Healthy and Abnormal Development of the Prefrontal Cortex

Developmental Neurorehabilitation, October 2009; 12(5): 279–297

Healthy and abnormal development of the prefrontal cortex

MEGAN SPENCER-SMITH1,2 & VICKI ANDERSON1,2,3

1Murdoch Childrens Research Institute, Melbourne, Australia, 2University of Melbourne, Melbourne, Australia, and 3Royal Children’s Hospital, Melbourne, Australia

(Received 8 October 2008; accepted 3 June 2009)

Abstract Background: While many children with brain conditions present with cognitive, behavioural, emotional, academic and social impairments, other children recover with seemingly few impairments. Animal studies and preliminary child studies have identified timing of brain lesion as a key predictor in determining functional outcome following early brain lesions. Review: This research suggests that knowledge of healthy developmental processes in brain structure and function is essential for better understanding functional recovery and outcome in children with brain lesions. This review paper aims to equip researchers with current knowledge of key principles of developmental processes in brain structure and function. Timetables for development of the prefrontal cortex (PFC), a brain region particularly vulnerable to lesions due to its protracted developmental course, are examined. In addition, timetables for development of executive skills, which emerge in childhood and have a prolonged developmental course that parallels development of the PFC, are also discussed. Conclusions: Equipped with this knowledge, researchers are now in a better position to understand functional recovery and outcome in children with brain conditions.

Keywords: Development, prefrontal cortex, executive functions, brain injury

Introduction are clearly determined by a complex and constantly

For personal use only. changing relationship with all of these factors. Many children with brain conditions present with Timing of brain lesion has been identified as a cognitive, behavioural, emotional, academic and central predictor of functional outcome in animal social impairments, often requiring lifetime inter- focal lesion studies [21–24] and preliminary child vention and support. Some children, however, studies [4,11]. Key principles that have emerged demonstrate considerable recovery and seemingly from this research suggest that developmental pro- few impairments. Research attempting to understand this variance has focused on identifying cesses occurring at the time of the brain lesion are predictors of outcome in groups of children with particularly vulnerable to disruption. Further, these specific brain conditions, such as traumatic brain studies suggest that aetiology of the brain condition may be only one of many factors that shape Dev Neurorehabil Downloaded from informahealthcare.com by Yeshiva University on 03/03/13 injury [1,2], focal brain injury [3–6], cerebral toxicity and childhood cancers [7–10], stroke [11], cerebral functional outcomes. Based on systematic studies infection [12,13], seizures [14–17], metabolic dis- of focal frontal lesions in rats, Kolb et al. [25] turbance [18,19] and prematurity [20]. Together propose critical periods in rat neurological develop- these studies are building a picture demonstrating ment when brain lesions are associated with poor or the capacity of the immature brain to recover and better functional outcome and further suggest these develop after a brain lesion. These studies also critical periods may extrapolate to humans. While suggest that outcome is related to identifiable brain human research provides preliminary support for lesion characteristics as well as developmental, these critical periods, the model has not yet been environmental and constitutional factors. systematically examined to determine whether it Individually these factors do not adequately explain applies to humans. Based on child and adult studies the variance in outcome observed in children with examining language outcome after brain injury, brain conditions. Functional recovery and outcome Dennis [26] proposed stages in skill maturation

Correspondence: Megan Spencer-Smith, Critical Care and Neurosciences, Murdoch Childrens Research Institute, Royal Children’s Hospital, Flemington Road, Parkville, VIC 3054, Australia. Tel: þ61 3 9090 5253. Fax: +61 3 9090 5212. E-mail: [email protected] ISSN 1751–8423 print/ISSN 1751–8431 online/09/050279–19 ß 2009 Informa UK Ltd. DOI: 10.1080/17518420903090701 280 M. Spencer-Smith & V. Anderson

when injury will be associated with poor or better cortical regions, connected via specific neural cir- outcome for that skill. This heuristic, however, has cuits [30,31]. Lesion studies and functional imaging not yet been empirically tested to determine whether studies demonstrate that separate frontal regions its principles extend to other cognitive skills. support specific cognitive processes. For example, Considerable research and theory has been direc- the medial prefrontal region has been shown to ted towards better understanding the development support attentional control processes including of structural and functional specificity through focused attention [32] and self-regulation [28]. childhood. Early studies argued strongly for innate Some evidence challenges this modular approach specialization of the brain [27], however more [33–35]. Stuss [35] has reported executive dysfunc- contemporary studies are accumulating that suggest tion in adults after extra-frontal brain damage and regions in the developing brain may not be as func- interpreted these findings as evidence that EF are tionally specific as those in the mature brain [28,29]. associated with complex frontal and extra-frontal Accordingly, damage to the developing brain, when systems. While the PFC is critical for EF, it appears brain networks are less established and therefore that integrity of the whole brain may be necessary for more brain regions are recruited to perform tasks, efficient EF [36–38]. This is especially the case in may result in more generalized dysfunction. the developing brain, which has less established Alternatively, reduced localization of function may connectivity and structure. allow for compensation or development of new How and when the brain becomes specialized is networks in the context of brain lesion. In order to particularly relevant to understanding the neurobe- determine when greater or less potential for recovery havioural consequences of brain lesions. Early might occur in children with brain conditions, researchers suggested contradicting possibilities. knowledge of healthy brain development is essential. Lenneberg [39] argued that the infant’s brain was This paper outlines healthy processes in develop- ‘equipotential’ and that functional specialization ment of brain structure and function that are emerged gradually through early childhood. essential for understanding functional outcomes in In contrast, the ‘innate specialization’ model argues children with brain conditions. General principles of that key skills such as language are localized at birth brain development that are helpful for understating [27]. More contemporary research examining the mature brain are discussed. A review of time- human functional brain development highlights the tables for key neurological processes in development importance of accounting for the influence of expe- of the prefrontal cortex (PFC) is presented. This rience and genetics on the developing organisation of For personal use only. brain region is especially vulnerable to brain lesions the brain. Johnson [30,40] acknowledges these due to its extended developmental trajectory. influences and identifies three separate, but not Research shows that, in adults, executive functions necessarily incompatible, approaches to understand- (EF) rely strongly on the integrity of the PFC, which ing progression of cognitive abilities in infants: (a) plays an important role in efficient EF. Therefore, maturation; (b) interactive specialization; and (c) skill timetables for development of executive skills are learning. also outlined and parallels in development of brain The maturational view proposes that the develop- structure and function are examined. This review mental sequence of specific neuroanatomical regions aims to provide an understanding of functional enables the hierarchical emergence of sensory, motor outcome in children with brain conditions. and cognitive processes. For example, the dorso- Dev Neurorehabil Downloaded from informahealthcare.com by Yeshiva University on 03/03/13 lateral PFC (DL-PFC) supports successful performance on the object retrieval task, designed to assess Healthy brain development working memory and inhibitory control in children [41]. Successful performance on the task involves While there is some understanding about healthy activation of several brain regions, but the particu- brain development, the impact of brain lesions on larly protracted development of the DL-PFC is the expected course of development is unknown. thought to be primarily responsible for change in Knowledge of how and when the brain becomes behaviour, limiting the child’s efficiency until these specialized, leading to its mature state, assists in brain regions are mature. understanding and investigation of functional and The interactive specialization view suggests that structural consequences of brain lesions. emergence of a new skill reflects refinement of connectivity between brain regions and not just Theories of human functional brain development activity in one or more region. For example, The healthy adult brain is highly specialized in Anderson et al. [42] reported differential language structure and function, thought to reflect a modular activation over time in 8 year-old identical twins organization. This approach attributes the processing discordant for a left frontal tumour and seizures of particular behavioural functions to distinct commencing at age 5. The affected twin initially Development of the prefrontal cortex 281

