A neurobiological model for the effects of early brainstem functioning
Journal of Child Psychology and Psychiatry 49:10 (2008), pp 1031–1041 doi:10.1111/j.1469-7610.2008.01918.x A neurobiological model for the effects of early brainstem functioning on the development of behavior and emotion regulation in infants: implications for prenatal and perinatal risk Ronny Geva and Ruth Feldman The Gonda Goldschmied Brain Research Center, Bar Ilan University, Ramat Gan, Israel Neurobiological models propose an evolutionary, vertical-integrative perspective on emotion and behavior regulation, which postulates that regulatory functions are processed along three core brain systems: the brainstem, limbic, and cortical systems. To date, few developmental studies applied these models to research on prenatal and perinatal risk. We propose a conceptual model that incorporates three integrated levels of observations for the study of early risk: (a) brainstem-related physiological regulation of cyclic processes and sensory integration, e.g., vagal regulation, circadian rhythms; (b) emotion and attention regulation capacities that draw on the integration of brainstem and limbic systems; and (c) higher-level outcomes that draw on the intactness of brainstem and limbic networks, including socio-emotional self-regulation, inhibitory control, and cognitive processing. We discuss implications of the model for the development of regulatory capacities during the prenatal and early postnatal stages in infants born with speciﬁc perinatal risk. We underscore the importance of assessing sub-cortical and brainstem systems and the longitudinal effects of transitory brainstem dysfunction on physiological homeostasis, motivation, arousal-modulated attention, stress reactivity, and mother- infant co-regulation. The assessment of brainstem dysfunction can be conducted during hospitalization and may help detect infants at risk for the development of self-regulatory deﬁcits at the ﬁrst weeks of life. Keywords: Audiology, brain development, emotion regulation, executive function, perinatal, prematurity. Abbreviations: ABR: auditory brainstem evoked responses; IVH: intraventricular hemorrhage; MRI: magnetic resonance imaging; CBSF: compromised brainstem functioning; VT: vagal-tone; AMA: arousal-modulated attention; CCK: cholecyctokinin; CNS: central nervous system; US: cranial ultra-sound; NICU: neonatal intensive care unit.Neurobiological models of emotions propose an evo- pre- and perinatal risk are at a greater risk forlutionary, vertical-integrative view on emotion and speciﬁc developmental disruptions of this system.behavior regulation (Panksepp, 2005; Tucker, Luu, To date, knowledge on the hierarchical functioning& Derryberry, 2005). Regulatory functions are theor- of the brain is based primarily on animal research.ized to be processed along three core brain systems: However, electrophysiological, biochemical, imaging,the brainstem, limbic, and cortical systems, which and behavioral data may be pulled together toare integrated into a vertical-integrative hierarchical examine the implications of these models for thesystem. This developing system draws upon brain- development of behavior and emotion regulationstem-related homeostatic systems, which provide during the very ﬁrst phases of postnatal life inthe physiological foundation for the regulation of infants born prematurely or with perinatal risk.state, attention, and emotional reactivity. Brain- Incorporating development into the model maystem-mediated systems, in turn, enable the develop- increase empirical attention to the functioning ofment of arousal, attention, and emotional regulation brainstem systems as predictors for the developmentthat drive high-order self-regulatory abilities, effort- of regulatory capacities in high-risk neonates.ful control, and socio-cognitive processes. This Evidence for the vertical-integrative perspectiveintegrated system is based upon brainstem relay, comes from neurochemical, imaging, electrophysio-which undergoes a rapid developmental maturation logical, and clinical studies, mostly with adults.during the last quarter of gestation. Optimal develop- Neurochemical systems, including the serotonergic,ment of the vertical-integrative system depends on dopaminergic, noradrenergic, and other neuropep-the provision of speciﬁcally-tailored environmental tidergic systems, involve hierarchical and synchron-and maternal stimulation. As such, infants born at ous functioning at brainstem, limbic, and cortical levels (Caldji, Francis, Sharma, Plotsky, & Meaney,Conﬂict of interest statement: No conﬂicts declared. 2000; Damasio et al., 2000; Jentsch, Roth, & Taylor,Ó 2008 The AuthorsJournal compilation Ó 2008 Association for Child and Adolescent Mental Health.Published by Blackwell Publishing, 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main Street, Malden, MA 02148, USA
1032 Ronny Geva and Ruth Feldman2000; Gunnar & Quevedo, 2007). Such vertical serve as an indicator of later neuro-functionalintegration of neurochemical systems also affects deﬁcits.emotion regulation in infants and toddlers (Rothbart& Rueda, 2005). The noradrenergic system, forinstance, has been shown to mediate arousal Effects of prenatal and perinatal risk onregulation in social contexts, such as mother–infant brainstem functionsinteractions, through a brainstem–limbic–right-hemisphere brain circuitry (Tucker et al., 2005; During late gestation, at 33–38 weeks, there areSchore, 1997) and ﬁght-or-ﬂight reactions to stress signiﬁcant developmental changes in the brainstem(Morilak et al., 2005). Speciﬁc dopaminergic and (Darnall, Ariagno, & Kinney, 2006). At this phase,serotonergic genes were found to mediate the various prenatal and perinatal risk factors affecteffortful control dimension of temperament. This brainstem functions and physiological homeostaticdimension, which involves prefrontal activity, regulation of the heart and lung as well as theemerges on the basis of brainstem–limbic-related regulation of state and satiety (Darnall et al., 2006).functions: the surgency/extroversion component Brainstem dysregulation may be indicated byand the negative affectivity component (Rothbart, anomalies in auditory brainstem evoked responsesSheese, & Posner, 2007; Posner, Rothbart, & Sheese, (ABR). Dynamical changes in latency of the three2007). major ABR components correspond well to concur- Imaging studies of human adults similarly point rent hypoxic-ischemic brainstem-related patho-to brainstem–cortical links in the processing and physiological changes in neonates (Jiang, Yin,regulation of emotions. For example, Damasio and Shao, & Wilkinson, 2004). In large communitycolleagues (2000) demonstrated the role of the studies, the risk for anomalies in ABR functions inbrainstem in the perception, experience, and mem- neonates with various neurological impairmentsory of self-relevant emotions. Although little imaging was substantially greater than among controlsresearch is available in neonates, behavioral studies (N = 1087; Salamy & Eldredge, 