BIOLOGICAL PSYCHOLOGY ELSEVIER Biological Psychology 54(000)241-257 ww..com/locate/biopsycho Structural and functional brain development and its relation to cognitive development B.J.Casey *.*Jay N.Giedd b,Kathleen M.Thomas C No Abstract Despite significant gains in the fields of pediatric neuroimaging and developmental neurobiology,surprisingly little is known about the developing human brain or the neural bases of cognitive development.This paper addresses MRI studies of structural and functional changes in the developing hun nan brain and their relation to changes in cognitive proces s over the nrst f Base on post-mort tem and pe e.the pr cortex appea s to be one of the l frontal cortex duri ood.tasks believed to involve this region are ideal for n nr a e mmt e fMRI studies examining prefrontal cortical activity in children during memory and attention tasks are reported.These studies,while largely limited to the domain of prefrontal function- 3ng support o r continued are consistent with the view that incr easing cognitive capacity during childhood may coincide with a gradual loss rather than formation of new synapses and presumably a strengthening of remaining synaptic connections.It is clear that innovative methods like fMRI together with MRI-based morphometry and nonhumar Keywords:Brain development:Neuroimaging:Prefrontal functioning:Magnetic resonance imaging see fron
Biological Psychology 54 (2000) 241–257 Structural and functional brain development and its relation to cognitive development B.J. Casey a,*, Jay N. Giedd b , Kathleen M. Thomas a a Department of Psychiatry, The Sackler Institute for De6elopmental Psychobiology, Weill Medical College of Cornell Uni6ersity, 525 East 68th Street, Box 171, New York, NY10021, USA b Child Psychiatry Branch, National Institute for Mental Health, New York, NY10021, USA Abstract Despite significant gains in the fields of pediatric neuroimaging and developmental neurobiology, surprisingly little is known about the developing human brain or the neural bases of cognitive development. This paper addresses MRI studies of structural and functional changes in the developing human brain and their relation to changes in cognitive processes over the first few decades of human life. Based on post-mortem and pediatric neuroimaging studies published to date, the prefrontal cortex appears to be one of the last brain regions to mature. Given the prolonged physiological development and organization of the prefrontal cortex during childhood, tasks believed to involve this region are ideal for investigating the neural bases of cognitive development. A number of normative pediatric fMRI studies examining prefrontal cortical activity in children during memory and attention tasks are reported. These studies, while largely limited to the domain of prefrontal functioning and its development, lend support for continued development of attention and memory both behaviorally and physiologically throughout childhood and adolescence. Specifically, the magnitude of activity observed in these studies was greater and more diffuse in children relative to adults. These findings are consistent with the view that increasing cognitive capacity during childhood may coincide with a gradual loss rather than formation of new synapses and presumably a strengthening of remaining synaptic connections. It is clear that innovative methods like fMRI together with MRI-based morphometry and nonhuman primate studies will transform our current understanding of human brain development and its relation to behavioral development. © 2000 Elsevier Science B.V. All rights reserved. Keywords: Brain development; Neuroimaging; Prefrontal functioning; Magnetic resonance imaging www.elsevier.com/locate/biopsycho * Corresponding author. Fax: +1-212-7465755. E-mail address: bjc2002@mail.med.cornell.edu (B.J. Casey). 0301-0511/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved. PII: S0301-0511(00)00058-2
242 B.J.Casey et al./Biological Psychology 54(2000)241-257 Magnetic resonance imaging (MRI).with its lack of ionizing radiation and capacity to provide exquisite anatomical detail,has revolutionized the study of human brain development.Other imaging modalities such as conventional radiog- raphy.computerized tomography,positron cmission tomography (PE)and singl oto the ompute raphy(SPECT While latter r tech 4 diatric c pa tient populations whe topes advancement of science are less clear (Casey and Cohen,1996;Morton,1996; Zametkin et al.,1996).The advent of functional MRI has now further extended the utility of MRI to explore the developing human brain as never before.This paper addresses MRI studies of structural and functional changes in the developing human brain and their relation to changes in cognitive processes over the first few decades of human life 1.Brain development:What do we know? Despite the significant gains in the fields