demonstrated typical left-sided brain activation on a (OFC) regions [50], in keeping with the develop- language paradigm. Over time, activation became mental timetables of executive skills which these brain bilateral, thought to be associated with growth in the regions underpin. Not all brain regions follow this tumour. However, with emerging and increasing pattern of development. Myelination of anterior right hemisphere activation over time, deterioration regions of the corpus callosum is complete prior to in expressive language skills was documented in the posterior regions, which do not mature until adoles- affected twin but not the unaffected twin. The cence [51,52]. authors suggest that the emerging right activation might reflect pathophysiologic effects of the tumour Additive and regressive events. Additive and regres- in the prototypical language cortex rather than sive developmental processes have been described as language transfer. Or, increasing right hemisphere important in refining and increasing efficiency of activation might represent an unsuccessful attempt cortical systems. Additive development is the ongoing to reorganize language to the non-dominant hemi- accumulation of growth processes, such as progres- sphere. In this case, disruption of left hemisphere sive linear myelination from infancy through to language by the epileptogenic, progressive tumour adulthood [48,53]. Some neuronal processes exhibit might have limited or prevented its functional periods of regression, a cycle characterized by an reintegration, instead provoking further recruitment initial over-production and then selective elimination of right hemisphere homologues. Alternatively, the of redundant elements. For example, excess synapses right hemisphere activation might reflect the loss of are formed in infancy and through experience the active inhibition from the homologous left frontal obsolete connections are pruned [54]. There is also region or loss of some other form of reciprocal an initial over-production of dendrites followed by interaction between frontal homologues. pruning to leave only the most functional branches The skill learning approach suggests that activa- [55,56]. Other measures of cortical maturation dem- tion of brain regions changes during skill acquisition. onstrate an inverse association over time. O’Donnell For example, recent functional neuroimaging studies et al. [57] reported cortical thickness in the fronto- demonstrate more diffuse activation within prefron- polar region and DL-PFC to decrease linearly with tal and extra-frontal regions in children performing age between 8–20 years. This is consistent with executive tasks compared with adults. Further, volumetric studies showing increases in frontal grey increasingly focal activation is observed with age matter during pre-adolescence followed by a decrease [28,29], reflecting an association between perfor-

For personal use only. during adolescence [44,58–60]. mance and emerging patterns of interactions between different regions. Growth spurts in development of the prefrontal Developmental progression of brain development cortex. Brain maturation is not linear, but is punctuated by a series of growth spurts (times There are several developmental processes acting associated with rapid development). Figure 1 illus- and interacting that contribute to brain develop- trates the onset and conclusion of key neurological ment, including: (1) hierarchical progression; (2) processes in the PFC, represented by the horizontal regressive and additive processes; and (3) growth bars. Based on current understanding of timetables spurts in neurological processes. in typical development of the PFC, a number of Dev Neurorehabil Downloaded from informahealthcare.com by Yeshiva University on 03/03/13 major growth periods can be identified: (a) 6–18 Hierarchical progression. In general, there is a hier- weeks gestation, involves rapid proliferation [61,62]; archical progression in the development of the central (b) 3–5 months gestation, involves rapid migration nervous system (CNS), with the brainstem and [63,64]; (c) 6–9 months gestation, when significant cerebellar regions developing first, followed by posterior areas and anterior regions reaching maturity last [43–47]. This pattern of posterior to anterior Proliferation maturation has been observed using many measures Migration Dendritic outgrowth of brain development, including whole brain volume Differentiation and white matter volume [48], electroencephalogra- Synaptogenesis phy (EEG) [45] and metabolic activity [49]. For Myelination example, increases in white matter volume (reflecting Synaptic pruning myelination progression) have been observed to occur in stages from primary and sensory areas, to gestation 3m 6m birth 2y 4y 6y 8y 10y 12y association areas and finally frontal regions [48]. Developmental timing Further, the process appears to be site-specific, with Figure 1. The onset and conclusion of neurological processes in DL-PFC maturing later than orbito-frontal cortex the PFC during childhood (represented by horizontal bars). 282 M. Spencer-Smith & V. Anderson

differentiation occurs [65]; (d) the first 3 years of connectivity within the PFC and between the PFC life, a time of major dendritic outgrowth [66,67], and other brain regions suggests that, although PFC peak in synaptogenesis [54,66] and the majority of may orchestrate behaviour, they are heavily depen- myelination occurs [48,68,69], followed by com- dent on all other brain areas for input. Efficient mencement of synaptic pruning [53]; (e) 7–9 years, a functioning is therefore reliant upon the quality of peak in myelination [70,71]; and (f) 10–12 years, information received from other regions. when peaks in myelination [70,71] and grey matter Highlighting this, Saint-Cyr et al. [82] identified volumes [44,48,59] occur. five frontal-subcortical circuits that involve pathways Studies examining maturation using a variety of connecting regions and integrating information methodological approaches such as brain volume influencing both behaviour and movements. These [48], EEG [45,46,72] and glucose metabolism [49] circuits include the motor, oculomotor, dorso-lateral report similar distinct growth periods in prefrontal prefrontal, orbito-frontal and anterior cingulate regions. Thatcher [72–74] describes three main circuits. The refinement and establishment of these growth spurts in brain maturation based on analyses circuits is likely to be crucial for efficient neurolog- of human EEG coherence. An initial growth spurt is ical and cognitive functioning. recorded between 1.5–5 years, a second between 5–10 years and a final spurt between 10–16 years. In addition, two transitional phases are identified; one Developmental timetables of the prefrontal occurring between 5–7 years in the left hemisphere cortex and another in the right hemisphere between 9–11 This study presents a review of developmental years. Hudspeth and Pribram [45,46] note similar timetables for key neurological processes in the developmental phases using EEG data and an addi- human PFC, demonstrating the prolonged and tional spurt between 16–19 years. The EEG coher- intricate orchestration of events that occur from ence is interpreted as repetitive sequences of synaptic gestation through to late childhood. Interruption to over-production followed by synaptic pruning. These neurological development has different structural growth spurts in development of the PFC are and functional consequences, which appear to vary supported by neuropsychological research, which based on timing of brain lesion. documents a series of developmental increments in executive skills, through infancy and into adolescence, with evidence of a plateau in mid-adolescence. Prenatal brain development For personal use only. The prenatal period is the most rapid phase of development across the lifespan and is devoted to The mature prefrontal cortex gross structural formation of the CNS [83]. During this phase the human CNS is transformed from a The PFC is the largest region in the human brain, thin layer of unspecified tissue into a complex system comprising a quarter to one third of the entire that can process information and organize actions cerebral cortex [75–77]. In defining functions of the [84,85]. This transformation is largely genetically PFC, studies increasingly emphasize that cytoarch- pre-determined, resulting from the intricate pro- itectonic differences between cortical areas may not cesses of neurulation, proliferation, migration, be as important as patterns of connectivity between axonal extension, synaptogenesis, differentiation Dev Neurorehabil Downloaded from informahealthcare.com by Yeshiva University on 03/03/13 and within the specific region [75]. Three sub- and apoptosis. These processes are further refined regions of the PFC have been distinguished by by experience, which may have advantageous or connections with different cerebral areas, which each deleterious developmental consequences. Due to the subserve different executive processes: medial PFC, complex choreography of events during prenatal DL-PFC and OFC [78,79]. The DL-PFC has development via intrinsic or extrinsic mechanisms, strongest connections with other cortical regions, development of the PFC is vulnerable to interrup- supporting the view that this region is associated tion at this time. with higher order cognitive functions. In contrast, the orbital medial prefrontal regions have strongest links with subcortical regions, including limbic Neural induction. At day 16 of gestation, neural structures, suggesting a greater role for this circuit induction begins [86], which involves the mesoderm in social and emotional control. Sub-regions of the layer of the embryo specifying the ectoderm to PFC are not independent and have strong connec- become the CNS [87]. The neural plate folds in on tions with one another [79–81]. The PFC is the itself to form the neural tube and a small group of most highly interconnected area of the brain, cells lateral to this form the neural crest, a process receiving afferent fibres of visual, auditory and completed around the 5th week of gestation [88,89]. somatic origin [75]. The complex pattern of The neural tube later gives rise to all cells of the CNS Development of the prefrontal cortex 283