1994). Similar ABRshow that deﬁcits in neonatal sub-cortical systems anomalies were found in preterm infants and inare related to later difﬁculties of attention organ- term infants with neurological impairments. Amongization and inhibitory control (Gardner, Karmel, & premature infants at the Neonatal Intensive CareFlory, 2003; Karmel, Gardner, & Freedland, 1996; Unit (NICU), 16.1–28% of neonates failed the ﬁrstGeva, 1995). More speciﬁcally, neonates with ABR test (N = 1613; Galambos, Hicks, & Wilson,brainstem dysfunctions showed poorer attention 1982; Murray, 1988). These studies highlight theregulation as a function of arousal states at susceptibility of preterm infants to brainstem dys-1 month of age (Gardner et al., 2003); poorer functions.attentional responses that were hyperresponsive to Several studies have used ABR technology withincreased endogenous arousal at 4 months (Karmel groups of preterm infants or infants with speciﬁcet al., 1996); and less regulated inhibitory control perinatal risks. Brainstem dysfunction was found toon rapid automatized naming tasks at 3 years of be common in selected populations of pretermage (Geva, 1995; Geva, Gardner, & Karmel, 2004). infants. Karmel and colleagues found functionalThis line of work is also complemented by basic brainstem dysfunctions in neonates with brainscience research and animal decortication models insult or with hydrocephalus (N = 416; Karmel,which highlight the role of brainstem structures in Gardner, Zappulla, Magnano, & Brown, 1988). ABRintegrating sensations from the environment with evaluations in neonates were found to be sensitiveone’s immediate goals and feelings in order to guide to perinatal asphyxia and hypoxic-ischemic damagebehavior and enable conscious awareness (Merker, in preterm infants (Jiang et al., 2004). Abnormal2007). These studies also indicate that higher-level ABRs increased in cases of transient low Apgarcapacities, such as executive functioning, self- scores even in the absence of chronic hypoxic-regulation, and representational thought, which ischemic encephalopathy (Jiang, Xiu, Brosi, Shao,most likely involve cortical activity, also require & Wilkinson, 2007) and in preterm infants dia-simultaneous processing at the brainstem and gnosed with chronic lung disease and bronchopul-limbic levels. Thus, brainstem-related systems are monary dysplasia in the neonatal period (Wilkinson,likely to play an important role in self-regulation. Brosi, & Jiang, 2007). Such anomalies areTaking this notion a step further, we propose diagnosed in young preterm infants at a criticalthat prenatal disruptions in brainstem-related period for the myelination of the equilibrium anddevelopmental processes are likely to impact on auditory pathways in the brainstem, axonalthe development of self-regulation across childhood sprouting, formation of central synaptic connec-and beyond. Furthermore, since brainstem struc- tions, improvement of synaptic efﬁciency, increasetures mature early and precede the development in axonal diameter, and development of centralof limbic and cortical structures, disrupted dendritic properties (Jiang, Brosi, & Wilkinson,development of brainstem structures and their 2006; Krumholz, Felix, Goldstein, & McKenzie,functions in preterm and high-risk infants may 1985; Moore, Perazzo, & Braun, 1995). Such poor Ó 2008 The Authors Journal compilation Ó 2008 Association for Child and Adolescent Mental Health.
A neurobiological model for the effects of early brainstem functioning 1033myelination of early-maturing brainstem structures structural brainstem disorder, the cause is fetalin preterm infants points to the potential links vascular accidents (Roig et al., 2003). Other studiesbetween brainstem dysfunction and the risk for examined physiological brainstem dysfunctions indisruption in the vertical integration. premature infants. Volpe (1995) pointed out that neuronal pathology can be detected at pontine levels of the brainstem in as many as 71% of the infantsRelations between prenatal and perinatal risk with intraventricular hemorrhage (IVH), and mag-and the development of the vertical-integrated netic resonance imaging (MRI) studies indicatedframework wider brainstem involvement than previously thought. Yet, very little information is available onSpeciﬁc prenatal and perinatal risks that interfere the predicative utility of morphological brainstemwith myelination and synaptic functions in the MRI and ABR ﬁndings for the development of self-brainstem may affect the development of adaptive regulation in infants. It is important to note, how-self-regulation. Follow-ups of premature infants ever, that the sensitivity and speciﬁcity of ABRindicate relations between CNS problems and poor assessments were found to be signiﬁcantly higheroutcome (Hack et al., 1994; Jongmans, Mercuri, than those reported for MRI for the detection ofDeVries, Dubowitz, & Henderson, 1997). These sensory-neuro deﬁcits (Valkama et al., 2001).studies, however, do not specify the neonatal CNSinjury and rarely deal with the underlying mechan-isms accounting for these deﬁcits. In particular, little Model-driven hypothesis of neonatalresearch has documented the contribution of brain- brainstem dysfunction and developmentalstem structures to developmental psychopathology. outcomeReliance on structural information or epidemio-logical factors alone may not be sufﬁcient to detect The proposed model (Figure 1) suggests both directsubtle neuro-functional deﬁcits that underpin self- neurobiological and indirect behavioral long-termregulatory capacities. effects of compromised brainstem functioning Recent studies have begun to address the evalu- (CBSF) on self-regulation. In line with the verticalation of brainstem functioning in fetuses, neonates, perspective of neuro-functions, it is hypothesizedand infants. These studies focus mainly on mor- that early brainstem trauma directly affects physio-phological changes or functional anomalies. Struc- logical regulation in the ﬁrst weeks of life.tural brainstem dysgenesis syndromes in fetuses, Physiological regulatory difﬁculties that reﬂectsuch as Pierre Rubin sequence, are rare and bear disturbed brainstem-mediated homeostasis may begrave outcomes (Abadie, Morisseau-Durand, evident in the following systems: (a) the autonomicBeyler, Manach, & Couly, 2002; Roig et al., 2003). nervous system as assessed, for example, by cardiacThe symptoms are closely dependent on the vagal-tone (VT; Porges, 1992) and by cardio-excessiveness of the affected brainstem loci and are respiratory regulation (Hunt, 2006); (b) circadianoften related to orodigestive and cardiorespiratory regulation of arousal (Karlsson, Gall, Mohns, Seelke,anomalies (Abadie et al., 2002). In most cases of & Blumberg, 2005); and (c) the modulation ofFigure 1 A schematic representation of the neurobiological model for the effects of early brainstem functioning onthe development of behavior and emotion regulation in infantsÓ 2008 The AuthorsJournal compilation Ó 2008 Association for Child and Adolescent Mental Health.