of pediatric neuroirnaging and develop- mental neurobiology.surprisingly little is known about the developing human brain.This is particularly the case during early and late childhood-a time when significant leaps in social and cognitive learning take place.In part,this is due to s across this e range in additi to the on this populati example,the vlev brain co i DC,contains only a dozen o so normal brains from roughly 500 that are from subjects between the ages of 4 and 18 (Haleem,1990).Nonetheless, pioneering work in both developmental neurobiology and pediatric brain imaging has begun to paint a picture of how the developing human brain unfolds through- out childhood. Most of the dynamic activity of brain development occurs in utero but change continue for the fi P I years s.By the brain has reached close to 80 its adul L W g rets nn et a 6).This is als t begins well befor birth in primates (Rakic. al..1988)and results in overproduction of synapses relative state.This process of synaptogenesis appears to occur concurrently across diverse regions of the non-human primate cerebral cortex (Rakic et al..1986).However.in humans postmortem data indicates that synaptogenesis does not occur concurrently with synaptic density peaking earlier in the auditory cortex,at three months,and later in the middle frontal gyr us,at 15 months(Huttenlocher,1997).In both human and non- uma the synaptic density pe wed by plateau ph se tha decreases during ch and 1 to adulthood The plateau anc pruning phases of some cortical regions (e.g.prefrontal cortex)in primates are relatively protracted compared to others (e.g.visual cortex)(Bourgeois et al.,1989. 1994;Huttenlocher,1990,1997).These regions of prolonged development are perhaps most interesting when considering the developing child throughout adoles- cence and into adulthood
242 B.J. Casey et al. / Biological Psychology 54 (2000) 241–257 Magnetic resonance imaging (MRI), with its lack of ionizing radiation and capacity to provide exquisite anatomical detail, has revolutionized the study of human brain development. Other imaging modalities such as conventional radiography, computerized tomography, positron emission tomography (PET), and single photon emission computerized tomography (SPECT) use ionizing radiation. While these latter techniques may be used with pediatric patient populations when clinically warranted, the ethics of exposing children to radioactive isotopes for the advancement of science are less clear (Casey and Cohen, 1996; Morton, 1996; Zametkin et al., 1996). The advent of functional MRI has now further extended the utility of MRI to explore the developing human brain as never before. This paper addresses MRI studies of structural and functional changes in the developing human brain and their relation to changes in cognitive processes over the first few decades of human life. 1. Brain development: What do we know? Despite the significant gains in the fields of pediatric neuroirnaging and developmental neurobiology, surprisingly little is known about the developing human brain. This is particularly the case during early and late childhood — a time when significant leaps in social and cognitive learning take place. In part, this is due to low mortality rates across this age range in addition to the rare occurrence of autopsies on this population. For example, the Yakovlev brain collection in Washington, DC, contains only a dozen or so normal brains from roughly 500 that are from subjects between the ages of 4 and 18 (Haleem, 1990). Nonetheless, pioneering work in both developmental neurobiology and pediatric brain imaging has begun to paint a picture of how the developing human brain unfolds throughout childhood. Most of the dynamic activity of brain development occurs in utero but changes continue for the first two postnatal years. By this point, the brain has reached close to 80% of its adult weight (Kretschmann et al., 1986). This is also a period of rapid synapse formation that begins well before birth in primates (Rakic, 1972, 1974; Rakic et al., 1988) and results in overproduction of synapses relative to its adult state. This process of synaptogenesis appears to occur concurrently across diverse regions of the non-human primate cerebral cortex (Rakic et al., 1986). However, in humans postmortem data indicates that synaptogenesis does not occur concurrently with synaptic density peaking earlier in the auditory cortex, at three months, and later in the middle frontal gyrus, at 15 months (Huttenlocher, 1997). In both human and non-human primate studies the early synaptic density peaks are followed by a plateau phase that decreases during childhood and into adulthood. The plateau and pruning phases of some cortical regions (e.g. prefrontal cortex) in primates are relatively protracted compared to others (e.g. visual cortex) (Bourgeois et al., 1989, 1994; Huttenlocher, 1990, 1997). These regions of prolonged development are perhaps most interesting when considering the developing child throughout adolescence and into adulthood