(brain and spinal cord) and the neural crest cells found closest to the proliferative zone, representing produce most of the peripheral nervous system. the first wave of migration and later born neurons Interruption to development at this time can result guided by radial glial fibres travel greater distances in neural tube defects, which commonly lead to from the germinal zone, representing the second termination of the foetus or profound birth defects wave of migration [99,100] occurring 11–16 weeks [84]. Spina bifida is a common and severely gestation [101]. At this time the telencephalon disabling neural tube defect which results in a expands and differentiates to form the cerebral range of physical and cognitive limitations, but not cortex, basal ganglia, corpus callosum and other necessarily intellectual disability [90]. Anencephaly structures [91]. Recent data indicate that migration arises when the rostral end of the neural tube fails to ceases 30 weeks gestation [102], however this is fuse correctly [91,92], resulting in the absence of the still a matter of debate. major portion of the brain and the top part of the The destination of the migrating cell is determined skull. Most infants with anencephaly will be stillborn by the pattern in which it migrates: radial or and those born alive will generally live for a very tangential. The majority (80–90%) of pyramidal short time. neurons migrate in a radial pattern [99– 101,103,104]. The activated receptor on the surface of the migrating neuron initiates a series of intracel- Proliferation. Once the neural tube is fused, neurons lular reactions that result in the neuron travelling intended to form the cerebral cortex are born as along radial glial fibres to the outer areas of the neuroblasts in the anterior periventricular region developing cortex. Here it receives a signal to between 6–18 weeks gestation [62]. These neuro- disassociate from the radial glial cell and become blasts proliferate and differentiate before migrating part of the cortex, where it will later be employed in towards the developing cortical plate [61]. The rapid the mature brain. The remaining cells migrate in a growth spurt of radial glial fibres, which guide tangential pattern, which enable neurons to travel migrating neuroblasts to their final destination, parallel to the surface of the developing brain, commences early and is completed by 20 weeks entering and exiting different brain regions guided gestation [93,94]. Proliferation ceases at 18 weeks by glial and axonal fibres [105]. It has been gestation and the last neuroblasts formed within the suggested that through this process of tangential neural tube move to their final destinations at this migration, cell movement and thus cell morphology, time. A growth spurt in glial cells also occurs, but later as well as neurotransmitter phenotype, is to some

For personal use only. in gestation, between 20–40 weeks. extent plastic [84]. It is possible that this process Interruptions to cell proliferation can result in might allow for the amelioration of errors in migra- microencephaly, a severe malformation associated tion and other developmental processes. It might with seizures and intellectual impairment [95]. also have detrimental consequences, permitting Developmental microencephalies of a genetic origin environmental perturbations to adversely affect the arise from a reduced production of neurons or radial developing CNS during the later part of foetal glial fibres during proliferation. Destructive micro- development. encephalies arise secondary to another process such Subsequently, minor aberrations to the expected as ischaemia, a toxic event or infection [96], which course of migration may not manifest in clinical may be a consequence of mitotic inhibition, symptoms and some evidence suggests that such

Dev Neurorehabil Downloaded from informahealthcare.com by Yeshiva University on 03/03/13 impaired neurite differentiation or destructive neu- aberrations may reflect a variant of normal develop- ronal depletion, depending on the time of exposure ment [92]. Gross malformations, however, do occur. [84,94,97]. Over-production of neurons may also Arrest of neuronal migration occurring before occur, as seen in megalencephaly, a condition 16 weeks gestation may result in Lissencephaly, a characterized by an abnormally large, heavy brain disorder affecting the entire brain that is depicted by [97,98]. a thickened cortex usually reduced to four layers. However, neuronal migration disorders may be Migration. Once neuroblasts are born they migrate restricted to focal cortical or subcortical areas. to their pre-destined brain region, a process which Subcortical band heterotopia is a relatively peaks between the 3rd and 5th months of gestation common brain condition that occurs when neurons [63,64]. At this final destination neurons aggregate fail to migrate to their intended destination, instead together with other cells of a similar type to form forming a band of heterotopic neurons, as illustrated vertical columns and by 7 months the six cortical in Figure 2. Periventricular nodular heterotopia is layers found in the adult brain have formed [94]. characterized by small clumps of neurons that have In most cortical and several subcortical areas, the not migrated correctly, forming nodules on the walls distribution of neurons has an ‘inside-out’ spatial- of the lateral ventricles. The underlying cause for temporal gradient [99]. Earliest born neurons are migratory disturbance is unclear, but there is some 284 M. Spencer-Smith & V. Anderson

Figure 2. Subcortical band heterotopia. Arrows show the diffuse, moderate band with frontal predominance.

evidence suggesting a genetic origin [97,106] and nearly half of all neurons during development and is extrinsic influences such as vulnerability to a virus therefore imperative for normal development. may also play a role [94]. Increased rates of apoptosis, however, may have negative consequences. Foetuses with Down syndrome have experienced high rates of apoptosis Dendritic development and synaptogenesis. Once [114], which is thought to account for intellectual migrating neurons reach their final destination impairment associated with this syndrome. rapid extension of the axon (the transmitting ele- As axons extend and dendrites arborize, the ment of a neuron) and arborization of dendrites developing CNS becomes more densely packed commences at 15 weeks gestation [56]. The first and the surface of the brain acquires convolutions