1034 Ronny Geva and Ruth Feldmanvisceral homeostasis of internal states, such as and emotion-regulation capacities (Sigman, Cohen,hunger and satiety (Batterham et al., 2007). These & Beckwith, 1997).systems, which are mediated by the brainstem, After the age of 3 months, through the maturationwere shown to interact with the development of of collicular–basal ganglia functions and the devel-emotion and attention regulation in infants opment of the posterior attention systems (Posner,(Porges, 1997). Consequently, the infant’s ability Petersen, Fox, & Raichle, 1988), there is a develop-to maintain proper physiological homeostasis in mental shift to sensory-speciﬁc attention (Karmel &order to attend to external stimuli, to modulate Gardner, 2005; Geva et al., 1999a, 1999b; Johnson,arousal, and to react to stressful situations may be Posner, & Rothbart, 1991). During this period,compromised. through mediation of norepinephrine and dopamine, Difﬁculties in the regulation of basic physiolo- modulation of attention affords the adaptive coordi-gical functions such as sleep, feeding, or self- nation of vigilance and distress during informationsoothing may disrupt the management of negative processing (Eckerman, Oehler, Hannan, & Molitor,emotions, the development of inhibitory control as 1995). The second relevant milestone is the con-expressed by conduct or antisocial problems, or nectivity to the limbic system. Tucker and colleagueslead to attention deﬁcit or hyperactivity disorders (2005) proposed that two midbrain structures, theat later stages. Several studies indicated that hypothalamus and thalamus, are pivotal in orga-certain sub-groups of premature infants exhibit nizing internal and external inﬂuences to ensuresuch symptoms more frequently than full-term homeostasis of complex vertebrates. The hypothal-infants, for instance infants diagnosed with intra- amus is central in securing visceral regulation ofuterine growth restriction (Geva, Eshel, Leitner, internal states, such as hunger, thirst, temperature,Fattal-Valevski, & Harel, 2005) or very low birth and pain, and the thalamus at the top of the brain-weight infants with periventricular leucomalacia stem mediates the sensory and motor interfaces(Skranes et al., 2007). During later stages, mat- via projections to the telecephalon, trafﬁckinguration of top-down fronto-limbic connections, limbic input as to the potential value of externaloften in the right prefrontal cortex, is described as inputs.the apex of the proposed hierarchy (Schore, 1997) The transition to self-regulatory behaviors duringand enables adaptive coping responses to stress the second year of life often draws upon higher(Ellenbogen, Schwartzman, Stewart, & Walker, control systems, reﬂecting the integration of the2006). Accordingly, the development of higher anterior cingulate gyrus that is implicated in thefunctions, such as inhibitory control and social- coordination of distress and attention. The cingu-emotional self-regulation, is hypothesized to be late is an integral component of the limbic system.compromised (Dennis, 2006). The functional connectivity to prefrontal loci marks the ﬁnal steps of the development of this system by exerting inhibitory control (Diamond, 1990). Thus, we propose that even transitoryA developmental neuropsychological dysfunction of brainstem structures at the new-perspective on vertical-integration of born period may disrupt the maturation of thebrainstem dysfunction and the development entire system that supports behavior and emotionof self-regulation regulation.Brainstem trauma, as assessed by abnormal ABR Although links have been found between physio-and cranial ultrasound and/or MRI, typically re- logical regulation and outcomes in preterm infants,solves during the neonatal period (Wilkinson et al., no information is typically provided on the speciﬁc2007). Nevertheless, its physiological and behavioral neuro-pathogenesis leading to emotion dysregula-consequences are identiﬁable in the neonatal period, tion. Several researchers have proposed mechan-provided one is searching for mechanisms that are isms that may mediate the effects of prematurity onmediated by brainstem functions. Mechanisms of emotion regulation. Anand and Scalzo (2000)arousal and attention are mediated by sub-cortical described two pathways by which prematurity dis-brainstem-related structures, especially prior to rupts behavior organization. Stimulus overload2–3 months of age (Gardner & Karmel, 1995; Geva, related to early maternal separation leads to apop-Gardner, Karmel, Feldman, & Freedland, 1999a; tosis (programmed cell-death) in multiple areas ofGeva, Gardner, & Karmel, 1999b). Arousal inﬂu- the immature brain. Additionally, exposure of theences not only tonic activity, but also gates speciﬁc immature CNS to pain causes excessive excitatorysensory processing when internal or external factors amino acid activation resulting in excitotoxicare manipulated through feeding or stimulation damage to developing neurons. Neurologically, these(Geva et al., 1999a, 1999b). This self-limiting conditions may lead to changes in prelimbicbrainstem-related system helps neonates maintain prefrontal areas, causing increased excitation andhomeostasis (Zeskind, Goff, & Marshall, 1991). hyper-reactivity (Risterucci, Terramorsi, Nieoullon,Disruptions in the ability to shift arousal or maintain & Amalric, 2003). Behaviorally, both conditions areequilibrium impact on later cognitive, behavioral, expressed in disturbed reactivity, difﬁculties in Ó 2008 The Authors Journal compilation Ó 2008 Association for Child and Adolescent Mental Health.
A neurobiological model for the effects of early brainstem functioning 1035sustained attention, and inability to self-regulate (a) Physiological regulation of arousal: sleep–wake cyc-(Chudasama et al., 2003). licity and cardiac tone. Abundant knowledge, using animal models, human adults, and infant studies, conﬁrms that the monitoring of physiological regu- latory status is located in multiple vital locales in theA conceptual model for the effects of neonatal brainstem. Those include the biological clocks andbrainstem dysfunction on behavior and the cyclic autonomic changes regarding state, sati-emotion regulation: risk and protective factors ety, temperature, and heart rate (Porges, 1997; GevaThe proposed model describes the behavioral regu- & Feldman, in press). Selected groups of prematurelatory manifestations of neurobiological matura- infants exhibit disturbed rhythms of activity and resttional changes that emerge as a function of time, (Feldman, Weller, Sirota, & Eidelman, 2002), indi-exposure to stimulation, and neural integrity. The cating relations between compromised CNS and themodel proposes three levels of direct and mediated development of physiological rhythms.hypotheses according to three hierarchical and Porges’ (1997) polyvagal evolutionary theory pro-nested levels, originating in the assessment of poses that the nucleus ambiguus moderates thebrainstem functions. The ﬁrst level includes physio- control of respiratory sinus arrhythmia, a functionlogical regulation of cyclic processes and sensory unique to the mammalian brainstem organizationintegration processes; the second level relates to and related to processes of attention, emotion, andfurther integration of three aspects of emotion and communication in humans. The polyvagal theory isattention regulation; and the ﬁnal level includes consistent with the developmental vertical-integra-an integration of higher-level complex behavioral tive model in proposing brainstem involvement inoutputs. Direct relations address links between higher cognitive and social-emotional processes.components at each level and the level directly Cardiac vagal-tone, a measure of respiratory sinusabove it. Long-term, potentially mediated relations arrhythmia, provides an index of attention regula-refer to links between each level with an outcome tion in newborns (Arditi, Feldman, & Eidelman,measure one or two levels above, which may be 2006), orientation in neonates (Feldman, 2006), andeither direct or mediated by factors at the same or at information processing during the ﬁrst months of lifelower levels. For instance, relations between brain- (Bornstein & Suess, 2000). Similarly, sustainedstem dysfunction and both arousal modulation heart rate lowering during visual ﬁxation marksand stress reactivity (Level 2) are expected. Such voluntary, sustained attention in infants (Richards &relations may be mediated by (a) physiological reg- Cronise, 2000). Respiratory sinus arrhythmia is re-ulation of cyclic processes and sensory integration lated to an increase in vagal ﬁring during sustained(Level 1), (b) mother–infant co-regulation (Level 2), attention and to its inhibition at attention termina-or (c) both. tion. Heart rate variability in the newborn period was found to predict cognitive development at 3 years in premature infants (Huffman et al., 1998). CardiacEvidence for the direct and mediated hypotheses of vagal-tone in preterm neonates was found to deter-the model mine the trajectories of cognitive and social emo-Evidence regarding the hypothesized direct and tional development from birth to 5 years of agemediated links is presented in the model along two (Feldman & Eidelman, in press) and sleep–wakeinterdependent paths: 1) linking brainstem dys- cyclicity predicted sustained exploration atfunction with cognitive processing and inhibitory 6 months in premature infants (Feldman et al.,control, and 2) linking brainstem dysfunction with 2002). These data point to bi-directional relationssocio-emotional self-regulation. between the cyclicity of arousal, attention orienta- tion, and circadian rhythmicity, functions mediated1: Effects of brainstem dysfunction on cognitive process- by brainstem-related systems, which contribute toing and inhibitory control. Two interdependent paths information processing and cognitive competenciesare proposed to account for the proposed brainstem among premature infants.effects on cognitive processing and inhibitory control(Figure 2).One path is through state regulation and (b) Arousal-modulated attention (AMA). Evidencethe other path passes through attention regulation. points to the relations between physiological statusExamples of these are presented in turn. and attention. For instance, when less aroused and Physiological state regulation Prenatal brainstem Cognitive processing -dysfunction inhibitory control Arousal modulated attention (AMA) and informationFigure 2Ó 2008 The AuthorsJournal compilation Ó 2008 Association for Child and Adolescent Mental Health.