B.J.Casey et al.Biological Psychology 54(2000)241-257 243 metaboism suggest that maturation of ocal metabolic course of overprodu ion and s equent pruning o synapses (Chugani et al.,1987)with the prefrontal cortex showing a prolonged maturation relative to visual cortex.PET studies,although informative,are typi- cally performed with clinical populations thus justifying their use with developmen- tal populations.The use of PET with pediatric patient populations to understand normal brain develop ent raises questions about the generalization of the results to truly healthy children.With the ent advances in mrico omes a whole new era in the study of the deve To ate,MRI ping huma brain in anatomica udies have revealed som interesting matura tionl chaneranuctur.The most infomative studies todater those based on carefully quantified volumetric measures and large sample sizes of 50 or more subjects (e.g.Giedd et al.,1996a,b:Reiss et al.,1996).The most consistent findings across these studies include:(1)a lack of any significant change in cerebral ofae (Giedd et a1996a;Giedd.et l 199b:Reissa ase in cortical gray matter after 12 years (Giedd et al. an ing ood ，199 Pfefferbaum et 94;C iness et al 1996 Rajapakse et al 1996;Reiss et a 996).Spec ally,subcortical gray regions (e.g basal ganglia)decrease during childhood,particularly in males(Giedd et al.,1996a Rajapakse et al.,1996;Reiss et al.,1996)while cortical gray matter in the frontal and parietal cortices does not appear to decrease until roughly puberty (Giedd et al.1999).White matter volume a opears to increase throughout childhood and well into adulthood (Caviness et al., 1996:Rajapakse et al..1996).These increases ear to be nal i na ure.Fo there appears to he ar ase in er in dors ntal cor n more ver ntal region tal cortex)(Reiss et al. 1996). l otal ter lobe volume appear relatively stable across the age range of 4 to 18 years.while hippocampal formation volume increases with age for females and amygdala volume increases with age for males (Giedd et al.,1996b).This latter finding may be consistent with the distribution of sex hormone receptors for these structures,with the amygdala having a predominance of androgen receptors (Clark et al.,1988:Sholl and Kim. 19)and the hippocampus having a predominnce of estr ogen eceptors(Morse et al,1986 Taken as a whole,th se neuroimaging rtern studies seem to sugges hat some ae-related changes are regional.One such brain region is the pref cortex.Based on the nonhuman and human primate post-mortern studies and pediatric neuroimaging studies published to date,the prefrontal cortex appears to be one of the last brain regions to mature,particularly the dorsolateral prefrontal cortex Are the last brain regions to mature the first'to go?If so,is the prefrontal cortex region mo ptible to the aging proc ss than othe ortical regions?The videnc efron al fur ion is se changes with age (Daigneault et al Braun 1993) impairment is paralleled by a disproportionate degeneration of the prefrontal cortex
B.J. Casey et al. / Biological Psychology 54 (2000) 241–257 243 PET studies of glucose metabolism suggest that maturation of local metabolic rates closely parallel the time course of overproduction and subsequent pruning of synapses (Chugani et al., 1987) with the prefrontal cortex showing a prolonged maturation relative to visual cortex. PET studies, although informative, are typically performed with clinical populations thus justifying their use with developmental populations. The use of PET with pediatric patient populations to understand normal brain development raises questions about the generalization of the results to truly healthy children. With the recent advances in MRI comes a whole new era in the study of the normally developing human brain in vivo. To date, MRI-based anatomical studies have revealed some interesting maturational changes in brain structure. The most informative studies to date are those based on carefully quantified volumetric measures and large sample sizes of 50 or more subjects (e.g. Giedd et al., 1996a,b; Reiss et al., 1996). The most consistent findings across these studies include: (1) a lack of any significant change in cerebral volume after five years of age (Giedd et al., 1996a; Giedd, et al., 1996b; Reiss, et al., 1996); (2) a significant decrease in cortical gray matter after 12 years (Giedd et al., 1999); and (3) an increase in cerebral white matter throughout childhood and young adulthood (Jernigan et al., 1991; Pfefferbaum et al., 1994; Caviness et al., 1996; Rajapakse et al., 1996; Reiss et al., 1996). Specifically, subcortical gray regions (e.g. basal ganglia) decrease during childhood, particularly in males (Giedd et al., 1996a; Rajapakse et al., 1996; Reiss et