For personal use only. apical dendrites of immature neurons are present at (sulci and gyri) to accommodate this increased 13.5 weeks gestation [65,107]. The outward growth cortical mass. Thus, through these processes of of the axon is guided by the growth cone, located at axonal outgrowth, dendritic development and synap- the tip of growing neurites (axons and dendrites) togenesis, the brain increases in size, connections are [108]. Finger like projections, filopodia, seek out an formed and the brain takes on a more mature appropriate environment by extending often several appearance [84]. Toxic or ischemic events occurring centimetres [109] into the surrounding environment after 20 weeks gestation are likely to affect neuro- and retracting when the encountered environment is transmitter production and cell-to-cell interactions unsuitable [110]. On reaching the target, axonal important in guiding the developing axon to its elongation ceases and the formation of a synapse is target. These CNS abnormalities are often difficult Dev Neurorehabil Downloaded from informahealthcare.com by Yeshiva University on 03/03/13 initiated, beginning at 27 weeks gestation in the to detect using present techniques and the sugges- frontal cortex [53,56]. The synaptic density tion that environmental agents may disrupt devel- increases to a level that greatly exceeds adult levels. opment is derived from the observation that The process of establishing and strengthening abnormalities are not apparent before 20 weeks connections with other neurons, crucial to normal gestation and therefore unlikely to be a result of a functioning [111], involves neurotrophic factors disruption in cell proliferation or migration. (signalling molecules that are necessary for neural Inhibition of neuronal and glial growth and matura- survival) such as nerve growth factor [112]. These tion may also manifest as late developmental molecules are in short supply in the CNS, with only microcephaly [98]. enough neurotrophic factors to permit half of the cells to live [113]. Axons that receive neurotrophic factors establish strong synapses, while axons that do Differentiation. Following migration, differentiation not are forced to seek other synaptic connections or of neurons occurs, the process of cells becoming risk cell death (most likely apoptosis, a form of more specialized over time [84]. Some cells undergo programmed cell death that eliminates cells with myelination and glial cells differentiate into oligo- poor and perhaps unnecessary synaptic connections) dendrocytes and astrocytes. Radial glial fibres lose [112]. Apoptosis is involved in the degeneration of their attachments and relocate in the white matter Development of the prefrontal cortex 285

and the lower part of the cerebral cortex where they first year of life, with increases in branching transform into astrocytes. The differentiating neuron continuing until early adulthood [117]. The must acquire specific enzymes necessary for the number of dendrites per neuron is at a constant production of neurotransmitters it will use [115]. level by 7.5 months and from this time to 12 months Differentiation of the cortex follows an inside-out there is a marked increase in length of the dendritic sequence of development, mimicking neuronal pro- field. Similarly, in Layer IV the number of dendrites liferation and migration [84]. Thus, neurons in the per neuron stabilizes by 12 months, although pro- deeper regions of the cortex differentiate before gressive elongation of the dendrite field continues neurons that migrated to the more superficial layers through to 5 years when they are morphologically of the cortex. In the PFC, the first differentiated mature. While caution should be taken when pyramidal neurons are apparent between 17–25 interpreting results of static samples used to examine weeks gestation (80% of neurons found in the dynamic processes, these findings emphasize the cortex are pyramidal, efferent neurons that provide intricacy of cerebral development. callosal, association and subcortical projections) Accelerated dendritic outgrowth occurs during the [99]. This differentiation is greatly accelerated first year of life [67], with growth continued at a between 26–35 weeks gestation, a time when reduced rate up to 5 years, followed by a stable inward growing thalamic fibres enter the cortical level up to at least age 27 [117,118]. Production of plate [65]. pyramidal neuron dendrites reaches a peak during Differentiation represents a time of rapid brain the 2nd year of life, coinciding with a peak in growth associated with particular vulnerability to synaptogenesis between 2–3 years [66]. During this teratogenic agents which may impact on glial multi- same period, non-pyramidal neurons demonstrate a plication, myelination and overall brain growth. This reduction in spine number [66]. Evidence indicates vulnerability to teratogenic processes has been an initial over-production of dendrites followed by shown in animals following nutritional deprivation pruning to leave only the most functional branches [116]. Excessive consumption of alcohol, as seen in [55,56]. foetal alcohol syndrome, may induce abnormally The non-linear pattern of dendritic development precocious transformation of the radial glial fibres is consistent with patterns in grey matter volume resulting in superficial ectopias and groups of ectopic changes. Grey matter volume of the frontal cortex neurons in the plexiform zone [94]. peaks 10 and 12 years of age in girls and boys, respectively, and from this time, there is an apparent For personal use only. Post-natal development of the prefrontal cortex loss in volume until 30 years of age [44,48,59]. The age-related changes in grey matter volume may Post-natal development is concerned with elabora- also include the maturational processes of neuronal tion of the CNS and is characterized by increased pruning and cell death [119] or a gain in white dendritic arborization, synaptogenesis and myelina- matter (myelination) [31,44]. An alternative expla- tion. In particular, the processes of synapse forma- nation is that the decrease in grey matter reflects tion and pruning have a rather different time course synaptic reorganization [54,120] and therefore in the PFC. Although largely genetically regulated, might reflect a wave of synapse proliferation [121]. neurological processes and the formation of neural Dendritic development is argued to be an impor- circuits are more susceptible to environmental events tant indicator of CNS change and has been linked to

Dev Neurorehabil Downloaded from informahealthcare.com by Yeshiva University on 03/03/13 [62,85]. Brain lesions occurring post-natally may functional ability. Herschkowitz et al. [122] found interfere with ongoing CNS elaboration and the that during the 2nd year of life, dendrites in Layer III development of interconnections and functional of the PFC elongate and form expansions deep into systems within the CNS. Disruption to develop- Layer IV, the target for axons from the limbic region. mental processes during the post-natal period may Parallelling this development (towards the end of the be qualitatively different depending on when the 2nd year) they document the emergence of self- brain lesion is sustained. awareness, a skill that has been linked to medial prefrontal and limbic function in adults [123]. Dendritic development. Dendritic development con- Early brain lesions have been associated with tinues into early adulthood [117]. Both regional and interruption to dendritic development, resulting in layer-specific differences in the time course of the reduced innervations due to tissue scarring or development of dendrites have been demonstrated development of aberrant connections [56]. In chil- within the PFC. Koenderink et al. [117,118] dren with intellectual disabilities, abnormalities in investigated basilar dendritic development of pyra- dendritic branching and spines have been found midal neurons in Layers III and IV of the PFC. [54,124,125], e.g. dendrites may be thinner, have Their findings indicate that neurons in Layer III of smaller numbers of spines or shorter branches. the DL-PFC undergo rapid dendritic growth in the As the formation of dendrites is associated with 286 M. Spencer-Smith & V. Anderson

