Studies of Brain and Cognitive Maturation
Through Childhood and Adolescence: A
Strategy for Testing Neurodevelopmental
Hypotheses
by Beatriz Luna and John A, Sweeney
Adolescence is an important period of development.
Recent neurobiological and psychological research indicates that far greater brain and cognitive maturation
occurs during this period than was traditionally believed.
Although basic cognitive and brain functions are, for the
most part, in place by school age, significant maturation
continues throughout and after puberty. Concurrent with
this brain maturation is the emergence of increasingly
elaborate cognitive abilities. The prefrontal cortex, with
the participation of other brain regions in widely distributed circuits, subserves many aspects of higher order
cognitive function in which there is robust developmental
change during adolescence. These functions include
working memory, voluntary inhibition of context-inappropriate behavior, and developing preparatory sets for
anticipated action (Goldman-Rakic 1990; Fuster 1997).
All of these functions require that cognitive processes be
held on line to allow for the appropriate binding of environmental cues and behavioral responses over time, so
that behavior is properly timed and adaptive to specific
environmental contexts. In schizophrenia, a wide range
of behavioral and functional imaging studies document
impairment in these higher order cognitive processes that
undergo considerable maturational change during adolescence (Weinberger et al. 1986; Park and Holzman 1992;
Merriam et al. 1999; Cohen et al. 1999). Evidence indicates that anomalies in the cytoarchitecture of prefrontal
cortex, including a decrease in neuropil, occur in schizophrenia patients (Lewis 1997; Selemon and GoldmanRakic 1999). The potential contribution of abnormal maturational processes during childhood and adolescence to
the reduced synaptic connectivity seen in adult patients
remains unclear.
Thus, cytoarchitectural, neuroimaging, and neurocognitive studies all converge in indicating abnormalities in
the anatomy and function of prefrontal cortex in individu-
Abstract
Although neurodevelopmental models of schizophrenia are now widely accepted, there is minimal direct
human evidence of dysmaturation in schizophrenia to
support this theory. This is especially the case regarding maturational changes during late childhood and
adolescence, which immediately precede the typical
age of onset of the disorder. By integrating new noninvasive methods of functional magnetic resonance
imaging with techniques of developmental cognitive
neuroscience, it is now possible to begin systematic
research programs to directly test hypotheses of neurodevelopmental abnormalities in schizophrenia. In
this article, we describe strategies for characterizing
developmental changes taking place during the critical
period of adolescence that can elucidate dysmaturation processes in schizophrenia. We emphasize the
need for studies characterizing normal development
before examining at-risk or clinical populations, and
the potential value of using neurobehavioral and neuroimaging approaches to directly characterize the dysmaturation associated with schizophrenia.
Keywords: spatial working memory, inhibition,
eye movements, cerebellum, neuroimaging, prefrontal
cortex.
Schizophrenia Bulletin, 27(3):443-455,2001.
Neurodevelopmental models of schizophrenia have
gained considerable interest in recent years (Waddington
et al. 1991; Hyde et al. 1992; Keshavan et al. 1994;
Weinberger and Lipska 1995), and this has opened a new
conceptual framework for thinking about the etiology of
this debilitating disease. Onset of schizophrenia typically
occurs during adolescence or young adulthood, which
itself raises interest in the nature of brain maturational
changes during adolescence that might be awry in individuals at risk for schizophrenia and thereby contribute to the
etiology of the disorder.
Send reprint requests to Dr. B. Luna, Western Psychiatric Institute and
Clinic, University of Pittsburgh, 3501 Forbes Avenue, Oxford Building
Room 743, Pittsburgh, PA 15213; e-mail: [email protected].
443
Schizophrenia Bulletin, Vol. 27, No. 3, 2001
B. Luna and J.A. Sweeney
als with schizophrenia. Further, clinical neuropsychological studies of "first-episode" patients, evaluated shortly
after illness onset, have reported robust disturbances of
prefrontal cortical functions even at the point of illness
onset (Hoff et al. 1992; Rubin et al. 1995; Merriam et al.