al., 1996) while cortical gray matter in the frontal and parietal cortices does not appear to decrease until roughly puberty (Giedd et al., 1999). White matter volume appears to increase throughout childhood and well into adulthood (Caviness et al., 1996; Rajapakse et al., 1996). These increases appear to be regional in nature. For example, there appears to be an increase in white matter in dorsal prefrontal cortex, but not in more ventral prefrontal regions (i.e. orbitofrontal cortex) (Reiss et al., 1996). Total temporal lobe volume appears relatively stable across the age range of 4 to 18 years, while hippocampal formation volume increases with age for females and amygdala volume increases with age for males (Giedd et al., 1996b). This latter finding may be consistent with the distribution of sex hormone receptors for these structures, with the amygdala having a predominance of androgen receptors (Clark et al., 1988; Sholl and Kim, 1989) and the hippocampus having a predominance of estrogen receptors (Morse et al., 1986). Taken as a whole, these neuroimaging and post-mortern studies seem to suggest that some age-related changes are regional. One such brain region is the prefrontal cortex. Based on the nonhuman and human primate post-mortern studies and pediatric neuroimaging studies published to date, the prefrontal cortex appears to be one of the last brain regions to mature, particularly the dorsolateral prefrontal cortex. Are the last brain regions to mature the first ‘to go’? If so, is the prefrontal cortex region more susceptible to the aging process than other cortical regions? There is neuropsychological evidence to suggest that prefrontal function is sensitive to changes with age (Daigneault et al., 1992; Daigneault and Braun, 1993). This impairment is paralleled by a disproportionate degeneration of the prefrontal cortex
244 B.J.Casey et al./Biological Psychology 54(2000)241-257 relative to temporal cortex or sensorimotor cortex(Coffey et al.,1992:Cowell et al. 1994;Raz et al.,1997).It appears that prefrontal white matter rather than gray matter may be most susceptible to normal aging as measured with MRI(Svenner- holm et al.,1994;Peters et al.,1996;Salat et al.,1999).This pattern of degeneration is different from that obse rved in individuals with alzhe disease (Stout et al 1996 Salat al1999).If this is in d the then why might the last are mature be the regions that ar e most plast over prolonged periods of development are more sensitive or susceptible to environ- mental factors (e.g.stressors,toxins)and thus more prone to insult or injury from such environmental influences.Related issues are addressed in Grady's paper in this issue 2.What is the relation of brain development to cognitive development? To date,little is known regarding the neural bases of cognition in normally developing children.In order to address the neural circuits underlying cognitive development,a means of assessing,in vivo,the developmental physiological course of the behavior is needed.With the advent of blood oxygenation level dependent (BOLD)imaging (Kwong et al.,1992;Ogawa et al.,1990:Turner et al.,1991).the field of imaging has been opened to address developmentally que of bra and behavior.This me gy cap n the fact that its gen ed 1 globin strongly param agnetic 1 Deoxy therefore be use d as a naturally occurring contrast agent with highly oxygenated brain regions producing a larger magnetic resonance(MR) signal than less oxygenated areas.This method eliminates the need for exogenous contrast agents,including radioactive isotopes. Given the prolonged physiological development and organization of the prefron- tal cortex during childhood tasks believed to involve this region are idea for investigating de ent with this methodolo ognitive pro esses that have ex I g m inhib d attentio (G an-Ra 1987 1989).Memory,inhibition,and attention are often treated as three distinct psycho logical constructs.However,aspects of these cognitive processes may be part of a single construct or common underlying circuitry.For example,memory and inhibition are both involved in maintenance of information in that when relevant information is represented and maintained in memory,competing representations or memories are subsequently suppressed or inhibited.Likewise,selective attention and inhi 10 of a in that en we attend to a relevan ent and c competing,but n ss irrelevant events are s or inhibited in favor of the relevant event.Similarly,selective attention and memory may represent a single construct in that the classic description of working memory (Baddeley,1986)includes a component referred to as a central executive that allocates attentional resources to relevant events.Therefore,memory can be defined in part as the selective allocation of attention to relevant events or representations