functional outcome, early PFC lesions are likely to developing brain. There is consensus in the literature be associated with deficits in EF. of a continuous increase in white matter volume, both global and local, from early childhood through to late adolescence using magnetic resonance ima- Development of synapses. Synaptic development ging (MRI) techniques such as diffusion-weighted roughly parallels the timeline for dendritic develop- imaging [48,68,130,131]. In a longitudinal MRI ment [21] and occurs concurrently with myelination. study, Giedd et al. [48] demonstrated that white Synaptic density accelerates during the first few years matter volume increased linearly in the frontal cortex of life, increasing to well over adult levels [53,54]. throughout the studied age-range of 4–20 years. While some researchers report maximum density is However, precisely when mature levels of myelina- reached at 15 months of age [53], there have also tion in the frontal regions are obtained remains been observations of a peak in PFC synaptogenesis controversial. Some studies report that myelination between 2–3 years [66], followed by a decline over is completed around late adolescence [48,68,69, the next 16 years. Specifically, synaptic density of 132,133] and others suggest it is not completed until pyramidal cells in layer III of the DL-PFC increases 25 years [134]. More recent volumetric imaging after birth and reaches a peak at 1 year of age [54]. Synapse elimination has been reported to commence studies indicate that it takes at least four decades in the middle frontal gyrus at 4 years of age and before the myelination process ceases, with intra- continue until mid-adolescence [54]. According to cortical connections being amongst the last to studies examining adolescent brain development, become myelinated [59,134]. there is a subsequent elimination and reorganization Increases in myelination results in improved of PFC synaptic connections after puberty processing of information within fronto-cortical [54,120,126]. circuits and between the frontal cortex and other Initial over-production of synapses may be related cortical and subcortical regions [31]. Ultimately, this to the functional property of the immature brain to supports more efficient EF. Myelination, however, is allow recovery and adaptation after a prenatal or not likely to be a primary causal factor in the post-natal brain lesion [25,127,128] and may repre- development of specific cognitive processes [135]. sent a critical period in development associated with While the association between myelination and better capacity for recovery. Bertenthal and Campos cognitive processes remains controversial, some [127] suggest that through the over-production of infant studies suggest a relationship between myelination delay and neurodevelopmental lag [136],

For personal use only. synapses, the CNS may be better able to incorporate environmental experiences whenever they occur. while others propose that delayed myelination Rakic et al. [129] have postulated that reduction in may be an indicator of global developmental both synapse number and density may reflect reor- delay, involving cortical immaturity that is not ganization for greater efficiency. The maturation of yet able to be demonstrated by current imaging cognitive and behavioural processes is thought to techniques [53]. parallel this improved efficiency in synapse organiza- Disruption to myelination processes in the context tion. Conversely, the over-production of synapses of brain conditions such as cranial irritation, head appears to correlate with the emergence of a cogni- injury and Acute Disseminated Encephalomyelitis tive process. Synaptic density in the frontal cortex (ADEM) is likely to contribute to decreased conduction velocity, increased refractory periods after Dev Neurorehabil Downloaded from informahealthcare.com by Yeshiva University on 03/03/13 dramatically increases at 8 months and peaks at 2 years [54], coinciding with increases in the length of synaptic firing, more frequent conduction failures, delay infants can tolerate on the A-not-B test. temporal dispersion of impulses and increased sus- ceptibility to extraneous influences [137]. Possible origins of myelin deficiencies are amino or organic Myelination. Synaptogenesis occurs concurrently acid disturbances, congenital hypothyroidism, mal- with myelination, a process of insulation that ensures nutrition and periventricular leukomalacia (PVL) rapid transmission of electrical signals [69,99]. [95]. Figure 3 shows cystic PVL on MRI in an In the PFC myelination commences around the extremely pre-term infant. The scan identifies sig- 4th month of life and the most rapid period of nificant white matter lesions in the periventricular myelination in this region occurs prior to 2 years of region, enlarged ventricles and delayed gyration. age [48,68,69]. Peaks in myelination have been documented at 7–9 years and 11–12 years [70,72], with some changes during adolescence and beyond Development of executive functions this age. Changes in the extent of white matter (myelinated Research shows that in adults, EF rely strongly on axons) are of interest because they are presumed to the PFC, which relies upon input from most brain reflect inter-regional communication in the regions for efficient functioning. In the developing Development of the prefrontal cortex 287

essential for efficient day-to-day functioning, required to perform both simple and more complex tasks [78,139]. Impairment in these skills is therefore likely to have serious implications for a child, who is rapidly acquiring a range of new skills and abilities. Developmental conceptualizations describe a number of distinct, yet integrated domains which underpin cognitive and behavioural aspects of EF: (a) attentional control; (b) cognitive flexibility; and (c) goal setting [139]. Each domain involves highly integrated cognitive skills and each receives and processes stimuli from various sources, including subcortical, motor and posterior brain regions. The domains are argued to have separate developmental trajectories: attentional control matures early and is essential for the development and efficient functioning of cognitive flexibility and goal setting, which are later developing domains. Attentional control involves component skills of selective attention, response inhibition, self-monitoring and self-regulation. These skills are key in development of other executive domains as well as efficient EF. Deficits in this area are likely to impact on the integrity of all other executive processes. Cognitive flexibility is Figure 3. Cystic periventricular leukomalacia in an extremely concerned with the processes of working memory, preterm infant. The scan shows significant white matter damage in the periventricular region, enlarged ventricles and delayed shift attention and conceptual transfer. Goal setting gyration. is associated with initiating, planning, problem- solving and strategic behaviour. Cognitive flexibility is strongly associated with goal setting, reflecting the brain cognitive functions are less localized than in importance of these domains in adaptive behaviour. For personal use only. the mature brain and therefore integrity of the whole brain, including the PFC, is important for efficient Prolonged and hierarchical development of executive EF. This presents a challenge for understanding how skills brain lesions impact on the development of executive skills and subsequent localization of function in Executive skills have a protracted developmental children. To better understand executive deficits in course, with studies showing that these skills emerge children with brain conditions, a developmental in infancy and continue to develop and refine well approach to understanding EF was examined. The into early adulthood. Development of EF is thought prolonged, hierarchical pattern of maturation of to unfold in a staged and hierarchical manner [140]. these skills and anatomical underpinnings are Different executive skills emerge at different rates, Dev Neurorehabil Downloaded from informahealthcare.com by Yeshiva University on 03/03/13 discussed, illustrating the vulnerability of EF to with adult-level performance on many standardized early brain lesions. measures attained at different ages during childhood and adolescence [141–143]. This pattern of maturation corresponds with developmental timetables of Defining executive functions brain development. Waber et al. [143] recently Despite the growing literature on EF, there is little commenced a longitudinal study to examine healthy consensus on its exact definition. Lezak [138] brain development using both neuropsychological described executive processes as those mental and neuroimaging meausures. Baseline neuropsy- capacities necessary for formulating goals, planning chological data of 385 children aged 6–18 years from how to achieve them and carrying out these plans the first assessment point demonstrated a steep effectively. She argued that executive processes are increase in performance on a range of tasks 6–10 the basis of all socially useful, personally enhancing, years of age and plateau at 10–12 years. The constructive and creative activities. EF in adults has researchers suggest that children reach adult levels of been conceptualized as taking a neurobehavioural performance on a range of neuropsychological tasks ‘managerial role’, directing attention, monitoring at around this age. On some tasks performance activity, coordinating and integrating information scores increased linearly throughout the age range and activity. Executive skills are thought to be studied (e.g. basic information processing tasks), 288 M. Spencer-Smith & V. Anderson

performance on some tasks demonstrated a dip in functional neuroimaging studies which demonstrate performance during adolescence (e.g. attentional significant activation of PFC whilst performing EF shifting for girls at 10–15 years) and the pattern of tasks [29,76,151,152]. In addition, child and adult performance on other tasks demonstrated an studies examining focal frontal lesions report striking increase in performance followed by a plateau and deficits in specific executive processes [4,153,154], then another period of acceleration in mid-adoles- providing further evidence for the importance of cence (e.g. attentional shifting). Anderson et al. frontal structures and systems in the execution of [144] demonstrate similar findings in their study of executive skills. 138 children, showing a generally flat developmental In children the contribution of extra-frontal and trajectory for EF during late childhood and early frontal brain regions to specific executive processes adolescence. However, findings for attentional con- may be less clearly delineated, due to the immaturity trol development differed. Anderson et al. reported a of cerebral structures, particularly the PFC. This has cross-over effect at 11–12 years, when girls been supported by functional MRI (fMRI) studies performed better on these tasks. In addition, a late [29,155]. For example, Tamm et al. [29] studied the growth spurt in attentional control-processing speed activation of frontal regions during performance of a was observed at 15 years. Go/No-Go test (a widely used measure of impulse Due to the extended development of EF, con- control) in 19 healthy participants aged 8–20 years. sequences of early brain lesions for the development Findings showed that there was no difference in of these skills may not be immediately apparent. accuracy on the task with age, although reaction Kennard [23,24,145] documented long-term devel- times to inhibit responses significantly decreased opmental implications of early focal frontal lesions in with age. However, fMRI data showed a negative monkeys, noting that some subtle deficits emerged age-related change in recruitment of specific regions over time following early lesions. Evidence from a of the PFC associated with performing the number of child studies supports this developmental Go/No-Go test. Specifically, younger participants model of emerging deficits. For example, Eslinger recruit greater regions of the left superior and middle et al. [146] reviewed case studies of early PFC frontal gyri than older participants, who demon- damage and concluded that immediate conse- strated similar patterns of activation to adults. This quences of these lesions are usually less evident study links development of the PFC and develop- than consequences of comparable lesions in adults. ment of executive skills. The researchers speculated Specifically, the pattern of skill impairment emerged that younger children recruited more regions of the For personal use only. only later in development, when the specific PFC due to inefficient strategies used to complete skills would normally be expected to emerge. Bates the task and relative immaturity of skills required for et al. [3] report similar findings for the develop- efficient response inhibition. An alternative explana- mental pattern of language skills in infants and tion is that extensive activation of the PFC in preschool children after single unilateral focal brain children may be a compensatory strategy used lesion sustained before 6 months of age. Some while the brain is less efficient in integrating the deficits have been reported to change over time, range of executive skills required to perform the Go/ some skills are initially delayed but have caught up No-Go test, such as working memory and inhibitory by 5 years of age, while other skills may be control [121,139]. This pattern of performance has functioning appropriately at the time the brain also been suggested by focal lesion studies [4]. Dev Neurorehabil Downloaded from informahealthcare.com by Yeshiva University on 03/03/13 lesion occurs and shortly after but show delays and A recent study by Jacobs et al. [4] provides further deficits over time [3,147,148]. Most children with evidence for the importance of whole brain integrity early unilateral brain lesions, however, go on to for efficient EF. They investigated localization of achieve levels of language performance within the executive skills to the PFC by examining EF task normal range [148]. performances in children aged 7–16 years of age with frontal pathology (n ¼ 38), extra-frontal pathology (n ¼ 20), generalized pathology (n ¼ 21) and healthy Anatomical underpinnings of executive skills children (n ¼ 40). Findings demonstrated that there During development cognitive skills emerge at dif- was very little differentiation in executive processes ferent rates, determined largely by the maturation of between frontal and extra-frontal pathology groups, particular brain structures that underpin specific contradicting the assumption that children’s EF are processes and the improved interconnectivity of localized to frontal regions. In fact, children with brain regions that form functional systems. Adult focal lesions to any brain region were shown to be studies demonstrate that the execution of EF relies vulnerable to a range of executive deficits that would strongly on the integrity of frontal structures and not normally be expected following similar pathology systems and in particular the PFC in adulthood. It is therefore argued that the integrity [33,75,78,149,150]. This has been supported by of PFC may be a necessary, but not sufficient, Development of the prefrontal cortex 289

condition for intact EF in children. Therefore, considerable increases in performance in selective children with brain conditions are vulnerable to attention from 3–6 years of age, with ceiling effects executive dysfunction, irrespective of pathology site. attained at 6 years. This is consistent with general increases in attention at this age, as well as increases Developmental spurts in executive function in aspects of inhibition and self-regulation. An additional time of rapid development in Research mapping the development of EF through selective attention has been consistently observed infancy, childhood and adolescence suggests that in children at 8–10 years of age development of executive skills progresses in spurts, [140,142,165,166]. From this time these skills are with specific age ranges associated with distinct thought to be functioning reliably [140]. A less rapid improvements in a skill [143,156,157]. These devel- improvement in performance has been documented opmental spurts are likely to be aligned with from 10 years through to early adolescence neurophysiological developmental changes such as [140,144,165,166], with a further spurt in develop- peaks in synaptogenesis [21], as well as critical ment thought to occur at 15 years [144,166]. periods in development. Studies examining developmental timetables of key executive skills demonstrate a number of development spurts in component skills. Inhibition Inhibition is conceptualized as the ability to inten- tionally suppress a dominant, automatic or pre- Developmental timetables for attentional potent response. This skill is required for withhold- control ing a response that, although prompted by current stimulation, might not be appropriate [167]. Studies Within the EF control system, the attentional control of infants have shown that the ability to inhibit domain is of particular interest because these skills certain behaviours emerges as early as 7–8 months of emerge early in development [140,158,159] and age, but, at this age skills are not consistently support the development of all other domains. Deficits in attentional control skills are therefore employed, reflecting skill immaturity. Diamond likely to have consequences for the development, [168] showed that at 7.5 months infants could acquisition and maintenance of all other cognitive correctly retrieve objects on a delayed response task and behavioural skills. Because deficits are defined when the delay was limited to 1 or 2 seconds. At relative to age expectations, this study plots the 12 months a delay of 10 seconds was necessary to For personal use only. developmental timetables for attentional control, elicit perseverative errors, suggestive of a failure to which includes selective attention, inhibition, self- maintain the current hiding place of an object in regulation and self-monitoring processes [139]. mind and inhibit a previously rewarded response. Inhibitory capacity develops steadily between 1–4 years of age, with basic self-control functional by this Selective attention time. A peak in performance is observed between Selective attention requires the individual to select 3–4 years on a number of inhibitory measures among competing stimuli and preferentially process including object retrieval tasks [169,170] and more relevant information [160]. This skill requires Statue [140]. Tasks with greater situational demands the ability to actively focus and maintain attention (processing and memory demands) are difficult for Dev Neurorehabil Downloaded from informahealthcare.com by Yeshiva University on 03/03/13 for a period of time. Observational and behavioural younger children, with fluctuations in performance studies have shown that elements of attentional common. Vaughn et al. [171] examined self-control functions are formed in the first years of life. Lawson skills in 72 toddlers aged 18–30 months. Capacity to and Ruff [161] demonstrated that infants aged 7–10 inhibit a response to a desired object was investi- months can focus attention on a novel object. gated using a task with hidden raisins, which Increases in selective attention have been reported required the infant to inhibit responding during a to occur earlier in less structured situations com- delay phase and then retrieve the raisin. Performance pared with more structured situations [162]. fluctuated according to the demands of the situation Selective attention measured by free play and tele- and time. However, the capacity and stability of the vision viewing has been shown to develop consider- skill improved with increase in age. ably between 2.5–3.5 years. In contrast, on Speed and accuracy on basic inhibition tasks structured tasks such as reaction time tasks [162], improves up to 6 years of age [170,172]. Over auditory stimuli tasks requiring the child to listen to the next couple of years minor improvements in a specific story in a complex auditory environment inhibitory control have been reported [173,174]. [163] or visual search tasks [164], substantial This time is then followed by a striking develop- changes in selective attention have been observed mental advance at 7–12 years of age, as reported by over the preschool years. Welsh et al. [164] describe studies employing a range of inhibitory control tests 290 M. Spencer-Smith & V. Anderson

such as the Go/No-Go test [175], stop-signal pro- visual and verbal attention sub-tests from the cedure [176], Matching Familiar Figures Test [164] NEPSY [140] and also on experimental tasks [183]. and a study employing an inhibition cognitive Although study findings report data that suggest dimension [177]. Some studies have observed an self-regulation and monitoring behaviours become increase in performance from this time through to more efficient with age, a number of studies have 15 years [144,178], with little developmental observed a regression in these skills for a short period change from 15–21 years [178]. 11 years [156,184]. Anderson et al. [156] examined children’s performance on the Tower of Self-regulation and monitoring London and found that children aged 11 completed the task faster than children aged 15, although Important skills associated with inhibition are those performing the task less accurately, with more failed of self-regulation and monitoring, the capacity to attempts before successfully solving the problem. manage one’s own thoughts, feelings and actions in Some researchers suggest that the regression adaptive and flexible ways across a variety of observed in performance may reflect a period of contexts [179]. Basic self-regulation skills have transition for the child, who now has a range of been reported to emerge prior to 2 years of age. newly functional skills to coordinate and balance Grazyna et al. [180] showed that children at competing demands [139,185], which ultimately 14 months demonstrate some compliance with reflects executive control. A decline in performance caregivers’ request, described as self-regulation around 11 years of age has been described for other because it requires the capacity to initiate, cease or executive skills. McGivern et al. [186] found that modulate behaviour in accord with parental stan- girls 10–11 years old and boys 11–12 years old dards [180,181]. They observed children and required more time to assess emotionally related caregivers in naturalistic environments at 14, 22, information on a match-to-sample task (participants 33 and 45 months and found an age-related increase were asked to decide if the face and word matched in development of self-regulation from 14 months to for the same emotion). The researchers linked the 33 months, with greatest gains occurring from ‘dip’ in task performance to proliferation of synapses 14 months to 22 months (an increase in compliance occurring around this time in frontal lobe develop- from 27% to 50%). Similarly, Rothbart et al. [182] ment. They speculated that improved performance found that reaction times following an error on the on the match-to-sample task in children from 13–14 Spatial Conflict task were 200 milliseconds longer years might be explained by the pruning of excess For personal use only. than those following a correct trial at 2.5 years and synapses into more specialized and efficient net- over 500 milliseconds longer at 3 years. In contrast, works at this time in frontal lobe development. no evidence of slowing was found at 2 years. While results may reflect a lapse in attention, the authors Executive dysfunction suggest that children were noticing their errors and using them to guide performance in the next trial. Impaired EF may present in a variety of ways, Espy et al. [169] showed that efficiency in perfor- consistent with its multi-dimensional structure. mance on the Shape School task (a colourful Dysfunction may include inability to focus or main- storybook designed to examine inhibition and tain attention, impulsivity, disinhibition, reduced switching processes) for children 3.5 years of age working memory, difficulties monitoring or regulat- Dev Neurorehabil Downloaded from informahealthcare.com by Yeshiva University on 03/03/13 differed from older age groups broken down into ing performance, inability to plan actions in advance, 6-month segments (4, 4.5, 5 and 6 years). Studies of disorganization, poor reasoning ability, difficulties infants and young children suggest a rapid phase in generating and/or implementing strategies, perse- development of self-regulation skills 2.5 and 3.5 verative behaviour, a resistance to change activities, years of age, a time when basic inhibitory and difficulties shifting between conflicting demands and attentional skills are functional, supporting the failure to learn from mistakes [185]. Executive voluntary control of actions needed to regulate dysfunction may also present as problems in one’s own behaviour. These studies demonstrate behavioural, social and emotional functioning, such the importance of parsing age into small units when as maladaptive affect, energy level, initiative and examining skill development during the rapid devel- moral and social behaviour [146,153,187]. opmental phase of childhood. Executive dysfunction has been consistently Self-regulation and monitoring skills are thought reported in children with different developmental to be functioning more reliably at 7 years of age and acquired CNS conditions [188–190]. These [140]. Studies consistently report a period of rapid include children with congenital brain disorders such development from 8–10 years of age on a number of as subcortical band heterotopia [191], acquired standardized tasks, including the Continuous brain conditions such as traumatic brain injury Performance Test, Digit Cancellation Task [166], [1,2], meningitis [12,13], phenylketonuria [192] Development of the prefrontal cortex 291

and low birth weight [20] and developmental and peptides and improved synaptic efficiency at the disorders such as autism and Attention Deficit molecular level. Hyperactivity Disorder [193]. In many instances Recent human developmental imaging studies impairments in function are described in children support previous animal studies, confirming the with comparatively intact intellectual abilities relationship between the physical growth of the [194–197]. Anderson [185] points out that in a brain and the emergence of new skills. Although this developmental context executive dysfunction may field is in its infancy, researchers have started to map not be considered ‘deviant’, such as in an infant or maturational changes in brain-behaviour relation- child, highlighting the importance of understanding ships across the lifespan. Marsh et al. [28] used developmental expectations of cognitive processes. fMRI in a cross-sectional study of 70 healthy individuals aged 7–57 years to examine the association between regional signal changes across the Parallels in development of brain structure brain during performance of a Stroop task at and function different ages. Age-related improvements in performance were associated with the increasing activation Recent advances in neuroimaging techniques have of the inferolateral portion of the PFC, confined enabled investigation into the parallels between the statistically to the right hemisphere. This parallel in functional emergence of executive skills and the development of brain structure and fucntion is structural maturation of frontal brain regions in consistent with the fMRI studies using different healthy individuals [28,29,198]. Prior to this tech- measures of inhibitory control such as the Go/No- nology researchers examined the relation between Go test [29,199]. These studies show that while both the physical growth of the brain and the emergence children and adults recruit prefrontal regions when of new behavioural abilities in non-human primates. performing inhibitory control tasks, a greater mag- Goldman-Rakic [21] linked synaptic patterns in nitude in signal of the lateral prefrontal region is development with the emergence and improvement observed in adults, a region known to underpin of cognitive processes. In her work with monkeys she inhibitory control skills [28]. This result is particu- demonstrated that the capacity to perform simple larly interesting as it implies different localization of delayed response tasks emerges around 4 months of inhibitory control in children and adults or may age, coinciding with the end of the period of highest reflect increasing localization with age as children synaptic density in the principal sulcus (the region become more efficient in performing the task or For personal use only. responsible for this skill in the adult monkey). She perhaps children are using different strategies to employed an autoradiographic method for studying adults and switch to more efficient strategies as prefrontal connections that enabled visualization of neural circuits become more refined. terminal fields and determination of the pathways by Neuroimaging studies suggest a more diffuse which the axons reach their targets. Specifically, pattern of activation in prefrontal regions in children radioactive isotopes are injected into the designated compared with adults when performing EF tasks area, the radio-labelled amino acids are converted by [29,200,201]. However, evidence from group and the cell body into proteins and transported through individual activation maps of the PFC and other to the terminal region. Goldman-Rakic concluded brain regions suggests that the location of activation that a growth spurt in synapses in a specific brain in the PFC does not differ between children and Dev Neurorehabil Downloaded from informahealthcare.com by Yeshiva University on 03/03/13 region is important for the emergence of cognitive adults, but that the overall volume of activation was skills that recruit the specific brain region for greater for children relative to adults [28,155]. Casey efficient function. However, it is clear that skill et al. [155] suggested this pattern may reflect a development progresses long after maximum synap- gradual decrease in the brain tissue required to tic density has been reached. To this, she argued that perform the task, which may parallel the loss rather mature capacity of a skill may depend upon the than formation of new synapses observed in post- elimination of excess synapses that occurs during mortem studies. A later study by Casey et al. [202] adolescence and young adulthood. This is consistent demonstrated different developmental patterns of with the view that presence of numerous synaptic activity in the DL-PFC when completing the Go/ contacts is required to form functional neuronal No-Go test, leading them to conclude that the DL- circuits, with the elimination of synapses enabling PFC in children is less specific to type of information shaping and refinement of systems, which ultimately and less efficient in representing information relative has functional significance. Goldman-Rakic also to adults. Further, Tamm et al. [29] speculated that emphasized the likely contribution of other neuro- the pattern of PFC recruitment in younger children biological processes for the expression of skill may reflect inefficient strategies for completing the progression, including continued myelination, fur- task and relative immaturity of skills required for ther regulation of receptors and neurotransmitters efficient response inhibition. Irrespective of the 292 M. Spencer-Smith & V. Anderson

reason for this differentiation, it is clear from these 3. Bates E, Thal D, Trauner D, Fenson J, Aram D, Eisele J, studies that the developing brain operates differently Nass R. From first words to grammar in children with focal from the mature brain when undertaking complex brain injury. Developmental Neuropsychology 1997;13:275–343. cognitive activities. 4. Jacobs R, Harvey A, Anderson V. Executive function following focal frontal lobe lesions: Impact of timing of lesion on outcome. Cortex 2007;43:792–805. Conclusions 5. Leblanc N, Chen S, Swank P, Ewing-Cobbs L, Barnes M, This review highlights the complex choreography of Dennis M, Max J, Levin H, Schachar R. Response inhibition developmental events that lead to the healthy mature after traumatic brain injury (TBI) in children: Impairment and recovery. Developmental Neuropsychology brain. The PFC has a protracted and well-specified 2005;28:829–848. course of development, continuing at least until early 6. Stiles J, Stern C, Appelbaum M, Nass R, Trauner D, adulthood and subsequently is particularly vulnera- Hesselink J. Efefcts of early focal brain injury on memory for ble to brain lesions. In the developing brain cognitive visuospatial patterns: Selective deficits of global-local proces- functions are less localized than in the mature brain sing. Neuropsychology 2008;22:61–73. 7. Chapman C, Waber D, Bernstein J, Pomeroy S, LaVally B, and therefore integrity of the whole brain is impor- Sallan S, Tarbell N. Neurobehavioural and neurologic tant for efficient EF. This presents a challenge for outcome in long-term survivors of posterior fossa brain understanding how brain lesions impact on the tumours: Role of age and perioperative factors. Journal of development of EF and subsequent localization of Child Neurology 1995;10:209–211. function in children. 8. Chin H, Maruyama Y, Early response and long-term results Equipped with current knowledge of timetables in the radiotherapy of childhood medulloblastoma. Journal of Neuro-oncology 1983;1:53–59. for healthy development of specific brain regions and 9. Jannoun L, Chessells J. Long-term psychologic effects of cognitive skills, researchers and clinicians are now in childhood leukemia and its treatment. Pediatric Hematology a good position to address gaps in understanding of and Oncology 1987;4:293–308. functional recovery and outcome in children with 10. Palmer S, Gajjar A, Reddick W, Glass J, Kun L, Wu S. brain conditions. The contribution of increasingly Predicting intellectual outcome among children treated with 35-40 Gy craniosinal irradiation for medulloblastoma. sophisticated neuroimaging techniques such as Neuropsychology 2003;17:548–555. diffusion-weighted imaging and fMRI will be invalu- 11. Pavlovic J, Kaufmann F, Boltshauser E, Capone Mori A, able in this investigation. The importance of devel- Gubser Mercati D, Haenggeli CA, Keller E, Lutschg J, opmental processes has previously been postulated Marcoz JP, Ramelli GP, et al. Neuropsychological problems in animal models [25] and child models [26]. While after paediatric stroke: Two year follow-up of Swiss children. For personal use only. child studies provide preliminary support for key Neuropediatrics 2006;37:13–19. 12. Anderson V, Anderson P, Grimwood K, Nolan T. Cognitive principles of these theoretical models, hypotheses and executive function 12 years after childhood bacterial have not yet been systematically examined in chil- meningitis: Effect of acute neurologic complications and age dren and subsequently the gap in knowledge regard- of onset. Journal of Pediatric Psychology 2004;29:67–81. ing timing of brain lesion effects remains. It will be 13. Pentland L, Anderson V, Wrennall J. The implications of important for researchers to employ the cur- childhood bacterial meningitis for language development. rent knowledge and imaging techniques to system- Child Neuropsychology 2000;6:87–100. 14. Isaacs E, Christie D, Vargha-Khadem F, Mishkin M. Effects atically examine the role of neurological of hemispheric side of injury, age at injury, and presence of developmental processes and level of skill matura- seizure disorder on functional ear and hand asymmetries in tion when the brain lesion occurs in determining hemiplegic children. Neuropsychologia 1996;34:127–137. Dev Neurorehabil Downloaded from informahealthcare.com by Yeshiva University on 03/03/13 functional recovery and outcome in children with 15. Strauss E, Hunter M, Wada J. Risk factors for cognitive brain conditions. impairment in epilepsy. Neuropsychology 1995;9:457–463. 16. Vargha-Khadem F, Isaacs E, Muter V. A review of cognitive outcome after unilateral lesions sustained during childhood. 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