed in relation to preschool social-emotional outcomes.● Larger right amygdala volumes at term-equivalent age were associated with impaired prosocial behaviour at age 5.● Procedural pain moderated the relationship between neonatal amygdala volumes and conduct problems at age 5, with early or late skin breaking procedures strengthening this association.● Dysregulated growth and maturation of the amygdala in preterm neonates were associated with differences in social functioning at 5 years old, with early life procedural pain playing a moderating role.

Date Created: 20240805 Date Completed: 20241202 Latest Revision: 20241202

20241204

10.1007/s00429-024-02845-w

39103553