244 B.J. Casey et al. / Biological Psychology 54 (2000) 241–257 relative to temporal cortex or sensorimotor cortex (Coffey et al., 1992; Cowell et al., 1994; Raz et al., 1997). It appears that prefrontal white matter rather than gray matter may be most susceptible to normal aging as measured with MRI (Svennerholm et al., 1994; Peters et al., 1996; Salat et al., 1999). This pattern of degeneration is different from that observed in individuals with Alzheimer disease (Stout et al., 1996; Salat et al., 1999). If this is indeed the case, then why might the last area to mature be the first to go? One possibility is that brain regions that are most plastic over prolonged periods of development are more sensitive or susceptible to environmental factors (e.g. stressors, toxins) and thus more prone to insult or injury from such environmental influences. Related issues are addressed in Grady’s paper in this issue. 2. What is the relation of brain development to cognitive development? To date, little is known regarding the neural bases of cognition in normally developing children. In order to address the neural circuits underlying cognitive development, a means of assessing, in vivo, the developmental physiological course of the behavior is needed. With the advent of blood oxygenation level dependent (BOLD) imaging (Kwong et al., 1992; Ogawa et al., 1990; Turner et al., 1991), the field of magnetic resonance imaging has been opened to address developmentally driven questions of brain and behavior. This methodology capitalizes on the fact that hemoglobin becomes strongly paramagnetic in its deoxygenated state. Deoxygenated hemoglobin can therefore be used as a naturally occurring contrast agent, with highly oxygenated brain regions producing a larger magnetic resonance (MR) signal than less oxygenated areas. This method eliminates the need for exogenous contrast agents, including radioactive isotopes. Given the prolonged physiological development and organization of the prefrontal cortex during childhood, tasks believed to involve this region are ideal for investigating development with this methodology. Cognitive processes that have been attributed to the prefrontal cortex include working memory, response inhibition and attention allocation (Goldman-Rakic, 1987; Diamond, 1988; Fuster, 1989). Memory, inhibition, and attention are often treated as three distinct psychological constructs. However, aspects of these cognitive processes may be part of a single construct or common underlying circuitry. For example, memory and inhibition are both involved in maintenance of information in that when relevant information is represented and maintained in memory, competing representations or memories are subsequently suppressed or inhibited. Likewise, selective attention and inhibition are part of a similar construct in that when we attend to a relevant event, other salient and competing, but nonetheless irrelevant events are suppressed or inhibited in favor of the relevant event. Similarly, selective attention and memory may represent a single construct in that the classic description of working memory (Baddeley, 1986) includes a component referred to as a central executive that allocates attentional resources to relevant events. Therefore, memory can be defined in part as the selective allocation of attention to relevant events or representations
B.J.Casey et al./Biological Psychology54(2000)241-257 245 This component of working memory does not significantly differ from selective attention Perhaps the common component of overlap in the three previous examples of the psychological constructs of attention,memory,and inhibition,is the presumed presence of interfering or competing information.In the case of attention,the interference may be from simultaneous input or output.In the case of memory, interference n ay be due en inhibit to compe emories/r esentations.If there is no interfe ory proc are see not nec and the structs of atter ion an ry may be i distingui ng componen within the temporal attention pre involving present information and memory involving past information.When there is interference from competing sources then the definitions of attention and memory are less discrete in that they can be defined as the ability to represent relevant events in the presence of salient,competing,and compelling,yet otherwise irrelevant events.How do we ignore and select from competing sources of information (stimulus selection)or fr natives sponse selection) or for that ter 01 respon (respon ution)?This que gnore or n suggests th ur at diferen attentional processing (i.e.during stimulus selection,during response selection,o during response execution)and likewise during memory of different types of information (e.g.stimulus sets,behavioral sets).So,both attention and memory appear to involve inhibitory processes when there is interference from competing sources inhibitory proc esses of this nature are of interest because they