1999; Bilder et al. 2000; Riley et al. 2000). Available evidence in young and midlife adult schizophrenia patients
does not suggest significant declines in cognitive function
over time (Goldberg et al. 1993; Censits et al. 1997; Rund
1998). Thus, cognitive abnormalities in schizophrenia
patients do not result primarily from treatment or course
of illness effects; therefore, it appears that schizophrenia
patients often fail to achieve an expected developmental
level of these functions before illness onset. This notion is
indirectly supported by studies showing that relatives of
individuals with schizophrenia, who themselves do not
manifest the illness, also have deficits in executive cognitive functions subserved primarily by prefrontal cortex
(Franke et al. 1992; Park et al. 1995; Staal et al. 2000).
Although findings from studies of relatives have been
somewhat inconsistent, observations of abnormalities of
prefrontal functions in the unaffected family members of
schizophrenia patients that have been reported suggest
that brain dysmaturation in this disorder may be under
genetic control and related to risk for the illness in a fundamental way. However, at present, we still lack the data
needed to determine whether and how maturational disturbances might contribute to prefrontal and other cognitive abnormalities associated with schizophrenia.
The temporal contiguity of illness onset and the relatively late maturation of prefrontal cortical functions indicate that a failure to achieve adequate maturational
changes in the intrinsic wiring or functional connectivity
of prefrontal cortex could prove to be a major factor in the
pathophysiology of schizophrenia. Such developmental
failure could lead to inadequate inhibitory modulatory
influence over mesial temporal cortex contributing to positive symptoms, and directly cause important neuropsychological deficits associated with the illness.
However, before we can test neurodevelopmental
models of schizophrenia by establishing actual developmental and brain maturational disturbances in the illness,
several preliminary steps need to be achieved. First, we
need to learn much more about the normal maturation of
cognition and functional brain systems during late childhood and adolescence. At present, little is known about
normal cognitive and neurophysiologic dimensions of adolescent maturational processes. Developmental neurobiology and the study of cognitive development have concentrated on the stages of development from conception to the
first years of life, leaving the investigation of late childhood and early adolescence a relatively understudied area
of research. Much basic psychological research is needed
to document the essential pattern of cognitive changes that
occur during late childhood and early adolescence and the
normal range of variability in these processes across individuals. This research is required to establish deviations
from normal development in clinical populations of interest. Second, we need to better understand the brain substrates of cognitive development during adolescence.
Neuroimaging research provides an important strategy for
achieving this aim. Whereas positron emission tomography (PET) and single-photon emission computed tomography require radioactive tracers to examine functional
changes in brain activity, functional magnetic resonance
imaging (fMRI) is a noninvasive procedure that monitors
regional brain function with high spatial resolution in a
manner that can be used safely with pediatric populations.
Studies of healthy children and adolescents with fMRI
have just begun to appear in the literature. As findings are
replicated and methods are validated in fMRI studies, we
will be able to probe the maturation of brain functions in
individuals at risk for schizophrenia, thereby identifying
specific failures in normal maturational processes.
Although prefrontal deficits are prominent, impairments
in other brain regions are suggested by the broader pattern
of associated neuropsychological deficits (Saykin et al.
1991; Levy and Holzman 1997; Sweeney et al. 1998;
Chen et al. 1999). Furthermore, human neuroimaging and
monkey unit recording studies consistently indicate that
higher order cognitive processes are subserved by widely
distributed systems in the brain that not only include prefrontal regions but also striato-thalamo-cortical and cerebello-thalamo-cortical circuits (Strick 1985; Robbins
1990; Middleton and Strick 1998). Functional MRI studies provide the ability to visualize function in the whole
brain to investigate localized abnormalities in different
regions of interest, as well as impairments at the network
level and impairments in functional connectivity.
We aim to briefly summarize what is known about
brain maturation and cognitive development during late
childhood and early adolescence and then describe our
preliminary efforts to characterize normative changes in
the maturation of brain function using neurophysiological
and fMRI approaches during this period.
