Human Growth and Development Theories/Adolesant Years
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FULL TEXT ARTICLE
Structural and functional brain correlates of behavioral
outcomes during adolescence Chiara Nosarti
Early Human Development, 2013-04-01, Volume 89, Issue 4, Pages 221-227, Copyright © 2013 Elsevier Ltd
Abstract
Several studies have described an association between very preterm birth and behavioral and psychiatric outcomes 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 behavioral
and psychiatric outcomes following very preterm birth. This article reviews studies that have directly
explored 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
externalizing scores, and psychosocial adjustment. The focus here is on neuroimaging research conducted
during adolescence, a period of life associated with the emergence and early expression of several
psychiatric disorders.
The neurodevelopmental hypothesis is used as a theoretical framework, according to which early brain
lesions interact with the developing brain to increase later vulnerability to psychopathology.
1 Introduction
Numerous studies have described an association between very preterm birth and behavioral and psychiatric outcome in childhood and adolescence 1 2 3 4. These are eloquently reviewed in Johnson et al. (2013, this
issue). Moreover, several investigations have suggested that individuals who were born very preterm are at
increased risk of developing psychiatric disorders in adulthood, including bipolar affective disorder, anxiety
disorder, depression, schizophrenia and avoidant personality problems 5 6 7. This raises the question: does
preterm birth lie on a causal pathway to the development of psychiatric illness? And if so, why?
Several theoretical frameworks have been used for exploring these questions. For instance, Paarlberg and
colleagues have proposed the idea that a common genetic liability may underlie both preterm birth and
psychiatric disorder. According to the genetic liability model, mothers-to-be with a psychiatric diagnosis are
at increased risk of delivering their offspring before term completion [8]. From a biopsychological
perspective, on the other hand, preterm birth constitutes one of a range of psychiatric risk factors, along
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witli genetic vulnerability and stress in the perinatal period, with effects accumulating over time and
resulting in the development of psychopathology [9].
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In this article I will focus on the neurodevelopmental hypothesis [10], according to which early brain lesions
(with genetic or environmental cause, or a combination of the two) interact with the developing brain to
increase the vulnerability to psychopathology in adolescence and adulthood. This hypothesis is supported by
results from animal studies, which have shown that a lesion may remain relatively silent until the neuronal
system affected reaches a degree of maturity, at which point abnormal behavior manifests [11]. Alterations
in neurodevelopment following very preterm birth will be used as a model to study the neurobiological
correlates of a variety of behavioral outcomes including psychiatric disorders. I will focus on neuroimaging
research conducted in preterm samples during adolescence, which will be regarded as a ‘sensitive period’ of
development (borrowing a term used in embryological research in the 1920s [12]), associated with the
emergence and early expression of several psychiatric disorders. When describing preterm-born samples I will include reference to individuals who were born with a low birth weight, as there is often overlap
between these events: the majority of babies born preterm are also born with a low birth weight [13].
In order to contextualize neuroimaging studies in adolescents who were born very preterm and their
relevance to the investigation of behavioral outcome, I will start by summarizing the neurodevelopmental
changes occurring in adolescence in normative samples; I will then describe structural and functional
neuroimaging studies in ex-preterm adolescents. In the third section of this article I will discuss studies that
have directly explored the structural and functional brain correlates of behavioral outcomes in ex-preterm
individuals. I will conclude by speculating on the mechanisms underlying the etiological significance 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. Adolescence is a
time associated with major hormonal and physical events, and with a magnitude of dynamic brain
developmental changes that rival only infancy, during which several brain regions underlying psychosocial
and high order cognitive functions reach maturity. During adolescence, dramatic developments in identity,
self-consciousness and cognitive flexibility occur [14].
In recent years, magnetic resonance imaging (MRI) has facilitated the investigation of structural and
functional brain development in unprecedented ways. MRI uses the property of nuclear magnetic resonance
(NMR) to align and image nuclei of atoms in a person's body. Most importantly, MRI techniques provide an
excellent contrast between different tissue types (e.g. gray matter and white matter in the brain), are non-
invasive, and allow for repeated scans to be performed on healthy individuals, thus permitting the study of
trajectories of brain development. A type of MRI that measures brain activity as indexed by the blood-
oxygen-level-dependent (BOLD) signal is referred to as functional MRI (fMRI). This method allows the
investigation of changes in brain hemodynamics that correspond to the brain at rest, or to mental
operations, which are typically performed by subjects during scanning.
Researchers at the National Institute of Mental Health in the US have conducted the largest pediatric
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neufoimaging project to date investigating maturational patterns of structural brain development in healthy individuals. Their studies suggest a pre-pubertal increase in gray matter, peaking in motor and sensory
cortex first, and later in “association” areas, which are thought to underlie cognition and complex adaptive
behavior [15]. The general pattern is then for gray matter to decrease after puberty, during the transition
from adolescence into adulthood. This heterogeneous maturational trajectory was studied by Shaw and
colleagues (2008), who proposed that the brain regions which are the last to mature may be
phylogenetically more recent, and associated with “higher” cognitive functions [16]. The cellular basis for
post-pubertal decreases in regional gray matter volume is not fully understood, but a possible explanation
refers to a greater organization of the brain through synaptic pruning, whereby connections that are used
repeatedly become strengthened and those that are rarely used are removed. In other words, synaptic
pruning may reflect “tuning” of the cortex which is accompanied by an increase in its efficiency, in line with
the hypothesis that developmental 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 associated with decreases in activation in brain areas which are not critically involved in task
completion with increasing participants' age, and with associated increases in activation in task-specific
areas [18]. These results may represent functional reorganization in cortical areas, possibly facilitating more
effective information processing in a parsimonious fashion [19]. An alternative explanation could be that
the apparent reduction of gray matter reflects ongoing intra-cortical myelination and reduction of tissue
appearing as gray matter on MRI [20]. Of course, these explanations are not mutually exclusive.
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Longitudinal developmental changes are also observed in white matter, which has been described as
showing general linear patterns of increases in volume and in micro-structural organization from childhood
through to adulthood [21], especially in frontal and parietal cortices during adolescence [22]. Such increases
could be due to on-going myelination [23], although other developmental processes such as increases in
axon diameter and growth of new axons could represent plausible explanatory mechanisms [24].
Electroencephalogram (EEG) studies have reported changes in coherence among brain subcomponents
during adolescence and into adulthood, supporting the idea of increased “connectedness” [25].
Recent studies have confirmed that maturational changes in normative samples continue beyond
adolescence. For instance, gray matter density reductions in frontal and striatal regions have been reported in the transition between adolescence and adulthood (age 30) [26], as well as non-linear age effects in
frontal and parietal regions [27] and age-related increases in the temporal lobe (including the hippocampus)
up to 38 years [28]. In addition, myelination in the human hippocampus has been reported to occur up to
adulthood [29]. Such lifetime dynamic brain changes may serve to optimally adapt our lives to our
environments and experiences [30]. Thus, it is not surprising that departures from the normal patterns of
development may be associated with psychopathology.
3 Preterm birth and behavioral outcome — a neurodevelopmental model
The theory that preterm birth is associated with impaired neurodevelopment has biological plausibility.
While neuronal proliferation is predominantly complete by the end of the second trimester of gestation, the
vast majority of brain development occurs in the third trimester, with the volume of the whole brain more
than doubling and the volume of cortical gray matter increasing approximately four-fold [31]. Being born at
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an immature developmental stage is likely to affect brain development because many major processes -
such as neurogenesis, neural migration and gyrification - are occurring between the 24th and the 32nd
gestational week. Due to its rapidly developing and complex characteristics, the immature nervous system is
particularly vulnerable to neonatal brain injury [32], which may result in alterations of the programmed
corticogenesis of the developing brain [33]. It may not be surprising, therefore, that individuals born at or
before 32 weeks compared with controls are more 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 school as term-born peers [36] and show an excess of
learning disabilities [37]. Furthermore, children who need to repeat grades or require special education
assistance in primary school are at greater risk than other children for long-term behavioral problems [38].