ear to be involved in both and social learni ng thre ughout childhood ten h e terms or y control'a and beh. regulation are used itory processes in co and (Posner and Rothbart,1998;Casey,in press).Clinically,inhibitory processes are important because they appear to be disrupted in a number of developmental disorders that have as a core deficit a problem inhibiting inappropriate behaviors and thoughts (e.g.Attention Deficit-Hyperactivity Disorder,Obsessive Compulsive Disorder.and Tourette syndrome).Interestingly,the prefrontal cortex and related circuitry have beet implicated in these develo mental disorders refron relate to the ormal devel opment of inhibitor processes?He emphasis may well be plac on t he prefrontal corte in supporting different types of information(e.g.verbal,spatial,moto emotional against interference over time and/or from competing sources (Goldman-Rakic 1987;Cohen and Servan-Schreiber,1992).A number of classic developmental studies have demonstrated that these memory and attention related processes develop throughout childhood and adolescence (Flavell et al.,1966:Pascual-Leone. 1970;Case,1972;Keating and Bobbitt,1978).Further,the converging evidence of ization prefr ex thr child. e(Hu ten et al. nd,198 1991, ugan 1996:Bourgeois et al 1994;Rakic et al.,1994)may suggest an importan parallel between brain development and cognitive development.The most impor-
B.J. Casey et al. / Biological Psychology 54 (2000) 241–257 245 This component of working memory does not significantly differ from selective attention. Perhaps the common component of overlap in the three previous examples of the psychological constructs of attention, memory, and inhibition, is the presumed presence of interfering or competing information. In the case of attention, the interference may be from simultaneous input or output. In the case of memory, interference may be due to competing memories/representations. If there is no interference, then inhibitory processes are seemingly not necessary and the constructs of attention and memory may be more easily distinguished. One distinguishing component is within the temporal domain with attention predominantly involving present information and memory involving past information. When there is interference from competing sources then the definitions of attention and memory are less discrete in that they can be defined as the ability to represent relevant events in the presence of salient, competing, and compelling, yet otherwise irrelevant events. How do we ignore and select from competing sources of information (stimulus selection), or from competing response alternatives (response selection), or for that matter, ignore or inhibit a behavior or response altogether (response execution)? This question suggests that inhibition can occur at different stages of attentional processing (i.e. during stimulus selection, during response selection, or during response execution) and likewise during memory of different types of information (e.g. stimulus sets, behavioral sets). So, both attention and memory appear to involve inhibitory processes when there is interference from competing sources. Developmentally, inhibitory processes of this nature are of interest because they appear to be involved in both cognitive and social learning throughout childhood and adolescence. Often, the terms ‘inhibitory control’ and ‘behavioral regulation’ are used to describe inhibitory processes in cognitive and social development (Posner and Rothbart, 1998; Casey, in press). Clinically, inhibitory processes are important because they appear to be disrupted in a number of developmental disorders that have as a core deficit a problem inhibiting inappropriate behaviors and thoughts (e.g. Attention Deficit-Hyperactivity Disorder, Obsessive Compulsive Disorder, and Tourette syndrome). Interestingly, the prefrontal cortex and related circuitry have been implicated in these developmental disorders. How does prefrontal circuitry relate to the normal development of inhibitory processes? Here, emphasis may well be placed on the role of the prefrontal cortex in supporting different types of information (e.g. verbal, spatial, motor, emotional) against interference over time and/or from competing sources (Goldman-Rakic, 1987; Cohen and Servan-Schreiber, 1992). A number of classic developmental studies have demonstrated that these memory and attention related processes develop throughout childhood and adolescence (Flavell et al., 1966; Pascual-Leone, 1970; Case, 1972; Keating and Bobbitt, 1978). Further, the converging evidence of prolonged development and organization of prefrontal cortex throughout childhood and adolescence (Huttenlocher, 1979; Chugani et al., 1987; Diamond, 1988, 1991, 1996; Bourgeois et al., 1994; Rakic et al., 1994) may suggest an important parallel between brain development and cognitive development. The most impor-