Brain Maturation
The degree of cortical folding (Armstrong et al. 1995),
overall size, and regional functional specialization of
the brain is, for the most part, in adult-like form by
early childhood (Caviness et al. 1996). However, significant refinements of brain systems including pruning of
synapses, elaboration of dendritic arborization
(Changeux and Danchin 1976; Huttenlocher 1990), and
increased myelination (Yakovlev and Lecours 1967;
Jernigan et al. 1991; Pfefferbaum et al. 1994) continue
444
Studies of Brain and Cognitive Maturation
Schizophrenia Bulletin, Vol. 27, No. 3, 2001
into adolescence. With special relevance to schizophrenia, synaptic density in the prefrontal cortex (layer III
of the middle frontal gyrus) peaks by the first year of
age, after which there is a steady elimination of
synapses that asymptotes in mid-adolescence
(Huttenlocher 1990). Synaptic pruning in layer III of
the prefrontal cortex appears to reduce dopaminergic
and excitatory inputs to pyramidal cells and is believed
to facilitate optimal organization of the circuitry
required to maintain reverberating inhibitory and excitatory circuits needed for cognitive processes
(Alexander and Goldman 1978; Lewis 1997).
Myelination provides a fatty lipid insulation to axons,
increasing the propagation of electrical signals throughout the central nervous system that optimizes the transfer of information throughout widely distributed circuits. Association areas in frontal, temporal, and
parietal regions do not reach mature myelination until
the third decade of life (Yakovlev and Lecours 1967).
The parahippocampal gyrus, believed to be involved in
the emotional component of cognition, continues to
show increased myelination into the sixth decade of life
(Benes 1998). The late myelination of hippocampal
connections during adolescence (Benes 1989), including those from the frontal cortex, could contribute to
anomalies in corticolimbic integration in schizophrenia
that are not evident earlier in life. In addition to histologic studies of postmortem brain tissue, recent in vivo
human studies using anatomic MRI (Giedd et al. 1999)
and diffusion tensor imaging (Klingberg et al. 1999)
studies evaluating white matter pathways have also
revealed late myelination of cortical region projections
to and from frontal cortex.
MRI studies have also revealed gray matter changes
that continue in cortical and subcortical areas throughout
adolescence. Gray matter volume in frontal and parietal
regions peaks in childhood, followed by a decrease
throughout adolescence, purportedly reflecting synaptic
pruning processes (Sowell and Jemigan 1998; Giedd et
al. 1999; Thompson et al. 2000). Decreases in gray matter
also persist during adolescence in the striatum, possibly
in association with reductions in frontal cortex (Sowell
and Jernigan 1998). These results indicate a critical
period in adolescence for maturation of fronto-striatal circuitry that makes changes in these regions of considerable
potential interest to schizophrenia investigators.
Taken together, the evidence is clear that brain maturation, especially of regions known to play primary roles
in higher order cognition and emotional regulation, are
still maturing into adulthood. This age period of highly
sophisticated refinement in brain processes may be a critical period that is especially sensitive to dysmaturation
processes believed to underlie the impairment in higher
order cognition present in schizophrenia.
Cognitive Development
Developmental psychologists have primarily concentrated
on understanding the cognitive milestones achieved in the
first few years of life. Relatively little research has been
dedicated to understanding the more subtle changes in cognition that occur after early childhood. However, available
evidence does indicate that cognitive processes become
significantly more sophisticated during adolescence.
Although basic cognitive processes, including working memory (Diamond and Goldman-Rakic 1989), are in
place by childhood, the sophisticated use of these abilities
increases throughout adolescence. This period is characterized by improvement in the capacity to manipulate
one's environment through abstract thought, planning,
and cognitive flexibility that takes place concurrently
with significant reorganization of neural connectivity in
the neocortex. Performance on visual pattern spatial
recognition and set-shifting tasks (Luciana and Nelson
1998), as well as performance on the Wisconsin Card
Sorting Task (Chelune and Baer 1986; Levin et al. 1991),
are adult-like by late childhood. However, complex planning skills show continued improvement past late childhood into adolescence on more complex problem-solving
tasks such as the Tower of London and the Tower of
Hanoi, as well as on verbal fluency and motor sequencing
tasks (Levin et al. 1991; Welsh et al. 1991).
The maturation of higher order cognitive abilities is
believed to result from improved processing and storing
of information (Case 1992; Dempster 1993) afforded primarily by the automation of lower level cognitive
processes and the ability to suppress or inhibit contextinappropriate responses (Bjorklund and Harnishfeger
1990; Case 1992; Ridderinkhof and van der Molen 1997;
Wilson and Kipp 1998). Higher order cognitive processes
are supported by the coordinated action of widespread
neural networks that enable adaptive neocortical modulation of behavior, particularly the executive orchestration
of activity in many brain regions by prefrontal cortex
(Hudspeth and Pribram 1990; Stuss 1992; Diamond and
Taylor 1996; Luciana and Nelson 1998). In this manner,
cognitive maturation can be conceptualized as a feedback
loop in which an increase of functional integration across
widely distributed brain regions allows for quicker, more
focused, and higher capacity cognitive processing, which
in turn frees up local neuronal circuitry for more optimized performance of cognitive functions. This mature
system provides a more dynamic and efficient processing
stream that allows for the sophisticated online planning
and flexibility needed for complex goal-directed behavior.
The disruption in maturation of these elements could have
significant consequences for higher order cognition.
There is much work that needs to be done to characterize the essential cognitive processes that benefit from
445
Schizophrenia Bulletin, Vol. 27, No. 3, 2001
B. Luna and J.A. Sweeney
brain maturation during the transition from puberty
through adulthood. To characterize neurodevelopmental dysmaturation in psychiatric disorders, it is important to recognize the impaired cognitive elements and
pinpoint the stage at which their disruption occurs.
First, however, it is necessary to characterize healthy
development during adolescence. Only after we have
validated procedures and replicated findings with large
samples of healthy individuals that document the patterns and their normal variability of development will
we be prepared to begin hypothesis-driven clinical
investigations to nail down the time course and essential components of developmental dysmaturation in
schizophrenia.
Figure 1. Diagram of regions known to comprise
the oculomotor system from single-cell recording and lesion studies of nonhuman primates
and human lesion and neuroimaging studies
Probing Brain and Cognitive Maturation
Given the need for normative cognitive and fMRI data
regarding processes that mature during adolescence
and are abnormal in schizophrenia, we began a set of
studies using oculomotor tasks. Oculomotor tasks are
especially well suited for investigating cognitive and
brain maturation for several reasons. First, eye movement tasks can be used to test the integrity of basic
sensorimotor function as well as multiple higher order
executive processes including attention shifting, working memory, and voluntary response suppression.
Second, specific cognitive processes can be isolated
and tested with eye movement paradigms in a way that
is rarely possible with standard neuropsychological
tests. Third, single-cell recording studies of nonhuman
primates and human lesion and neuroimaging studies
have characterized the physiology, anatomy, and neurochemistry of the brain processes underlying the executive control of the oculomotor system, providing an
especially strong base for designing and interpreting
clinical and developmental studies (Leigh and Zee
1999). The same tasks used in lesion and neurophysiological studies of behaving nonhuman primates can be
brought directly into the clinical laboratory. From these
studies we know which brain regions are required for
normal task performance and how they form a widely
distributed circuitry (figure 1), including key brain
areas known to be disrupted in schizophrenia including
prefrontal, thalamic, striatal, and cerebellar regions.
Fourth, eye movement tasks are particularly well
suited for neuroimaging work in that they recruit
robust increases in brain activity (O'Driscoll et al.
1995; Sweeney et al. 1996; Petit et al. 1997; Luna et al.
1998; Luna and Sweeney 1999; Luna et al. 2001).
Finally, serious psychiatric and neurologic disorders
are known to be associated with specific abnormalities
in eye movement control (Kennard and Rose 1988;
Park and Holzman 1992; Clementz et al. 1994;
Sweeney et al. 1998; Levy et al. 1998; Leigh and Zee
1999).
The oculomotor system is a particularly appropriate target for developmental studies because children
as well as adults can readily perform eye movement
tasks. Additionally, cognitive studies using oculomotor tasks have revealed delayed maturation of executive processes in psychiatric disorders through adolescence (Rosenberg et al. 1997). Cross-sectional
developmental studies have revealed improved performance throughout childhood in the speed of shifting attention and eye movements to visual targets, in
the ability to suppress saccades to anticipated targets,
in maintaining fixed gaze, and in accurately tracking
moving targets (Miller 1969; Paus et al. 1990; Ross et
al. 1993, 1994; Fischer et al. 1997; Katsanis et al.
1998; Munoz et al. 1998).
Different eye movement tasks can be used to probe
different brain processes. Simple tasks such as the visually guided saccade task, which requires that subjects
direct their gaze to suddenly appearing visual targets, and
pursuit tasks in which subjects visually track a moving
stimulus, can be used to study the integrity of basic sensorimotor and attention systems. Cognitive components
can be added to simple eye movement tasks to probe
higher order cognition and draw inferences about its
underlying brain circuitry. The oculomotor delayed
response task (also called a memory-guided saccade task)
446
Studies of Brain and Cognitive Maturation
Schizophrenia Bulletin, Vol. 27, No. 3, 2001
requires that subjects make an eye movement guided
only by the memory of the spatial location of a stimulus.
This task has been used to define the basic neuronal circuitry of spatial working memory in studies of nonhuman
primates (Hikosaka and Wurtz 1983; Funahashi et al.
1989; Sawaguchi and Goldman-Rakic 1991). The antisaccade task requires that subjects suppress eye movements to visual targets that appear in the periphery, and
instead look away from them. The antisaccade task is
used to probe the capacity for voluntary response suppression. These eye movement tasks have been used in
nonhuman primate single-cell and lesion studies as well
as in human lesion and neuroimaging studies, providing a
solid depiction of the brain circuitry subserving their performance (Funahashi et al. 1989; Pierrot-Deseilligny
1991; Darby et al. 1996; Everling et al. 1999).
We have used these eye movement tasks to assess
working memory and voluntary response suppression to
characterize the development of these higher order cognitive processes from 8 to 45 years of age, and have
found significant improvements in these processes
throughout adolescence (Luna et al. 2000, 2001).
Although 8- to 10-year-old children demonstrate adult
level performance in the velocity and accuracy of saccadic eye movements to visual targets, they do not perform as well as adults in the cognitive components of
these tasks. The accuracy of eye movements made to
remembered spatial locations during the memory-guided
saccade task did not reach adult levels until mid-adolescence. Similarly, in the antisaccade task, not until midadolescence did subjects reach adult levels in the percentage of trials in which they could voluntarily
suppress the reflexive tendency to look toward suddenly
appearing targets (Luna et al. 2000). Improvement in the
performance of the antisaccade task has also been found
in large cohorts in other laboratories and appears to be a
reliable measure of the development of the capacity for
voluntary response suppression (Fischer et al. 1997;
Munoz et al. 1998). These results indicate that there is
significant cognitive development occurring throughout
adolescence, and it can be evaluated using cognitively
demanding eye movement tasks.
Given the multiple indications of frontal pathology
in schizophrenia, it is not surprising that individuals
with schizophrenia have a well-replicated diminished
ability to perform antisaccade, memory-guided saccade,
and pursuit tasks (Fukushima et al. 1990; Rosse et al.
1993; Clementz et al. 1994; Matsue et al. 1994;
Crawford et al. 1995; Katsanis et al. 1997; Sweeney et
al. 1998, 1999). Hence, investigations probing the oculomotor system are particularly well suited to study
neurodevelopmental components of schizophrenia.
Studying Development of Brain
Function during Childhood and
Adolescence
The study of development during adolescence has been
composed, for the most part, of two major lines of
research. One area has characterized changes that occur
in brain structure through childhood and adolescence.
This area has seen major recent advances in methodologies for characterizing region-specific changes in brain
anatomy (Caviness et al. 1996; Kennedy et al. 1998), in
approaches for measuring both the form and volume of
brain structures (Rademacher et al. 1993; Gelenbe et al.
1996), and in the development of diffusion tensor imaging for evaluating white matter pathways (Pfefferbaum et
al. 2000). The second area of study has focused on how
cognitive capabilities improve with age. It is evident that
cognitive development and brain maturation are inherently intertwined; however, until recently, we have not
had the methods to systematically investigate how these
two dimensions of developmental maturation fit together.
Functional brain imaging promises to provide the
bridge between anatomic studies of brain maturation and
neuropsychological studies of cognitive development that
are needed to understand the dynamic relationship
between brain and cognitive development. One approach
with especially great promise is using fMRI to investigate
how the functional organization of brain regions contributing to cognitive functions changes with development to support the emergence of adult cognition.
Advances in this field will be extremely valuable for
directly testing neurodevelopmental models of schizophrenia. As we delineate the brain circuitry underlying
healthy cognitive development, we will be better able to
identify specific abnormalities in functional brain circuitry and neurocognitive control that occur in individuals with schizophrenia and in those at familial risk for the
illness during childhood and adolescence. As such findings about brain function are linked to findings of
anatomic abnormalities in brain maturation, we will be
able to provide direct tests of neurodevelopmental models of schizophrenia.
Before the development of fMRI, brain function in
children and adolescents was typically assessed with
electroencephalography (EEG) and PET. Thatcher
(Thatcher 1991) measured EEG coherence among neocortical regions and reported that the coherence of EEG
activity increased throughout adolescence, especially
between frontal and other cortical areas. Similar results
were found using PET, with which Chugani et al. (1998)
demonstrated that local cerebral resting metabolic rates
447
Schizophrenia Bulletin, Vol. 27, No. 3, 2001
B. Luna and J.A. Sweeney
decrease in frontal, parietal, and temporal regions
throughout childhood and only reach adult levels in
adolescence. Although the neurobiological substrate of
this latter effect is not completely clear, the most likely
cause is that synaptic pruning related to brain maturation reduces net metabolic activity. However, there are
limitations to these methods and findings. EEG studies
lack sufficient spatial resolution to adequately localize
developmental changes in specific brain regions. PET,
because of the somewhat invasive nature of the procedure, has rarely been used to study healthy pediatric
populations.
Functional MRI allows noninvasive imaging of brain
function in vivo during cognitive activity. Because it is
noninvasive, fMRI permits the characterization of
changes in brain activity that occur during development in
pediatric populations. The minimal risk from repeated
exposure also permits longitudinal fMRI studies of developmental changes in brain-behavior systems. This is especially important because it provides a basis for actually
following developmental trajectories in individual subjects, rather than using only cross-sectional studies to
investigate developmental trends. Because development
often proceeds in bursts rather than in a smooth, gradual
manner (Thatcher 1991), longitudinal studies provide a
better way to characterize patterns of development. For
these reasons, fMRI is likely to be a valuable tool for
bridging cognitive and biological studies of brain development.
Functional MRI works on the principle that neuronal
activation associated with cognitive activity results in
increased metabolic demand and that metabolic demand,
in turn, brings increased blood flow to the region. The
increase in blood flow produces a change in the ratio of
oxygenated to deoxygenated blood, which changes the
magnetic properties of blood in a way that can be detected
in MRI studies. Using sophisticated image reconstruction
and analysis procedures, these changes in regional magnetic properties in the brain can be used to provide a
detailed picture of brain regions involved in performing a
particular cognitive act. The psychological tasks that subjects perform in the MRI scanner need to be carefully
selected to probe specific cognitive processes of interest.
A diagram of the MRI environment is presented in
figure 2.
Pediatric fMRI studies have been performed to guide
excision of lesions (Stapleton et al. 1997), to localize language areas (Benson et al. 1996; Hertz-Pannier et al.
1997), to identify similarities between children and adults
in the regions recruited for higher order cognition (Casey
et al. 1995, 1997; Thomas et al. 1999; Luna et al. 2001),
and to characterize functional impairments in attention
deficit hyperactivity disorder (Vaidya et al. 1998; Rubia et
al. 2000). Initial developmental neuroimaging studies sug-
Figure 2. Diagram of functional magnetic resonance imaging environment
Stimulus
Mirror
I Microphone
S Speakers
~\ Rear Projection Screen
Head Coil
IR Camera
gest that similar brain circuitry is recruited in children and
adults during performance of a nonspatial working memory task (Casey et al. 1995).
Our own findings have revealed changes in the
functional distribution of brain regions from childhood
through adolescence during performance of a voluntary
response suppression task (Luna et al. 2001). We conducted an fMRI study of 36 healthy subjects ranging in
age from 8 to 30 years to study developmental changes
in the brain substrate of antisaccade task performance.
Blocks of antisaccade and prosaccade trials were presented. The stimuli used for the two eye movement
tasks were similar except for the color of the fixation
light. During antisaccade trials, the fixation light was
red and subjects were instructed to look in the opposite
direction of targets appearing in the periphery. During
prosaccade trials, the fixation light was green and subjects were instructed to look toward the peripheral targets. Activity during these two tasks was then contrasted to localize brain regions associated with
voluntary response suppression, with the rationale that
comparison with a visually guided saccade task would
"subtract" activation effects associated with basic visual
and sensorimotor processes. The difference in activation
then would be attributable to the changes in regional
neuronal activity related to the task demand for voluntary response suppression.
Results indicated that, across the age span, subjects
recruited a widely distributed circuitry including
frontal, supplementary, and parietal eye fields, dorsolateral prefrontal cortex, thalamus, and striatum (figure 3).
However, comparisons of children, adolescents, and
adults revealed that only adults recruited some regions
known to play a primary role in establishing the
preparatory state needed to successfully perform antisaccades, including the superior colliculus (Everling et
al. 1999), extensive regions of the frontal eye field
(Everling and Munoz 2000), and regions in the lateral
cerebellum that form a functional circuit with the pre-
448
Schizophrenia Bulletin, Vol. 27, No. 3, 2001
Studies of Brain and Cognitive Maturation
adolescence, likely providing the maturational refinements needed for efficient voluntary control of behavior
on this task. We still need to characterize how synaptic
pruning and myelination processes occurring during this
age period are associated with this developmental
change in functional organization. Further, from the
perspective of the neurodevelopmental model of schizophrenia, whether there is a maturational failure in schizophrenia in the functional interconnectivity of brain
regions subserving key cognitive functions such as the
voluntary suppression of prepotent responses needs to
be determined.
Figure 3. Group activation maps (t > 4.0) during
an antisaccade task relative to a visually guided
prosaccade task superimposed on the structural
anatomic image of a representative subject (26
year old female) warped into Talairach space.
Columns show the average activation for each
age group. Rows depict the orientation (rows 1,4
= axial; 2, 5 = coronal; 3 = sagittal) that optimally illustrates activation in brain regions of
interest. BG = basal ganglia; TH = thalamus;
DLPFC = dorsolateral prefrontal cortex; SC =
superior colliculus; FEF = frontal eye field; IPS
= intraparietal sulcus; L-Cer = lateral cerebellum; and DN = dentate nucleus of the cerebellum. The data in this figure have been published
previously in Luna et al. (2001).
8-13 yrs.
14-17 yrs.
Conclusion
This is an exciting time for those interested in putting
neurodevelopmental models of schizophrenia to direct
test. Although a host of data points to developmental
abnormalities in the perinatal period and early childhood
in schizophrenia (Fish et al. 1992), developmental disturbances during late childhood and adolescence may be of
equal, if not greater, importance (Marcus et al. 1993; Hans
et al. 1999) given that the incidence rates for schizophrenia rise sharply at the age when these maturational events
are being completed. Undoubtedly, there is a considerable
likelihood that perinatal factors could influence brain maturation in adolescence, a possibility that certainly needs to
be systematically examined.
Efforts to consider disturbances in late developmental
processes as risk factors for schizophrenia have been hindered by two major factors: (1) a lack of a broad interest
in this period by developmental psychologists and neurobiologists, which has led to a modest empirical framework for testing hypotheses about abnormal development
associated with schizophrenia, and (2) a lack of validated
methodologies for noninvasively assessing brain-behavior
systems during this age period. The growing interest in
adolescent development and the availability of MRI technologies for evaluating brain anatomy and function in
new noninvasive ways now provide the basis for studying
individuals at risk for schizophrenia during childhood and
adolescence and determining what, if any, maturational
abnormalities in brain and cognitive systems occur in
these individuals.