1036 Ronny Geva and Ruth Feldmanfollowing feeding, full-term neonates look at more risk variables in shaping developmental trajectoriesstimulating and novel events, and when more (Sameroff & Rosenblum, 2006). A child with morearoused, such as during the period before feeding, regulated dispositions, for example, may elicit morethey look at less stimulating and familiar events. positive parenting, leading to improved emotionSuch modulation is signiﬁcantly altered in high-risk regulation and self-regulatory capacities even amonginfants (Gardner et al., 2003). The greater the CNS infants at greater biological risk.insult, a lower change in attention toward higher A multi-level model of self-regulation in childrenstimulation or novelty would occur during states of with CBSF reﬂects the interaction of risk (e.g.,lower arousal. This pattern of neonatal arousal- brainstem dysfunction) and resiliency (e.g., mother–modulated attention differentiates normal neonates child co-regulation and synchrony) factors. Simi-from infants with compromised brainstem func- larly, the early development of brainstem structurestioning (CBSF; Karmel et al., 1996). Furthermore, is moderated by social interactions. Neonatal devel-feeding-based arousal also modulates visual recog- opment of the vertical-integrative system is thusnition memory in early infancy, such that infants hypothesized to be mediated by the nature of earlyare able to prefer novel stimuli when less aroused social interactions. Early maturing arousal systems(Geva et al., 1999a, 1999b). At 3 and 6 months of are shaped by the rapid maturation of the reticularage, the cyclical pattern of arousal during habitu- activating system in the brainstem and the effects ofation has been shown to determine the efﬁciency environmental stimulation and social interactionsof infants’ information processing in terms of (Schore, 1997) and mother–infant contact and syn-processing speed and recognition memory (Feldman chrony shape the infant’s emerging regulatory skills& Mayes, 1999). (Feldman, 2007a). Thus, a developmental model The development of higher levels of output regu- should accommodate both brain programming mat-lation requires inhibitory control capacities that urational processes and openness to environmentalwould allow for stopping, reﬂecting, and considering stimulation to account for the development ofoptions prior to the execution of output. Deﬁcits in behavioral and emotional regulation.inhibitory control and executive attention may be Two interdependent paths are proposed in thereﬂected in the child’s difﬁculties in making mental model to account for the effects of brainstem systemsor behavioral shifts, which result in perseverative, on socio-emotional self-regulatory skills. The ﬁrstimpulsive, or distractible behavior (Diamond, 1990; path passes through the development of emotionFeldman, Gardner, Karmel, & Freedland, 1999a). regulation and stress reactivity path and the secondThese phenomena accord well with Rueda, Posner, passes through the mother–infant co-regulation andand Rothbart’s (2005) conceptualization on the synchrony. As to the ﬁrst path, brainstem-relatedcontribution of attention networks to the develop- mechanisms were shown to be activated in pretermment of self-regulation and executive control. Hence, infants during emotional arousal. Cardiac vagal-toneit appears that over the long term CBSF may affect has been shown to predict infants’ response tothe development of regulatory capacities by inter- intrusive environmental stimulation (Huffman et al.,fering with the development of inhibitory control and 1998; Bazhenova, Plonskaia, & Porges, 2001; Feld-cognitive self-regulation. man, 2006). Relationships between satiety and social behavior were also found. This relationship2. Effects of brainstem dysfunction on social-emotional was shown in lambs, which exhibit differences inself-regulation. Models of development and psycho- preferential relationship with the mother as apathology emphasize the cumulative and interactive function of nutritional and non-nutritional signalseffects of risk factors on child outcomes and the originating from the gastrointestinal region, viaongoing interaction between the child and the social mediation of cholecystokinin (CCK; Weller &environment in shaping development (Cicchetti & Feldman, 2003). This body of research highlightsCohen, 1995) (Figure 3). Speciﬁc risk factors may be the major role of post-ingestive mechanisms playedmore disruptive to the infant’s social environment, by the gut–brain axis in the development of ﬁlialand certain environments may be more or less ready bonding (Val-Laillet, Simon, & Nowak, 2004).to respond to the excessive needs of a high-risk in- As to the second path, which focuses on thefant. In addition to the effects of risk, resilience mother’s role in the development of self-regulation,components in the child and the family interact with Hofer’s (1995) model on ‘hidden regulators’ under- Mother–infant co- regulation Brainstem Physiological Socio-emotional dysfunction regulation of cyclic self-regulation processes and Emotion regulation and sensory integration stress reactivityFigure 3 Ó 2008 The Authors Journal compilation Ó 2008 Association for Child and Adolescent Mental Health.
A neurobiological model for the effects of early brainstem functioning 1037scores the role of maternal proximity and contact in 13 years (Feldman, 2007b). As such, brainstemthe post-birth period to the infant’s physiological dysfunction in preterm infants or in affected neo-regulation. Maternal milk, touch, smell, body heat, nates, with its ensuing regulatory deﬁcits, is thusand biological rhythms provide a set of bio-behav- likely to have a negative impact on the developmentioral regulators to the infant’s autonomic, thermo- of social-emotional regulatory skills.regulation, feeding, and stress-management Overall the conceptual model highlights potentialsystems, most of which are mediated by the brain- longitudinal links between brainstem functions andstem. Hence, maternal–infant contact provides the the development of regulatory capacities acrossbasis for the development of physiological and emo- early childhood in several areas of development,tional regulatory processes (Ferber, Laudon, Kuint, including physiological systems, attention, stress,Weller, & Zisapel, 2002; Feldman, 2004). Early and parent–infant synchrony. There is sufﬁcientcontact improves the infant’s emotion regulation, data to support the hypotheses both within eachstress reactivity, and social and cognitive develop- level of the model and between lower and higherment (Feldman et al., 2002), pointing to the role of levels. Previous studies support the proposed linkscontact, as moderated by brainstem systems, in the between disruption to brainstem system anddevelopment of appropriate mechanisms of stress difﬁculties at the level of physiological regulation,and emotional coping. between physiological homeostatic systems and the The developmental sequence of social-emotional development of emotion regulation, attention mod-self-regulation is bi-directional. Maternal touch ulation, and stress reactivity, and between thoseaffects the secretion of brainstem-related biochem- and the development of higher-order cognitive andical substances that mediate homeostasis, comfort, social processes.and arousal (Poeggel et al., 1999). Studies showed Based on the aforementioned studies, direct rela-that there is a relationship between secretion of gut tions are also proposed between non-adjacent levelshormones (CCK) and touch effects in pups (Weller & of the model. For instance, the model proposes linksFeldman, 2003). Scheduled maternal touch, applied between brainstem-mediated physiological func-to term infants in the early postnatal period, organ- tions, such as cardiac vagal-tone with higher-orderized the infant’s activity–rest cycle (8 weeks) and cognitive and social self-regulatory outcomes, whichregulated melatonin rhythms during the nocturnal may be either direct or mediated by attentionperiod (12 weeks; Ferber et al., 2002). These results modulation and stress management. Finally, theimply that maternal touch in the perinatal period model presents hypothesized relations that call forserve as a zeitgeber-moderator to enhance brain- further research, particularly between brainstemstem-related coordination of the developing circa- functioning and higher-order prefrontally-mediateddian system with environmental cues. Together, functions, such as socio-emotional regulation, orthese ﬁndings point to the interrelationships between brainstem dysfunction and disorders inbetween physiological regulation, stress reactivity, higher cortically-mediated skills, such as observedand maternal–infant co-regulation (Feldman, 2007a, in attention deﬁcit and hyperactivity disorder or2007b). It may also suggest that maternal–infant conduct disorder.co-regulation, in the form of bodily contact or affec-tive synchrony, may facilitate the development ofself-regulation even among infants born with brain- Expected signiﬁcance of the vertical integratedstem dysfunctions. model Socio-emotional self-regulation capacities ofchildren with CBSF are likely to be compromised. The vertical-integrative model offers several uniqueAccording Kopp (1982), self-regulation is built on the windows into important current issues, such asmaturation of inhibitory functions as well as on the prenatal and perinatal trauma and recovery, themutuality between mother and infant. Kochanska, neurological basis of emotions and self-regulation,Murray, and Coy (1997) showed that toddlers’ and the role of the environment in shaping develop-inhibitory control and mother–child emotional mental outcomes of speciﬁc prenatal and perinatalresponsiveness independently predicted socialized pathological processes which implicate brainstemcompliance, and mother–infant affect synchrony at 3 systems. Several points are highlighted by the model.and 9 months was found to predict the development First, the model incorporates multidimensionalof self-regulation at 2 years (Feldman, Greenbaum, regulatory expressions of the CBSF phenomenon:& Yirmiya, 1999b). Self-regulation, socialization, biochemical (e.g., melatonin, cortisol), autonomicand moral internalization were found to be predicted (vagal-tone; sleep; feeding), attentional-cognitiveby physiological self-regulation, inhibitory control, (e.g., arousal-modulated attention, inhibitory con-and mother–infant affect synchrony (Feldman, trol); emotional reactivity to stress; and co-regulation2007a). In turn, a longitudinal follow-up from of emotional responsivity. These interdependentinfancy to adolescence showed that affect synchrony expressions are proposed to set the foundation for theat 3 months has a direct impact on the development development of higher-order complex cognitive andof the child’s moral orientation and empathy at emotional processes. Second, the model allows forÓ 2008 The AuthorsJournal compilation Ó 2008 Association for Child and Adolescent Mental Health.
1038 Ronny Geva and Ruth Feldmanbetter understanding of the relations between life (Volpe, 1995; Woodward, Anderson, Austin,domains of performance (e.g., attentional versus Howard, & Inder (2006). Functional integrity of thesocio-emotional) and proposes links between these CNS is sometimes evaluated in the same period bydomains of functioning. Third, the model points to an ABR recordings using portable evoked potentialimportant yet understudied area of research – brain- equipment (Karmel et al., 1988; Jiang et al., 2007).stem functioning. It may drive further research on the Advances in medical care have resulted in aspeciﬁc paths leading from compromised brainstem marked decrease in severe intracranial hemor-functioning to the development of cognitive effortful rhage. However, there is no indication of anycontrol and socio-emotional regulation of behavior, decrease in the suspected involvement of brainstemand such future work will shape and specify the and other subcortical regions (Volpe, 1995). Theseproposed preliminary model. Fourth, the model sug- regions are difﬁcult to visualize by ultrasound or bygests potential mechanisms for the development of MRI (Volpe, 1995; Fraser et al., 2007), but areself-regulation in the emotional and behavioral easily studied functionally by ABRs (Jiang et al.,domains that may be applied to developmental theory 2007; Wilkinson et al., 2007). Although providingin general. Fifth, the model proposes pathways of different forms of information, agreement betweenrecovery from neonatal brainstem – related patho- cranial ultrasound and evoked potential proceduresgenic processes in a developing system. Finally, the is high, between 78% and 86% (Karmel et al.,model implies that perinatal diagnosis of CBSF may 1988). The disagreements probably reﬂect foremostafford speciﬁc guidelines to neonatologists, clini- substantive differences in regional CNS injuries,cians, and parents rearing children who are at risk for their differential courses of recovery, or the dis-behavioral and emotional dysregulation by providing tinction between structural and functional integritymore speciﬁc information for diagnosis, intervention, of the CNS.and social policies. In view of the vertical-integrative framework, we suggest that early evaluations of brainstem and lower-level structures in infants born preterm and even in fetuses may be highly informative as aImplications of the vertical-integrative model potential early marker of self-regulation deﬁcits.for early diagnosis of infants born prematurely Since vulnerabilities in ABR functions have beenThe aforementioned developmental progression of reported in preterm infants born between 30 andthe vertical-integrative model highlights the impor- 34 weeks’ gestation (Pasman, Rotteveel, de Graaf,tance of assessing dysfunctions related to lower Maassen, & Visco, 1996), infants born at theselevels of CNS functioning, particularly of brainstem ages at low medical risk may still present com-dysfunctions, already at the NICU. Disruptions to promised brainstem functioning. Such assessmentthe development of these lower-level systems can is particularly important for infants born beforeserve as important indicators of risk for the emer- the full maturation of brainstem functions (i.e.,gence of self-regulatory capacities. before 34 weeks’ gestation). Detection of neonatal An ABR evaluation may be a particularly valuable brainstem dysfunctions may help target infantsdiagnostic tool for premature infants during the who are at risk for self-regulation deﬁcits and allowneonatal phase, since it has speciﬁc features that are for speciﬁc early interventions that may improveidentiﬁed as dependent on maturation (Karmel et al., the self-regulatory difﬁculties so commonly obs-1988). ABR recordings in preterm infants ﬁrst erved in premature infants across childhood andappear at 26 weeks of gestation, around the age of beyond.extra-uterine viability. The ABR function thenundergoes detectable maturational changes until34 weeks’ gestational age and thus overlaps the Acknowledgementsperiod of NICU care for most preterm neonates. Supported by the US-Israel Bi-National ScienceDuring this period, ABR functions are highly sensit- Foundation (# 2001-241).ive to acute complications, and these are observed bysystematic changes in the latency, amplitude, orthreshold of the ABRs. Using supra-thresholdintensities of 60 dB hearing level or more, it is Correspondence toevocable in all newborn infants with at least some Ronny Geva, The Gonda Goldschmied Brainminimal hearing capacities (Karmel et al., 1988; Research Center, Bar Ilan University, Ramat Gan,Jiang et al., 2004). Israel 52900; Email: firstname.lastname@example.org In view of the vertical-integrated framework model,evaluation of brainstem functioning in the ﬁnalweeks of pregnancy or in premature infants is highly Referencesinformative. It is also feasible. Structural integrity ofthe CNS is routinely assessed in NICUs with cranial Abadie, V., Morisseau-Durand, M.P., Beyler, C.,ultra-sound (US) and/or MRI within the ﬁrst days of Manach, Y., & Couly, G. (2002). Brainstem dysfunc- Ó 2008 The Authors Journal compilation Ó 2008 Association for Child and Adolescent Mental Health.
A neurobiological model for the effects of early brainstem functioning 1039 tion: A possible neuroembryological pathogenesis of Ellenbogen, M.A., Schwartzman, A.E., Stewart, J., & isolated Pierre Robin sequence. European Journal of Walker, C.D. (2006). Automatic and effortful emo- Pediatrics, 161, 275–280. tional information processing regulates differentAnand, K.J., & Scalzo, F.M. (2000). Can adverse aspects of the stress response. Psychoneuroendocri- neonatal experiences alter brain development and nology, 31, 373–387. subsequent behavior? Biology of the Neonate, 77, Feldman, R. (2004). Mother–infant skin-to-skin contact 69–82. and the development of emotion regulation. In S.P.Arditi, H., Feldman, R., & Eidelman, A.I. (2006). Effects Shohov (Ed.), Advances in psychology research (vol. of human contact and vagal regulation on pain 27, pp. 113–131). Hauppauge, NY: Nova Science. reactivity and visual attention in newborns. Develop- Feldman, R. (2006). From biological rhythms to social mental Psychobiology, 48, 561–573. rhythms: Physiological precursors of mother–infantBatterham, R.L., ffytche, D.H., Rosenthal, J.M., Zelaya, synchrony. Developmental Psychology, 42, 175–188. F.O., Barker, G.J., Withers, D.J., & Williams, S.C. Feldman, R. (2007a). Parent–infant synchrony and the (2007). PYY modulation of cortical and hypothalamic construction of shared timing; Physiological precur- brain areas predicts feeding behaviour in humans. sors, developmental outcomes, and risk conditions. Nature, 450, 106–109. Journal of Child Psychology and Psychiatry, 48,Bazhenova, O.V., Plonskaia, O., & Porges, W.S. (2001). 329–354. Vagal reactivity and affective adjustment in infants Feldman, R. (2007b). Mother–infant synchrony and the during interaction challenges. Child Development, 72, development of moral orientation in childhood and 1287–1604. adolescence: Direct and indirect mechanisms ofBornstein, M.H., & Suess, P.E. (2000). Physiological developmental continuity. American Journal of Ortho- self-regulation and information processing in infancy: psychiatry, 77, 582–597. Cardiac vagal tone and habituation. Child Develop- Feldman, L.J., Gardner, J.M., Karmel, B.Z, & Freed- ment, 71, 273–287. land, R.L. (1999a). Development of focused attentionCaldji, C., Francis, D., Sharma, S., Plotsky, P.M., & from 10 to 16 months in low- and high-risk infants. Meaney, M.J. (2000). The effects of early rearing Paper presented at ECDP meeting, Spetses, Greece, environment on the development of GABA and central September. benzodiazepine receptor levels and novelty-induced Feldman, R., & Eidelman, A.I. (in press). Biological and fearfulness in the rat. Neuropsychopharmacology, 22, environmental initial conditions shape the trajecto- 219–229. ries cognitive and social-emotional developmentChudasama, Y., Passetti, F., Rhodes, S.E., Lopian, D., across the ﬁrst ﬁve years of life. Developmental Desai, A., & Robbins, T.W. (2003). Dissociable Science. aspects of performance on the 5-choice serial reaction Feldman, R., Greenbaum, C.W., & Yirmiya, N. (1999b). time task following lesions of the dorsal anterior Mother–infant affect synchrony as an antecedent to cingulate, infralimbic and orbitofrontal cortex in the the emergence of self-control. Developmental Psycho- rat: Differential effects on selectivity, impulsivity and logy, 35, 223–231. compulsivity. Behavioral Brain Research, 30, Feldman, R., & Mayes, L.C. (1999). The rhythmic 105–119. organization of infant attention during habituationCicchetti, D., & Cohen, D.J. (1995). Developmental is related to infants’ information processing. Infant psychopathology. New York: Wiley. Behavior and Development, 22, 37–49.Damasio, A.R., Grabowski, T.J., Bechara, A., Damasio, Feldman, R., Weller, A., Sirota, L., & Eidelman, A.I. H., Ponto, L.L., Parvizi, J., & Hichwa, R.D. (2000). (2002). Skin-to-skin contact (kangaroo care) Subcortical and cortical brain activity during the promotes self-regulation in premature infants: feeling of self-generated emotions. Nature Neuro- Sleep–wake cyclicity, arousal modulation, and sus- science, 3, 1049–1056. tained exploration. Developmental Psychology, 38,Darnall, R.A., Ariagno, R.L., & Kinney, H.C. (2006). The 194–207. late preterm infant and the control of breathing, Ferber, S.G, Laudon, M., Kuint, J., Weller, A., & Zisapel, sleep, and brainstem development: A review. Clinics N. (2002). Massage therapy by mothers enhances the in Perinatology, 33, 883–914. adjustment of circadian rhythms to the nocturnalDennis, T. (2006). Emotional self-regulation in pre- period in full-term infants. Journal of Developmental schoolers: The interplay of child approach reactivity, and Behavioral Pediatrics, 23, 410–415. parenting, and control capacities. Developmental Fraser, M., Bennet, L., Helliwell, R., Wells, S., Williams, Psychology, 42, 84–97. C., Gluckman, P., Gunn, A.J., & Inder, T. (2007).Diamond, A. (1990). The development and neural bases Regional speciﬁcity of magnetic resonance imaging of memory functions as indexed by the AB and and histopathology following cerebral ischemia delayed response tasks in human infants and infant in preterm fetal sheep. Reproductive Science, 14, monkeys. In A. Diamond (ed.), The development and 182–191. neural bases of higher cognitive functions. Annals of Galambos, R., Hicks, G., & Wilson, M.J. (1982). Hearing the New York Academy of Sciences. vol. 608, pp. 267– loss in graduates of a tertiary intensive care nursery. 317). New York: The New York Academy of Sciences. Ear and Hearing, 3, 87–90.Eckerman, C.O., Oehler, J.M., Hannan, T.E., & Molitor, Gardner, J.M., Karmel, B.Z., & Flory, M.J. (2003). A. (1995). The development prior to term age of very Arousal modulation of neonatal visual attention: prematurely born newborns’ responsiveness in en Implications for development. In S. Saroci (Ed.), face exchanges. Infant Behavior and Development, 17, Perspectives on fundamental processes in intellectual 55–70. functioning: Vol. 2. Visual information processing andÓ 2008 The AuthorsJournal compilation Ó 2008 Association for Child and Adolescent Mental Health.
1040 Ronny Geva and Ruth Feldman individual differences. Stamford, CT: Ablex, JAI (Else- Jiang, Z.D., Xiu, X., Brosi, D.M., Shao, X.M., & Wilkin- vier). son, A.R. (2007). Sub-optimal function of the auditoryGardner, J.M., & Karmel, B.Z. (1995). Development brainstem in term infants with transient low Apgar of arousal-modulated visual preferences in early scores. Clinical Neurophysiology, 118, 1088–1096. infancy. Developmental Psychology, 31, 473–482. Jiang, Z.D., Yin, R., Shao, X.M., & Wilkinson, A.R.Geva, R. (1995). Relationships between neonatal risk, (2004). Brain-stem auditory impairment during the cognitive development and inhibitory control at three neonatal period in term infants after asphyxia: years of age. Unpublished doctoral dissertation. New Dynamic changes in brain-stem auditory evoked York: City University of New York. response to clicks of different rates. Clinical Neuro-Geva, R., Eshel, R., Leitner, Y., Fattal-Valevski, A., & physiology, 115, 1605–1615. Harel, S. (2005). Prenatal diagnosis and management Johnson, M.H., Posner, M.I., & Rothbart, M.K. (1991). of intrauterine growth retardation (IUGR): A long- Components of visual orienting in early infancy: term prospective study on outcome and maternal Contingency learning, anticipatory looking, and coping. Infant Mental Health Journal, 26, 481–495. disengaging. Journal of Cognitive Neuroscience, 3,Geva, R., & Feldman, R. (in press). Circadian sleep– 335–344. wake rhythms in preterm infants. In F. Columbus, Jongmans, M., Mercuri, E., DeVries, L., Dubowitz, L., & (Ed), Circadian rhythms and health research trends. Henderson, S.E. (1997). Minor neurological signs and Advances in psychology research. Hauppauge, NY: perceptual-motor difﬁculties in prematurely born NOVA Science Publishers. children. Archives of disease in childhood, 76, F9–Geva, R., Gardner, J.M., Karmel, B.Z., Feldman, I.J., & F14. Freedland, R.L. (1999a). Inhibitory control of cocaine- Karlsson, K.A., Gall, A.J., Mohns, E.J., Seelke, A.M., & exposed infants at 3 years. In L.S. Harris (ed.), Blumberg, M.S. (2005). The neural substrates of Problems of drug dependence 1998 (NIDA Research infant sleep in rats. PLoS Biology, 3, e143. Monograph No. 179, 98). Washington, DC: Depart- Karmel, B.Z., & Gardner, J.M. (2005). Neurobehavioral ment of Health and Human Services. assessment in the neonatal period – the impact ofGeva, R., Gardner, J.M., & Karmel, B.Z. (1999b). Ferenc Katona. Ideggyogy Sz., 58, 315–323. Feeding-based arousal effects on visual recognition Karmel, B.Z., Gardner, J.M., & Freedland, R.L. (1996). memory in early infancy. Developmental Psychology, Arousal-modulated attention at four months as a 35, 640–650. function of intrauterine cocaine exposure and centralGeva, R., Gardner, J.M., & Karmel, B.Z. (June, 2004). nervous system injury. Journal of Pediatric Psycho- Non-competitive information load effect on a rapid logy, 21, 821–832. sequential automated naming task (RSANT). A poster Karmel, B.Z., Gardner, J.M., Zappulla, R.A., Magnano, presented at Conference on Human Development, C.L., & Brown, E.G. (1988). Brainstem auditory Washington, DC. evoked responses as indicators of early brain insult.Gunnar, M.R., & Quevedo, K.M. (2007). The neurobio- Electroencephalography and Clinical Neurophysio- logy of stress and development. Annual Review of logy, 71, 429–442. Psychology, 58, 145–173. Kochanska, G., Murray, K., & Coy, K.C. (1997). Inhib-Hack, M., Taylor, H.G., Klein, N., Eiben, R., itory control as a contributor to conscience in child- Schatschneider, C., & Mercuri-Minich, N. (1994). hood: From toddler to early school age. Child School-age outcomes in children with birth weights Development, 68, 263–277. under 750g. New England Journal of Medicine, 331, Kopp, C.B. (1982). Antecedents of self-regulation: 753–759. A developmental perspective. Developmental Psycho-Hofer, M.A. (1995). Hidden regulators: Implication for a logy, 18, 199–214. new understanding of attachment, separation, and Krumholz, A., Felix, J.K., Goldstein, P.J., & McKenzie, loss. In S. Golberg, R. Muir, & J. Kerr (Eds.), E. (1985). Maturation of the brain stem auditory Attachment theory: Social, developmental, and clinical evoked potential in premature infants. Electroenceph- perspectives (pp. 203–230). Hillsdale, NJ: Analytic alography and Clinical Neurophysiology, 62, Press. 124–134.Huffman, L.C., Bryan, Y.E., del Carmen, R., Pedersen, Merker, B. (2007). Consciousness without a cerebral F.A., Doussard-Roosevelt, J.A., & Porges, S.W. cortex: A challenge for neuroscience and medicine. (1998). Infant temperament and cardiac vagal tone: Behavioral and Brain Sciences, 30, 63–81. Assessments at twelve weeks of age. Child Develop- Moore, J.K., Perazzo, L.M., & Braun, A. (1995). Time ment, 69, 624–635. course of axonal myelination in the human brainstemHunt, C.E. (2006). Ontogeny of autonomic regulation auditory pathway. Hearing Research, 87, 21–31. in late preterm infants born at 34–37 weeks post- Morilak, D.A., Barrera, G., Echevarria, D.J., Garcia, menstrual age. Seminars in Perinatology, 30, 73–76. A.S., Hernandez, A., Ma, S., et al. (2005). Role of brainJentsch, J.D., Roth, H.R., & Taylor, J.R. (2000). Role for norepinephrine in the behavioral response to stress. dopamine in the behavioral functions of the prefron- Progress in Neuro-Psychopharmacology and Biological tal corticostriatal system: Implications For mental Psychiatry, 29, 1214–1224. disorders and psychotropic drug addiction. Progress Murray, A.D. (1988). Newborn auditory brainstem in Brain Research, 126, 433–453. evoked responses (ABRs): Longitudinal correlates inJiang, Z., Brosi, D.M., & Wilkinson, A.R. (2006). Brain- the ﬁrst year. Child Development, 59, 1542–1554. stem auditory function in very preterm infants with Panksepp, J. (2005). Affective consciousness: Core chronic lung disease: Delayed neural conduction. emotional feelings in animals and human. Conscious- Clinical Neurophysiology, 117, 1551–1559. ness and Cognition, 14, 30–80. Ó 2008 The Authors Journal compilation Ó 2008 Association for Child and Adolescent Mental Health.
A neurobiological model for the effects of early brainstem functioning 1041Pasman, J.W., Rotteveel, J.J, de Graaf, R., Maassen, B., to the emergence of self-regulation. Developmental & Visco, Y.M. (1996). The effects of early and late Neuropsychology, 28, 573–594. preterm birth on brainstem and middle-latency Salamy, A., & Eldredge, L. (1994). Risk for ABR abnor- auditory evoked responses in children with normal malities in the nursery. Electroencephalography and neurodevelopment. Journal of Clinical Neurophysio- Clinical Neurophysiology, 92, 392–395. logy, 13, 234–241. Sameroff, A.J., & Rosenblum, K.L. (2006). PsychosocialPoeggel, G., Lange, E., Hase, C., Metzger, M., Gulyaeva, constraints on the development of resilience. Annals N., & Braun, K. (1999). Maternal separation and early of New York Academy of Sciences, 1094, 116–124. social deprivation in Octodon degua: Quantitative Schore, A.N. (1997). Early organization of the nonlinear changes of nicotinamide adenine dinucleotide phos- right brain and development of a predisposition to phate-diaphorase-reactive neurons in the prefrontal psychiatric disorders. Development and Psycho- cortex and nucleus accumbens. Neuroscience, 94, pathology, 9, 595–631. 497–504. Sigman, M., Cohen, S.E., & Beckwith, L. (1997). WhyPorges, S.W. (1992). Vagal tone: A physiologic marker of does infant attention predict adolescent intelligence? stress vulnerability. Pediatrics, 90, 498–504. Infant Behavior and Development, 20, 133–140.Porges, S.W. (1997). Emotion: An evolutionary Skranes, J., Vangberg, T.R., Kulseng, S., Indredavik, by-product of the neural regulation of the autonomic M.S., Evensen, K.A., Martinussen, M., et al. (2007). nervous system. Annals of the New York Academy of Clinical ﬁndings and white matter abnormalities seen Sciences, 807, 62–77. on diffusion tensor imaging in adolescents with veryPosner, M.I., Petersen, S.E., Fox, P.T., & Raichle, M.E. low birth weight. Brain, 130, 654–666. (1988). Localization of cognitive operations in the Tucker, D.M., Luu, P., & Derryberry, D. (2005). Love human brain. Science, 217, 1627–1631. hurts: The evolution of empathic concern through thePosner, M.I., Rothbart, M.K., & Sheese, B.E. (2007). encephalization of nociceptive capacity. Development Attention genes. Developmental Science, 10, 24– and Psychopathology, 17, 699–713. 29. Valkama, A.M., Tolonen, E.U., Kerttul, L.I., Paakko,Richards, J.E., & Cronise, K. (2000). Extended visual E.L., Vainionpaa, L.K., & Koivist, M.E. (2001). Brain- ﬁxation in the early preschool years: Look duration, stem size and function at term age in relation to later heart rate changes, and attentional inertia. Child neurosensory disability in high-risk, preterm infants. Development, 71, 602–620. Acta Paediatrica, 90, 909–915.Risterucci, C., Terramorsi, D., Nieoullon, A., & Amalric, Val-Laillet, D., Simon, M., & Nowak, R. (2004). Full M. (2003). Excitotoxic lesions of the prelimbic–infra- belly and colostrum: Two major determinants of ﬁlial limbic areas of the rodent prefrontal cortex disrupt love. Developmental Psychobiology, 45, 163–173. motor preparatory processes. European Journal of Volpe, J.J. (1995). Brain injury in the premature infant – Neuroscience, 17, 1498–1508. current concepts. Preventative Medicine, 23, 638–645.Roig, Q.M., Gratacos, M., Vazquez, E., Del Toro, M., Weller, A., & Feldman, R. (2003). Emotion regulation Foguet, A., Ferrer, I., & Macaya, A. (2003). Brainstem and touch in infants: The role of cholecystokinin and dysgenesis: Report of ﬁve patients with congenital opioids. Peptides, 24, 779–788. hypotonia, multiple cranial nerve involvement, and Wilkinson, A.R., Brosi, D.M., & Jiang, Z.D (2007). ocular motor apraxia. Developmental Medicine and Functional impairment of the brainstem in infants Child Neurology, 45, 489–493. with bronchopulmonary dysplasia. Pediatrics, 120,Rothbart, M.K., & Rueda, M.R. (2005). The development 362–371. of effortful control. In U. Mayr, E. Awh, & S.W. Keele Woodward, L.J., Anderson, P.J., Austin, N.C., Howard, (Eds.), Developing individuality in the human brain: A K., & Inder, T.E. (2006). Neonatal MRI to predict tribute to Michael I. Posner (pp. 167–188). Washing- neurodevelopmental outcomes in preterm infants. ton, DC: American Psychological Association. New England Journal of Medcine, 355, 685–694.Rothbart, M.K., Sheese, B.E., & Posner, M.I. (2007). Zeskind, P.S., Goff, D.M., & Marshall, T.R. (1991). Executive attention and effortful control: Linking Rhythmic organization of neonatal heart rate and temperament, brain networks, and genes. Child its relation to atypical fetal growth. Developmental Development Perspectives, 1, 2–7. Psychobiology, 24, 413–429.Rueda, M.R., Posner, M.I., & Rothbart, M.K. (2005). The development of executive attention: Contributions Manuscript accepted 25 February 2008Ó 2008 The AuthorsJournal compilation Ó 2008 Association for Child and Adolescent Mental Health.