Please refer to Anderson et al. (2013, this issue) for a comprehensive discussion on the relationship between
high order cognitive functions and behavior in adolescence following preterm birth.
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Long-lasting and widespread structural and functional brain alterations have been described following very
preterm birth. In adolescence, gray matter and white matter volumes are reported as being linearly
associated with gestational age [34 39], and regional volumetric differences are described in subgroups of ex
preterm individuals with varying degrees of neonatal brain injury, as detected by neonatal ultrasonographic
classification [34].
One of the brain regions that have been most consistently found to be altered in ex-preterm samples is the
hippocampus, possibly consequent to hypoxic-ischemic damage [40]. Smaller hippocampal volumes have
been described in preterm-born individuals compared to controls in the first two decades of life, from
infancy [41] to adolescence [42]. We reported that bilateral hippocampal volume was 14% smaller in our ex
preterm cohort compared with controls at age 14 years [43]. However, long-term alterations in brain
structure have been also described in other brain regions including the thalamus [44], caudate nucleus [45],
corpus callosum [46] and cerebellum [47]. Using voxel based morphometry (VBM), we conducted the
largest study to date which demonstrated widespread gray and white matter alterations especially in frontal
and temporal lobes in mid-adolescence [34], some of which were subsequently replicated by others [39].
We further demonstrated that regional decreases in gray and white matter volume mediated cognitive
impairment [34]. Complementary studies investigating cortical thickness have reported thinner frontal,
temporal and parietal cortices in ex-preterm adolescents vs. controls [48].
A number of studies have used diffusion MRI (DT-MRI) in ex-preterm adolescents. This is a technique that
is sensitive to the diffusion of water molecules, and provides data that can be used both to reconstruct white
matter tract anatomy and to provide information about its coherence and connectivity. Extensive alterations
of white matter microstructure have been reported in ex-preterm individuals compared with controls in the
major intra- and inter-hemispheric fibers (e.g., corpus callosum, uncinate and fronto-occipital fasciculi) 49
50 51 .
Alterations in brain function, studied with functional magnetic resonance imaging (fMRI), have been
reported in ex-preterm adolescents compared with controls in frontal, temporal and hippocampal regions
during performance of a variety of cognitive tasks, including face-name learning [52] and response inhibition
[53]. We have demonstrated altered prefrontal and temporal neuroanatomical alterations in ex-preterm
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individuals at age 20 who did not differ in performance compared with controls during tasks involving
response inhibition, attention allocation [54], the learning of visual [55] and verbal paired associates [56]
and verbal fluency [57]. Studies investigating functional neural connectivity described alterations in brain
areas subserving language processing in ex-preterm adolescents compared with controls. A decreased
interconnectivity between the superior and middle temporal gyri and the frontal lobes was observed during
completion of a semantic association task [58], as well as an increased interconnectivity between left
Wernicke's area and the right supramarginal g5Tus during a passive language task [59]. A very recent study
further demonstrated increased functional connectivity between three lobules of the left cerebellum in ex
preterm 20 year olds compared with controls [60]. These findings could help to elucidate the
neurobiological basis of language deficits observed in individuals who were born very preterm in childhood
and beyond [61]. All together, neuroimaging studies looking at brain structure and function following very
preterm birth suggest long-term developmental alterations predominantly in frontal and temporal cortices,
hippocampus and striatum.
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The structural and functional brain findings described in this section could be interpreted within a
‘neuroplastic’ framework, which posits that developmental changes in any brain region may result in a
cascade of alterations in many other regions [62] . Animal data in fact suggest that anatomical changes in the
hippocampus may be sufficient to disrupt typical maturation of the prefrontal cortex [63], mimicldng
aspects of the pathophysiology of schizophrenia [64] . Some researchers have even proposed that some
processes of brain development outside the intrauterine environment, which occur following very preterm
birth, can result in the formation of a different brain [65]. This idea would be consistent with the hypothesis
proposed by Thomas and Karmiloff-Smith (2002) who suggested that the entire brain develops differently
in individuals with neurodevelopmental disorders, so that the end-state functional architecture of
developmentally altered brains may contain 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 adolescent brain correlates of cognitive
functions [34] and clinical outcome measures [67 68], very few studies to date have examined behavioral and
psychiatric outcome following very preterm birth in association with alterations of brain structure and
function, especially in adolescence and adult life. The majority of studies have focused on attentional
problems and their cognitive correlates, others have investigated overall mental health functioning
including internalizing and externalizing scores, while others have concentrated on psychosocial
adjustment.
Based on the observation that ex-preterm individuals are at increased risk of developing attentional
problems as well as attention deficit hyperactivity disorder (ADHD) (reviewed in [1]), we studied the
functional neuroanatomy of response inhibition processing using a ‘go/no go task’ in very-preterm born
adolescents compared with controls [53]. Poor performance in tasks involving response inhibition has been
reported in ADHD, obsessive compulsive disorder and schizophrenia [69]. Furthermore, neuronal
activation during response inhibition tasks has been found to be altered in ADHD [70] and schizophrenia
[71]. Our study demonstrated neuroanatomical alterations mainly in fronto-striatal and temporal regions in
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ex-preterm adolescent boys. Reduced BOLD signal was observed bilaterally in cerebellum, prefrontal cortex
and subcortical areas including right caudate nucleus, thalamus, and left globus pallidus. Decreased signal
in these areas was accompanied by increased signal in right prefrontal cortex, in temporal regions bilaterally
and right posterior cingulate gyrus. In order to understand these results, we hypothesized that the areas of
hyper-activation observed in ex-preterm individuals during successful response inhibition counteracted a
potential dysfunction of frontal-striatal-cerebellar circuitry, by engaging alternative response pathways in
order to maintain satisfactory performance. This hypothesis was put forward by other groups in relation to
the study 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 interest MRI we reported reduced volume of left
caudate nucleus in association with attention deficit-type problems (i.e. ‘hyperactivity scores’ obtained with
the Rutter Parents' Scale) in ex-preterm male adolescents [72]. These results were compatible with the idea
of the involvement of the basal ganglia in the pathogenesis of ADHD [73], in line with current models that
propose a dysfunction of fronto-striatal circuitry in the disorder, which are hypothesized be associated with
alterations in dopaminergic and noradrenergic function [74]. However, another volumetric morphological
MRI study of ex-preterm adolescents, found that bilateral hippocampal volumes, but not caudate volumes,
were nearly 12% smaller in individuals with attention deficits, recorded using the Connor's Hyperactivity
scale. These inconsistencies could be explained by the use of diverse methodologies including the use of
different anatomical landmarks for the delineation of regions of interest.
Studies using DT-MRI have reported microstructural white matter disorganization in the internal capsule
and the posterior corpus callosum at age 11 years in ex-preterm individuals with attention deficits [75] . At
age 15 years white matter alterations in periventricular regions were associated with ADHD and with overall
mental health functioning scores [68], measured with the Children's Global Assessment Scale (CGAS). In
the same study, ex-preterm adolescents with high inattention scores displayed further white matter
microstructural alterations in external capsule and superior and middle fascicles. The authors interpreted
their results in terms of altered white matter connectivity in widespread white matter regions throughout
the brain and especially in long association fibers. Disturbed structural connectivity has been described in
ADHD especially in fronto-striatal and fronto-cerebellar networks and direct correlations between white
matter integrity and measures of both impulsivity and attention have been also shown [76].
Recently, we investigated neonatal ultrasound classification in relation to adolescent behavioral outcome
using the Rutter Parents' Scale, which assesses emotional, attentional and conduct problems [77]. The
rationale for this study was to study whether we could identify early predictors of the long-term behavioral
sequelae of infants at risk. The neonatal ultrasonographic results were classified as: a) normal US, b)
periventricular hemorrhage (PVH), and c) PVH and ventricular dilatation (PVH DIL) [34]. Results of this
study showed that ex-preterm adolescents with PVH -1- DIL had increased generalized behavioral problems
compared with ex-preterm individuals with uncomplicated PVH and those with normal ultrasound results.
Moreover, ex-preterm adolescents with PVH -h DIL had a younger gestational age compared with those with
normal ultrasound results. When controlling for gestational age in the analyses, the adverse behavioral
outcomes reported in the PVH -1- DIL group remained statistically significant, in line with the results of
previous studies [78]. Additionally, the PVH -h DIL group continued to show more generalized behavioral
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problems after adjusting for IQ at assessment. Pathological alterations following PVH and ventricular dilatation have been described in the literature and could help to elucidate the continuing
neurodevelopmental problems experienced by some ex-preterm individuals 79 80 81 . Several of the brain
regions we previously reported as being altered in preterm adolescents with a history of PVH + DIL [34],
including the thalamus, prefrontal cortex and cerebellum have been described as altered in psychiatric
disorders with typical onset during adolescence [82] , and thalamo-cortical circuits have been postulated to
be involved in modulating adaptive behavioral responses to environmental stimuli [83].
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When investigating internalizing (withdrawal, somatic complaints, anxiety/depression) and externalizing
scores (delinquency and aggressive behavior), as measured by the Child Behavior Checklist, in relation to
cortical morphology in ex-preterm children with periventricular leucomalacia (PVL), positive correlations have been observed with cortical thickness in frontal cortex [84], which apart from its central involvement in
executive functions, plays a critical role in the development of self reflection in adolescence [85]. In another
study, internalizing scores correlated with cortical thickness in fusiform gyrus, which is a brain area
regarded as a core ‘neural signature’ of autism showing neuroanatomical alterations in both individuals with
autism spectrum disorder (ASD) and their unaffected siblings [86]. The authors speculated that a thicker
cortex could be due to disruptions in synaptic pruning, which may be partly responsible for behavioral
abnormalities, and is in fact observed in several neurodevelopmental disorders including autism [87].
The majority of neuroimaging studies conducted to date have investigated brain volumes at defined cross-
sectional time points and only a few have described longitudinal volumetric changes in ex-preterm
individuals beyond the first weeks of life. We studied changes in cerebellar volume between ex-preterm individuals and controls in the transition from mid- to late adolescence (14-19 years) and observed a 3%
decrease in the preterm group compared with a non-significant change in controls [88]. These changes had
functional consequences, with cerebellar shrinkage being associated with worse self-reported mental health
as measured by the General Health Questionnaire (GHQ) and specifically in the following domains:
concentration, feeling useful, confidence, decision-making capacity and feeling of worthlessness. The
investigation of longitudinal changes in brain development is particularly important in light of recent
studies, suggesting that dynamic sequences of cortical and subcortical maturation across prolonged time
periods, rather than cross-sectional measurements at defined time points, may be better predictors of
psychiatric outcome [89].
In the same study in which we found significant associations between volume of left caudate nucleus and
attention deficit-type problems in ex-preterm adolescent boys [72] we further studied the association
between caudate volume and scores on the social adjustment scale of Cannon-Spoor, which covers peer
relationships, the ability to function outside the nuclear family (e.g., school performance and adaptation)
and the capacity to form intimate social ties across two different age periods (middle/late childhood (5-11
years) and adolescence (12-16 years). The rationale for assessing social adjustment was that preterm individuals have demonstrated difficulties in scholastic adjustment [90], socialization skills and social
competence [91]. We reported a statistically significant correlation between left caudate volume and Social
Adjustment score in childhood. These results are consistent with the findings in literature that the caudate
nucleus, apart from its involvement in the pathophysiology of ADHD, is associated with reciprocal social
and communicative impairment in conditions such as ASD [92].
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Associations between measures of white matter integrity and social function have been studied by Skranes
and colleagues (2007), who reported that ex-preterm adolescents with high scores on an autism spectrum
screening questionnaire showed white matter microstructural alterations in external capsule and in superior
fasciculus [68]. White matter alterations in these two regions, as well as in internal capsule and occipital
regions, have been found to best discriminate children with ASD and controls, possibly due to their
involvement in connecting regions implicated in social cognition [93].
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It has been suggested that the evaluation of increased social threat, social defeat and chronic stress may
underlie an increased risk for psychiatric disorder [94]. Adolescence is a time during which social
communication becomes increasingly sophisticated and the social networks in which adolescents operate
become more complex; therefore, any pre-existing vulnerability in socialization is likely to become more
evident during this period. Animal and human models have shown a relationship between abnormal aspects
of social functioning and later development of psychosis [95 96]. Studies of children and adolescents at risk
for psychosis have described atypical social development [97], increased social anxiety [98] and decreased
social competence [99 100].
The hypothesis that increased stress vulnerability may be sequelae of very preterm birth was investigated
using frontal electroencephalogram (EEG) activity asymmetry in young adults who were born with an
extremely low birth weight (ELBW; < 1000 g) [101] . ELBW individuals exhibited more internalizing
problems compared with controls and also showed significantly greater relative right frontal EEG activity,
which has been associated with processing of negative emotions (e.g., distress and sorrow) [102]. The
authors suggested that greater frontal EEG activity may represent a mechanism predisposing ELBW
individuals to experience difficulties in regulating stress. Data from a Swedish psychological conscript
assessment in young males support this idea and suggest that low birth weight or impaired fetal growth may
increase susceptibility to stress at a psychological assessment of stress tolerance [103]. The following
section will discuss the potential mechanisms linking altered neurodevelopment, stress vulnerability and
psychopathology.
3.2 Linking neurodevelopment following preterm birth and psychopathology — some hypotheses
The underlying mechanisms that lead from alterations in neurodevelopment to behavioral problems and
psychopathology are unknown, but a possible facilitating factor could be a dysregulation of
neurotransmitters implicated in psychiatric disorders. Some hypotheses suggest that an early injury leads to
altered prefrontal-hippocampal development, as observed following very preterm birth, leading in turn to
increased striatal dopamine release [104].
Apart from their central involvement in high-order cognitive functions, structural and functional alterations
in fronto-hippocampal networks have been associated with an increased vulnerability to develop behavioral
problems in a variety of clinical and sub-clinical samples, including schizophrenia and individuals at risk of
the disorder [105]. Elevated pre-synaptic striatal dopamine availability has been described in psychosis [104]
and in the “extended phenotype”: people with schizotypy [106] and in first-degree relatives of individuals
with schizophrenia [107]. The idea that early brain insult would lead to abnormal control of dopamine has
high biological plausibility. Animal models have shown that pre- and perinatal factors can lead to long-term
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hyperactivity in striatal dopamine function [108] . Neonatal excitotoxic hippocampal damage, for instance,
has been found to lead to altered brain development, finally resulting in increased mesolimbic dopamine
response to both stressful and pharmacologic stimuli in lesioned compared with healthy animals [109].
Excitotoxic lesions to the medial prefrontal cortex have also resulted in increased dopamine-mediated
behavioral responses in rats [110]. Similarly, work in animal models by Boksa and colleagues has suggested
that obstetric complications implicating a wide range of perinatal insults including hypoxia may interact
with stress at adulthood to produce lasting effects on dopamine function [111]. Animal studies have shown
that a lesion may remain relatively silent until the neuronal system affected reaches a degree of maturity, at
which point abnormal behavior results. For example, newborn rats subjected to hippocampal lesions appear
relatively unimpaired until they reach maturity, after which gross behavioral disturbance results [112].
Rodent models further show that animals with neonatal ventral hippocampal lesions show a greater
sensitivity to sensitization by repeated treatment with social stressors [11].
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While further work is clearly needed to investigate the mechanisms through which early brain lesions may
interact with the developing brain to increase the vulnerability to psychopathology in adulthood, the rodent
studies reviewed here provide a rational link between altered neurodevelopment following preterm birth,
leading to abnormalities in dopamine release, especially during critical stages of development such as
adolescence. Social vulnerability may also lie on the causal pathway to developing psychiatric disorder and result from individuals' increased evaluation of and exposure to psychosocial stress, which may result in
dopaminergic dysregulation and increase the risk for psychiatric disorder [94]. However, it is also possible
that a pre-existing dopaminergic dysregulation may increase an individual's perceived social anxiety and environmental stress.
Increased susceptibility for psychopathology conferred by preterm birth could interact with genetic factors.
We showed that very preterm born 19 year olds had higher rates of anxiety and depression compared with
controls, and that those with a history of psychiatric disorder in a first-degree relative had a further
increased risk [7]. A number of studies have shown that specific genetic variants may not be associated with
increased vulnerability to psychopathology in the absence of a particular biological risk. For instance, a
stepwise decrease in hippocampal volumes according to genetic liability was found among controls, non-
affected siblings and individuals with schizophrenia, with the greatest volumetric decreases in individuals
with schizophrenia who had been exposed to hypoxia in the neonatal period [113]. Of course the
contribution of other factors such as personality style, life experiences and interactions with peers - or
possibly a combination of these and others - cannot be excluded.
Furthermore, results of twin studies investigating interacting genetic and environmental factors have
described important effects of age on heritability of variation in brain structures. For instance, brain regions associated with basic sensorimotor functions seem to be predominantly affected by genetic influences
earlier and by environmental influences later in development, whereas brain regions known to subserve
high order cognitive functions, such as language, become increasingly heritable with time [114]. The idea of
an age-specific endophenotype has been put forward by Gogtay and colleagues (2007), based on the
observation that healthy siblings of individuals with childhood-onset schizophrenia, while sharing gray
matter deficits in prefrontal and temporal cortices with their probands in childhood, show compensatory
normalization by early adulthood [115]. These findings suggest two non-mutually exclusive possibilities: 1)
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during the transition to adulthood individuals with a genetic liability to the development of schizophrenia
who remain healthy may benefit from adaptive environmental influences; and 2) probands with
schizophrenia may be susceptible to environmental stressors resulting in increased stress-induced striatal
dopamine release. The observation that selective brain regions may be more susceptible to environmental
interventions at specific time points during development may have important implications for the
development of age-appropriate strategies aimed at attenuating the neurodevelopmental impact of very
preterm birth.
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4 Research directions
The studies reviewed in this paper underline the importance of continuing to investigate trajectories of
brain development in adolescence and beyond in order to improve our understanding of: 1) the association between structural and functional brain correlates and behavioral outcomes following very preterm birth;
and 2) the patterns of structural and functional brain development which differ according to outcome (e.g.
the presence of psychiatric problems and healthy psychosocial development).
5 Key guidelines
The study of the structural and functional brain correlates of behavioral outcome following preterm birth is
clinically important in leading to recognize the link between certain brain developmental patterns and an
increased vulnerability to develop a psychiatric disorder. Such research is essential in informing the design
and implementation of psychological and biological remediation strategies. These could include those
interventions which may best optimize healthy development and promote education, as well as those which
may aid proactive prevention and early diagnosis and management of psychiatric disorders earlier in life,
exploiting the plastic properties of the developing brain, rather than treating symptoms later on.
Conflicts of interest
The author has no conflicts of interest.
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