The purpose of this article was to lay out a general
strategy for testing models of "late" neurodevelopmental
disturbances in schizophrenia. To pursue work in this
area, one approach is to follow childhood onset cases
(Gordon et al. 1994). Although this is an important
approach, these cases can in some ways be atypical and
rare, and the effects of illness and treatment on developmental parameters of interest are difficult to sort out.
Even adolescent-onset cases can have especially poor
18-30 yrs.
DLPFC
flRH?.) IM^Rv
frontal cortex (Kim et al. 1994). On the other hand, adolescents did demonstrate increased activation of dorsolateral prefrontal cortex and striatum relative to children, possibly reflecting their ability to more effectively
recruit fronto-striatal circuitry to perform the antisaccade task.
These results provide evidence that brain function
underlying response suppression as seen in the antisaccade task becomes more widely distributed throughout
449
Schizophrenia Bulletin, Vol. 27, No. 3, 2001
B. Luna and J.A. Sweeney
courses of illness and treatment response (Pollack et al.
1968). An alternative approach is to study unaffected family members of patients or schizotypal individuals
(Keshavan et al. 1991; Thaker et al. 1996) and to study
developmental processes in these individuals. Although a
difficult task in its own right, this approach provides one
feasible way to directly test models of abnormal neurodevelopmental processes in schizophrenia.
There are multiple ways to conduct clinical in vivo
studies to investigate dysmaturation in schizophrenia.
MRI methods provide a useful approach for studying
brain anatomy and function. To systematically study functional aspects of brain development that may be awry in
schizophrenia, an approach with several steps is required.
First, neurocognitive domains that are abnormal in individuals with schizophrenia need to be selected for developmental studies. Second, once a neurocognitive domain
is identified, its developmental profile needs to be characterized in healthy individuals. This is essential so that
hypotheses about dysmaturation can be tested by comparing development in healthy individuals with that of clinical groups or their unaffected family members. Third,
when focusing on a clinical developmental hypothesis,
clarifying the brain substrate of cognitive developmental
abnormalities is a key issue. For this purpose, now that
the utility of fMRI for studying pediatric populations is
established, functional brain imaging is a natural approach
for an integrative investigation of neurocognitive developmental disturbances associated with schizophrenia. This
requires validating activation tasks assessing neuropsychological domains of interest in healthy pediatric populations to have a model of the brain circuitry involved and
to test hypotheses about areas that may develop abnormally in schizophrenia.
One factor that is important to consider in selecting
tasks and neurocognitive domains to study is the degree to
which the neurophysiology of brain processes subserving
cognitive functions of interest is understood. Using tasks
such as cognitively demanding oculomotor paradigms, in
which the brain substrates of cognition have been extensively investigated in behaving primates and are thereby
understood in terms of biochemical processes and the time
course of task-relevant neuronal activity, can facilitate a
much more direct linkage of behavioral abnormalities to
their brain substrate. Although establishing normal developmental trends in cognitive domains of interest and clarifying normal patterns of neurodevelopmental trajectories
with fMRI are complex and consuming endeavors for conducting human in vivo studies of developmental dysmaturation in schizophrenia, achieving these aims will lay a firm
foundation for testing neurodevelopmental models of schizophrenia. This work may not only be important for testing
neurodevelopmental models of schizophrenia, but also may
450
help facilitate identification of new approaches for early
diagnosis, as well as identify individuals at risk and provide
preventive interventions for them.
References
Alexander, G.E., and Goldman, P.S. Functional development of the dorsolateral prefrontal cortex: An analysis utilizing reversible cryogenic depression. Brain Research,
143:233-249, 1978.
Armstrong, E.; Schleicher, A.; Omran, H.; Curtis, M ; and
Zilles, K. The ontogeny of human gyrification. Cerebral
Cortex, 5:56-63, 1995.
Benes, F.M. Myelination of cortical-hippocampal relays
during late adolescence. Schizophrenia
Bulletin,
15(4):585-593, 1989.
Benes, F.M. Brain development, VII: Human brain
growth spans decades. American Journal of Psychiatry,
155:1489,1998.
Benson, R.R.; Logan, W.; Cosgrove, G.; Cole, A.J.;
Jiang, H.; LeSueur, L.L.; Buchbinder, B.R.; