Structural and functional brain correlates of subclinical psychotic symptoms in 11–13 year old schoolchildren

Early Human Development 89 (2013) 221–227

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Early Human Development

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Best practice guidelines

Structural and functional brain correlates of behavioral outcomes during adolescence

Chiara Nosarti ⁎Department of Psychosis Studies, Institute of Psychiatry, King's Health Partners, King's College London, De Crespigny Park, London, SE5 8AF, UK

⁎ Tel.: +44 20 7848 0133; fax: +44 20 7701 9044.E-mail address: [email protected].

0378-3782/$ – see front matter © 2013 Elsevier Irelandhttp://dx.doi.org/10.1016/j.earlhumdev.2013.02.002

a b s t r a c t

Keywords:

Several studies have described an association between very preterm birth and behavioral and psychiatricoutcomes in childhood and adolescence. The exact mechanisms underlying this association are unknown,but impaired neurodevelopment has been proposed as a possible etiological factor.Existing research suggests a selective vulnerability of brain regions associated with a variety of behavioraland psychiatric outcomes following very preterm birth. This article reviews studies that have directly ex-plored the structural and functional brain correlates of behavioral outcomes in ex-preterm individuals,with an emphasis on attentional problems, overall mental health functioning including internalizing and ex-ternalizing scores, and psychosocial adjustment. The focus here is on neuroimaging research conducted dur-ing adolescence, a period of life associated with the emergence and early expression of several psychiatricdisorders.The neurodevelopmental hypothesis is used as a theoretical framework, according to which early brain le-sions interact with the developing brain to increase later vulnerability to psychopathology.

© 2013 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2212. What is special about adolescence? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2223. Preterm birth and behavioral outcome — a neurodevelopmental model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

3.1. Linking brain and behavior in ex-preterm adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2233.2. Linking neurodevelopment following preterm birth and psychopathology — some hypotheses . . . . . . . . . . . . . . . . . . . . 224

4. Research directions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2255. Key guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

1. Introduction

Numerous studies have described an association between very pre-term birth and behavioral and psychiatric outcome in childhood and ad-olescence [1–4]. These are eloquently reviewed in Johnson et al. (2013,this issue). Moreover, several investigations have suggested that individ-uals who were born very preterm are at increased risk of developingpsychiatric disorders in adulthood, including bipolar affective disorder,anxiety disorder, depression, schizophrenia and avoidant personalityproblems [5–7]. This raises the question: does preterm birth lie on acausal pathway to the development of psychiatric illness? And if so,why?

Several theoretical frameworks have been used for exploring thesequestions. For instance, Paarlberg and colleagues have proposed the

Ltd. All rights reserved.

idea that a common genetic liability may underlie both preterm birthand psychiatric disorder. According to the genetic liability model,mothers-to-be with a psychiatric diagnosis are at increased risk of de-livering their offspring before term completion [8]. From a biopsycho-logical perspective, on the other hand, preterm birth constitutes oneof a range of psychiatric risk factors, along with genetic vulnerabilityand stress in the perinatal period, with effects accumulating over timeand resulting in the development of psychopathology [9].

In this article I will focus on the neurodevelopmental hypothesis [10],according to which early brain lesions (with genetic or environmentalcause, or a combination of the two) interact with the developing brainto increase the vulnerability to psychopathology in adolescence andadulthood. This hypothesis is supported by results from animal studies,which have shown that a lesion may remain relatively silent until theneuronal system affected reaches a degree of maturity, at which pointabnormal behavior manifests [11]. Alterations in neurodevelopment

222 C. Nosarti / Early Human Development 89 (2013) 221–227

following very preterm birth will be used as a model to study the neuro-biological correlates of a variety of behavioral outcomes includingpsychiatric disorders. I will focus on neuroimaging research conductedin preterm samples during adolescence,whichwill be regarded as a ‘sen-sitive period’ of development (borrowing a term used in embryologicalresearch in the 1920s [12]), associatedwith the emergence and early ex-pression of several psychiatric disorders.When describing preterm-bornsamples I will include reference to individualswhowere bornwith a lowbirthweight, as there is often overlap between these events: themajorityof babies born preterm are also born with a low birth weight [13].

In order to contextualize neuroimaging studies in adolescents whowere born very preterm and their relevance to the investigation of be-havioral outcome, I will start by summarizing the neurodevelopmentalchanges occurring in adolescence in normative samples; I will then de-scribe structural and functional neuroimaging studies in ex-pretermadolescents. In the third section of this article I will discuss studiesthat have directly explored the structural and functional brain corre-lates of behavioral outcomes in ex-preterm individuals. I will concludeby speculating on the mechanisms underlying the etiological signifi-cance of the association between preterm birth and psychopathology.

2. What is special about adolescence?

Although there is no single universally accepted definition for‘adolescence’, in this article I will regard it as the period of physical,psychological and social transition from childhood to adulthood. Ad-olescence is a time associated with major hormonal and physicalevents, and with a magnitude of dynamic brain developmentalchanges that rival only infancy, during which several brain regionsunderlying psychosocial and high order cognitive functions reachma-turity. During adolescence, dramatic developments in identity,self-consciousness and cognitive flexibility occur [14].

In recent years, magnetic resonance imaging (MRI) has facilitatedthe investigation of structural and functional brain development inunprecedented ways. MRI uses the property of nuclear magneticresonance (NMR) to align and image nuclei of atoms in a person'sbody. Most importantly, MRI techniques provide an excellent contrastbetween different tissue types (e.g. gray matter and white matterin the brain), are non-invasive, and allow for repeated scans to beperformed on healthy individuals, thus permitting the study of trajec-tories of brain development. A type of MRI that measures brain activ-ity as indexed by the blood-oxygen-level-dependent (BOLD) signal isreferred to as functional MRI (fMRI). This method allows the investi-gation of changes in brain hemodynamics that correspond to thebrain at rest, or to mental operations, which are typically performedby subjects during scanning.

Researchers at the National Institute of Mental Health in the UShave conducted the largest pediatric neuroimaging project to dateinvestigating maturational patterns of structural brain developmentin healthy individuals. Their studies suggest a pre-pubertal increasein gray matter, peaking in motor and sensory cortex first, and laterin “association” areas, which are thought to underlie cognition andcomplex adaptive behavior [15]. The general pattern is then for graymatter to decrease after puberty, during the transition from adoles-cence into adulthood. This heterogeneous maturational trajectorywas studied by Shaw and colleagues (2008), who proposed that thebrain regions which are the last to mature may be phylogeneticallymore recent, and associated with “higher” cognitive functions [16].The cellular basis for post-pubertal decreases in regional gray mattervolume is not fully understood, but a possible explanation refers to agreater organization of the brain through synaptic pruning, wherebyconnections that are used repeatedly become strengthened andthose that are rarely used are removed. In other words, synapticpruning may reflect “tuning” of the cortex which is accompanied byan increase in its efficiency, in line with the hypothesis that develop-mental changes that occur in adolescence may underline advances in

processing capacity, rather than the development of new skills [17].At the neuroanatomical level, developmental changes are associatedwith decreases in activation in brain areas which are not critically in-volved in task completion with increasing participants' age, and withassociated increases in activation in task-specific areas [18]. These re-sults may represent functional reorganization in cortical areas, possiblyfacilitating more effective information processing in a parsimoniousfashion [19]. An alternative explanation could be that the apparent re-duction of gray matter reflects ongoing intra-cortical myelination andreduction of tissue appearing as gray matter on MRI [20]. Of course,these explanations are not mutually exclusive.

Longitudinal developmental changes are also observed in whitematter, which has been described as showing general linear patternsof increases in volume and in micro-structural organization fromchildhood through to adulthood [21], especially in frontal and parietalcortices during adolescence [22]. Such increases could be due toon-going myelination [23], although other developmental processessuch as increases in axon diameter and growth of new axons could rep-resent plausible explanatory mechanisms [24]. Electroencephalogram(EEG) studies have reported changes in coherence among brain sub-components during adolescence and into adulthood, supporting theidea of increased “connectedness” [25].

Recent studies have confirmed that maturational changes in norma-tive samples continue beyond adolescence. For instance, gray matterdensity reductions in frontal and striatal regions have been reportedin the transition between adolescence and adulthood (age 30) [26], aswell as non-linear age effects in frontal and parietal regions [27] andage-related increases in the temporal lobe (including the hippocampus)up to 38 years [28]. In addition,myelination in the humanhippocampushas been reported to occur up to adulthood [29]. Such lifetime dynamicbrain changes may serve to optimally adapt our lives to our environ-ments and experiences [30]. Thus, it is not surprising that departuresfrom the normal patterns of development may be associated withpsychopathology.

3. Preterm birth and behavioral outcome —

a neurodevelopmental model

The theory that preterm birth is associated with impairedneurodevelopment has biological plausibility. While neuronal prolif-eration is predominantly complete by the end of the second trimesterof gestation, the vast majority of brain development occurs in thethird trimester, with the volume of the whole brain more than dou-bling and the volume of cortical gray matter increasing approximatelyfour-fold [31]. Being born at an immature developmental stage islikely to affect brain development because many major processes –

such as neurogenesis, neural migration and gyrification – are occur-ring between the 24th and the 32nd gestational week. Due to itsrapidly developing and complex characteristics, the immature ner-vous system is particularly vulnerable to neonatal brain injury [32],which may result in alterations of the programmed corticogenesis ofthe developing brain [33]. It may not be surprising, therefore, thatindividuals born at or before 32 weeks compared with controls aremore likely to experience neurological disorders, neuropsychological,and behavioral impairments in childhood and later in life [1,34,35].Overall, very preterm-born children do not perform as well at schoolas term-born peers [36] and show an excess of learning disabilities[37]. Furthermore, children who need to repeat grades or require spe-cial education assistance in primary school are at greater risk thanother children for long-term behavioral problems [38]. Please referto Anderson et al. (2013, this issue) for a comprehensive discussionon the relationship between high order cognitive functions and be-havior in adolescence following preterm birth.

Long-lasting and widespread structural and functional brain alter-ations have been described following very preterm birth. In adoles-cence, gray matter and white matter volumes are reported as being

223C. Nosarti / Early Human Development 89 (2013) 221–227

linearly associated with gestational age [34,39], and regional volu-metric differences are described in subgroups of ex-preterm individ-uals with varying degrees of neonatal brain injury, as detected byneonatal ultrasonographic classification [34].

One of the brain regions that have been most consistently found tobe altered in ex-preterm samples is the hippocampus, possibly conse-quent to hypoxic–ischemic damage [40]. Smaller hippocampal volumeshave been described in preterm-born individuals compared to controlsin thefirst two decades of life, from infancy [41] to adolescence [42].Wereported that bilateral hippocampal volume was 14% smaller in ourex-preterm cohort compared with controls at age 14 years [43]. How-ever, long-term alterations in brain structure have been also describedin other brain regions including the thalamus [44], caudate nucleus[45], corpus callosum [46] and cerebellum [47]. Using voxel basedmor-phometry (VBM), we conducted the largest study to date which dem-onstrated widespread gray and white matter alterations especially infrontal and temporal lobes in mid-adolescence [34], some of whichwere subsequently replicated by others [39]. We further demonstratedthat regional decreases in gray andwhite matter volumemediated cog-nitive impairment [34]. Complementary studies investigating corticalthickness have reported thinner frontal, temporal and parietal corticesin ex-preterm adolescents vs. controls [48].

A number of studies have used diffusion MRI (DT-MRI) inex-preterm adolescents. This is a technique that is sensitive to the dif-fusion of water molecules, and provides data that can be used both toreconstruct white matter tract anatomy and to provide informationabout its coherence and connectivity. Extensive alterations of whitematter microstructure have been reported in ex-preterm individualscompared with controls in the major intra- and inter-hemisphericfibers (e.g., corpus callosum, uncinate and fronto-occipital fasciculi)[49–51].

Alterations in brain function, studied with functional magneticresonance imaging (fMRI), have been reported in ex-preterm adoles-cents compared with controls in frontal, temporal and hippocampalregions during performance of a variety of cognitive tasks, includingface-name learning [52] and response inhibition [53]. We have dem-onstrated altered prefrontal and temporal neuroanatomical alter-ations in ex-preterm individuals at age 20 who did not differ inperformance compared with controls during tasks involving responseinhibition, attention allocation [54], the learning of visual [55] andverbal paired associates [56] and verbal fluency [57]. Studies investi-gating functional neural connectivity described alterations in brainareas subserving language processing in ex-preterm adolescentscompared with controls. A decreased interconnectivity between thesuperior and middle temporal gyri and the frontal lobes was observedduring completion of a semantic association task [58], as well as anincreased interconnectivity between left Wernicke's area and theright supramarginal gyrus during a passive language task [59]. Avery recent study further demonstrated increased functional connec-tivity between three lobules of the left cerebellum in ex-preterm20 year olds compared with controls [60]. These findings could helpto elucidate the neurobiological basis of language deficits observedin individuals who were born very preterm in childhood and beyond[61]. All together, neuroimaging studies looking at brain structure andfunction following very preterm birth suggest long-term develop-mental alterations predominantly in frontal and temporal cortices,hippocampus and striatum.

The structural and functional brain findings described in this sectioncould be interpreted within a ‘neuroplastic’ framework, which positsthat developmental changes in any brain regionmay result in a cascadeof alterations in many other regions [62]. Animal data in fact suggestthat anatomical changes in the hippocampus may be sufficient to dis-rupt typical maturation of the prefrontal cortex [63], mimicking aspectsof the pathophysiology of schizophrenia [64]. Some researchers haveeven proposed that some processes of brain development outside theintrauterine environment, which occur following very preterm birth,

can result in the formation of a different brain [65]. This idea would beconsistent with the hypothesis proposed by Thomas and Karmiloff-Smith (2002) who suggested that the entire brain develops differentlyin individuals with neurodevelopmental disorders, so that the end-state functional architecture of developmentally altered brains maycontain modules that are not present in normally developing brains;or, in their words, are characterized by “different functional structures”[66].

3.1. Linking brain and behavior in ex-preterm adolescents

While the majority of published studies have investigated the ad-olescent brain correlates of cognitive functions [34] and clinical out-come measures [67,68], very few studies to date have examinedbehavioral and psychiatric outcome following very preterm birth inassociation with alterations of brain structure and function, especiallyin adolescence and adult life. The majority of studies have focused onattentional problems and their cognitive correlates, others have in-vestigated overall mental health functioning including internalizingand externalizing scores, while others have concentrated on psycho-social adjustment.

Based on the observation that ex-preterm individuals are at in-creased risk of developing attentional problems as well as attentiondeficit hyperactivity disorder (ADHD) (reviewed in [1]), we studiedthe functional neuroanatomy of response inhibition processingusing a ‘go/no go task’ in very-preterm born adolescents comparedwith controls [53]. Poor performance in tasks involving response inhi-bition has been reported in ADHD, obsessive compulsive disorder andschizophrenia [69]. Furthermore, neuronal activation during responseinhibition tasks has been found to be altered in ADHD [70] andschizophrenia [71]. Our study demonstrated neuroanatomical alter-ations mainly in fronto-striatal and temporal regions in ex-pretermadolescent boys. Reduced BOLD signal was observed bilaterally in cer-ebellum, prefrontal cortex and subcortical areas including right cau-date nucleus, thalamus, and left globus pallidus. Decreased signal inthese areas was accompanied by increased signal in right prefrontalcortex, in temporal regions bilaterally and right posterior cingulategyrus. In order to understand these results, we hypothesized thatthe areas of hyper-activation observed in ex-preterm individuals dur-ing successful response inhibition counteracted a potential dysfunc-tion of frontal–striatal–cerebellar circuitry, by engaging alternativeresponse pathways in order to maintain satisfactory performance.This hypothesis was put forward by other groups in relation to thestudy of functional neuroanatomy of high order cognitive function,such as language, which I described earlier [58,59].

In terms of structural changes, using volumetric region of interestMRI we reported reduced volume of left caudate nucleus in associa-tion with attention deficit-type problems (i.e. ‘hyperactivity scores’obtained with the Rutter Parents' Scale) in ex-preterm male adoles-cents [72]. These results were compatible with the idea of the involve-ment of the basal ganglia in the pathogenesis of ADHD [73], in linewith current models that propose a dysfunction of fronto–striatal cir-cuitry in the disorder, which are hypothesized be associated with al-terations in dopaminergic and noradrenergic function [74]. However,another volumetric morphological MRI study of ex-preterm adoles-cents, found that bilateral hippocampal volumes, but not caudatevolumes, were nearly 12% smaller in individuals with attention defi-cits, recorded using the Connor's Hyperactivity scale. These inconsis-tencies could be explained by the use of diverse methodologiesincluding the use of different anatomical landmarks for the delinea-tion of regions of interest.

Studies using DT-MRI have reported microstructural white matterdisorganization in the internal capsule and the posterior corpuscallosum at age 11 years in ex-preterm individuals with attention defi-cits [75]. At age 15 years white matter alterations in periventricularregions were associated with ADHD and with overall mental health

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functioning scores [68], measured with the Children's Global Assess-ment Scale (CGAS). In the same study, ex-preterm adolescents withhigh inattention scores displayed further white matter microstructuralalterations in external capsule and superior and middle fascicles. Theauthors interpreted their results in terms of altered white matter con-nectivity in widespread white matter regions throughout the brainand especially in long association fibers. Disturbed structural connectiv-ity has been described in ADHD especially in fronto–striatal and fronto–cerebellar networks and direct correlations between white matter in-tegrity and measures of both impulsivity and attention have been alsoshown [76].

Recently, we investigated neonatal ultrasound classification in re-lation to adolescent behavioral outcome using the Rutter Parents'Scale, which assesses emotional, attentional and conduct prob-lems [77]. The rationale for this study was to study whether wecould identify early predictors of the long-term behavioral sequelaeof infants at risk. The neonatal ultrasonographic results were classi-fied as: a) normal US, b) periventricular hemorrhage (PVH), andc) PVH and ventricular dilatation (PVH+DIL) [34]. Results of thisstudy showed that ex-preterm adolescents with PVH+DIL had in-creased generalized behavioral problems compared with ex-pretermindividuals with uncomplicated PVH and those with normal ultra-sound results. Moreover, ex-preterm adolescents with PVH+DILhad a younger gestational age compared with those with normal ul-trasound results. When controlling for gestational age in the analyses,the adverse behavioral outcomes reported in the PVH+DIL groupremained statistically significant, in line with the results of previousstudies [78]. Additionally, the PVH+DIL group continued to showmore generalized behavioral problems after adjusting for IQ atassessment. Pathological alterations following PVH and ventriculardilatation have been described in the literature and could help to elu-cidate the continuing neurodevelopmental problems experienced bysome ex-preterm individuals [79–81]. Several of the brain regionswe previously reported as being altered in preterm adolescents witha history of PVH+DIL [34], including the thalamus, prefrontal cortexand cerebellum have been described as altered in psychiatric disor-ders with typical onset during adolescence [82], and thalamo–corticalcircuits have been postulated to be involved in modulating adaptivebehavioral responses to environmental stimuli [83].

When investigating internalizing (withdrawal, somatic com-plaints, anxiety/depression) and externalizing scores (delinquencyand aggressive behavior), as measured by the Child Behavior Check-list, in relation to cortical morphology in ex-preterm children withperiventricular leucomalacia (PVL), positive correlations have beenobserved with cortical thickness in frontal cortex [84], which apartfrom its central involvement in executive functions, plays a criticalrole in the development of self reflection in adolescence [85]. Inanother study, internalizing scores correlated with cortical thicknessin fusiform gyrus, which is a brain area regarded as a core ‘neural sig-nature’ of autism showing neuroanatomical alterations in both indi-viduals with autism spectrum disorder (ASD) and their unaffectedsiblings [86]. The authors speculated that a thicker cortex could bedue to disruptions in synaptic pruning, which may be partly respon-sible for behavioral abnormalities, and is in fact observed in severalneurodevelopmental disorders including autism [87].

Themajority of neuroimaging studies conducted to date have inves-tigated brain volumes at defined cross-sectional time points and only afewhave described longitudinal volumetric changes in ex-preterm indi-viduals beyond the first weeks of life. We studied changes in cerebellarvolume between ex-preterm individuals and controls in the transitionfrom mid- to late adolescence (14–19 years) and observed a 3% de-crease in the preterm group compared with a non-significant changein controls [88]. These changes had functional consequences, with cer-ebellar shrinkage being associated with worse self-reported mentalhealth as measured by the General Health Questionnaire (GHQ) andspecifically in the following domains: concentration, feeling useful,

confidence, decision-making capacity and feeling of worthlessness.The investigation of longitudinal changes in brain development is par-ticularly important in light of recent studies, suggesting that dynamicsequences of cortical and subcortical maturation across prolongedtime periods, rather than cross-sectional measurements at definedtime points, may be better predictors of psychiatric outcome [89].

In the same study in which we found significant associations be-tween volume of left caudate nucleus and attention deficit-typeproblems in ex-preterm adolescent boys [72] we further studied the as-sociation between caudate volume and scores on the social adjustmentscale of Cannon-Spoor, which covers peer relationships, the ability tofunction outside the nuclear family (e.g., school performance andadaptation) and the capacity to form intimate social ties across twodifferent age periods (middle/late childhood (5–11 years) and adoles-cence (12–16 years). The rationale for assessing social adjustmentwas that preterm individuals have demonstrated difficulties in scholas-tic adjustment [90], socialization skills and social competence [91]. Wereported a statistically significant correlation between left caudate vol-ume and Social Adjustment score in childhood. These results are consis-tent with the findings in literature that the caudate nucleus, apart fromits involvement in the pathophysiology of ADHD, is associated with re-ciprocal social and communicative impairment in conditions such asASD [92].

Associations between measures of white matter integrity and so-cial function have been studied by Skranes and colleagues (2007),who reported that ex-preterm adolescents with high scores on an au-tism spectrum screening questionnaire showed white matter micro-structural alterations in external capsule and in superior fasciculus[68]. White matter alterations in these two regions, as well as ininternal capsule and occipital regions, have been found to best dis-criminate children with ASD and controls, possibly due to their in-volvement in connecting regions implicated in social cognition [93].

It has been suggested that the evaluation of increased socialthreat, social defeat and chronic stress may underlie an increasedrisk for psychiatric disorder [94]. Adolescence is a time duringwhich social communication becomes increasingly sophisticatedand the social networks in which adolescents operate become morecomplex; therefore, any pre-existing vulnerability in socialization islikely to become more evident during this period. Animal andhuman models have shown a relationship between abnormal aspectsof social functioning and later development of psychosis [95,96].Studies of children and adolescents at risk for psychosis have de-scribed atypical social development [97], increased social anxiety[98] and decreased social competence [99,100].

The hypothesis that increased stress vulnerability may be sequelaeof very preterm birth was investigated using frontal electroencephalo-gram (EEG) activity asymmetry in young adults who were born withan extremely low birth weight (ELBW; b1000 g) [101]. ELBW individ-uals exhibited more internalizing problems compared with controlsand also showed significantly greater relative right frontal EEG activ-ity, which has been associated with processing of negative emotions(e.g., distress and sorrow) [102]. The authors suggested that greaterfrontal EEG activity may represent a mechanism predisposing ELBWindividuals to experience difficulties in regulating stress. Data froma Swedish psychological conscript assessment in young males supportthis idea and suggest that low birth weight or impaired fetal growthmay increase susceptibility to stress at a psychological assessment ofstress tolerance [103]. The following section will discuss the potentialmechanisms linking altered neurodevelopment, stress vulnerabilityand psychopathology.

3.2. Linking neurodevelopment following preterm birth andpsychopathology — some hypotheses

The underlying mechanisms that lead from alterations inneurodevelopment to behavioral problems and psychopathology are

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unknown, but a possible facilitating factor could be a dysregulation ofneurotransmitters implicated in psychiatric disorders. Some hypothe-ses suggest that an early injury leads to altered prefrontal–hippocampaldevelopment, as observed following very preterm birth, leading in turnto increased striatal dopamine release [104].

Apart from their central involvement in high-order cognitive func-tions, structural and functional alterations in fronto–hippocampalnetworks have been associated with an increased vulnerability to de-velop behavioral problems in a variety of clinical and sub-clinicalsamples, including schizophrenia and individuals at risk of the disor-der [105]. Elevated pre-synaptic striatal dopamine availability hasbeen described in psychosis [104] and in the “extended phenotype”:people with schizotypy [106] and in first-degree relatives of individ-uals with schizophrenia [107]. The idea that early brain insult wouldlead to abnormal control of dopamine has high biological plausibility.Animal models have shown that pre- and perinatal factors can lead tolong-term hyperactivity in striatal dopamine function [108]. Neonatalexcitotoxic hippocampal damage, for instance, has been found tolead to altered brain development, finally resulting in increasedmesolimbic dopamine response to both stressful and pharmacologicstimuli in lesioned compared with healthy animals [109]. Excitotoxiclesions to the medial prefrontal cortex have also resulted in increaseddopamine-mediated behavioral responses in rats [110]. Similarly,work in animal models by Boksa and colleagues has suggested thatobstetric complications implicating a wide range of perinatal insultsincluding hypoxia may interact with stress at adulthood to producelasting effects on dopamine function [111]. Animal studies haveshown that a lesion may remain relatively silent until the neuronalsystem affected reaches a degree of maturity, at which point ab-normal behavior results. For example, newborn rats subjected to hip-pocampal lesions appear relatively unimpaired until they reachmaturity, after which gross behavioral disturbance results [112].Rodent models further show that animals with neonatal ventral hip-pocampal lesions show a greater sensitivity to sensitization by re-peated treatment with social stressors [11].

While further work is clearly needed to investigate the mecha-nisms through which early brain lesions may interact with the devel-oping brain to increase the vulnerability to psychopathology inadulthood, the rodent studies reviewed here provide a rational linkbetween altered neurodevelopment following preterm birth, leadingto abnormalities in dopamine release, especially during critical stagesof development such as adolescence. Social vulnerability may also lieon the causal pathway to developing psychiatric disorder and resultfrom individuals' increased evaluation of and exposure to psychoso-cial stress, which may result in dopaminergic dysregulation and in-crease the risk for psychiatric disorder [94]. However, it is alsopossible that a pre-existing dopaminergic dysregulation may increasean individual's perceived social anxiety and environmental stress.

Increased susceptibility for psychopathology conferred by pretermbirth could interact with genetic factors. We showed that very pre-term born 19 year olds had higher rates of anxiety and depressioncompared with controls, and that those with a history of psychiatricdisorder in a first-degree relative had a further increased risk [7]. Anumber of studies have shown that specific genetic variants maynot be associated with increased vulnerability to psychopathology inthe absence of a particular biological risk. For instance, a stepwise de-crease in hippocampal volumes according to genetic liability wasfound among controls, non-affected siblings and individuals withschizophrenia, with the greatest volumetric decreases in individualswith schizophrenia who had been exposed to hypoxia in the neonatalperiod [113]. Of course the contribution of other factors such as per-sonality style, life experiences and interactions with peers – or possi-bly a combination of these and others – cannot be excluded.

Furthermore, results of twin studies investigating interacting geneticand environmental factors have described important effects of age onheritability of variation in brain structures. For instance, brain regions

associated with basic sensorimotor functions seem to be predominantlyaffected by genetic influences earlier and by environmental influenceslater in development, whereas brain regions known to subserve highorder cognitive functions, such as language, become increasingly herita-blewith time [114]. The idea of an age-specific endophenotype has beenput forward by Gogtay and colleagues (2007), based on the observationthat healthy siblings of individuals with childhood-onset schizophrenia,while sharing gray matter deficits in prefrontal and temporal corticeswith their probands in childhood, show compensatory normalizationby early adulthood [115]. These findings suggest two non-mutually ex-clusive possibilities: 1) during the transition to adulthood individualswith a genetic liability to the development of schizophreniawho remainhealthy may benefit from adaptive environmental influences; and2) probands with schizophrenia may be susceptible to environmentalstressors resulting in increased stress-induced striatal dopamine release.The observation that selective brain regions may be more susceptibleto environmental interventions at specific time points during develop-ment may have important implications for the development of age-appropriate strategies aimed at attenuating the neurodevelopmentalimpact of very preterm birth.

4. Research directions

The studies reviewed in this paper underline the importance ofcontinuing to investigate trajectories of brain development in adoles-cence and beyond in order to improve our understanding of: 1) theassociation between structural and functional brain correlates andbehavioral outcomes following very preterm birth; and 2) the pat-terns of structural and functional brain development which differaccording to outcome (e.g. the presence of psychiatric problems andhealthy psychosocial development).

5. Key guidelines

The study of the structural and functional brain correlates of be-havioral outcome following preterm birth is clinically important inleading to recognize the link between certain brain developmentalpatterns and an increased vulnerability to develop a psychiatric disor-der. Such research is essential in informing the design and implemen-tation of psychological and biological remediation strategies. Thesecould include those interventions which may best optimize healthydevelopment and promote education, as well as those which mayaid proactive prevention and early diagnosis and management of psy-chiatric disorders earlier in life, exploiting the plastic properties of thedeveloping brain, rather than treating symptoms later on.

Conflicts of interest

The author has no conflicts of interest.

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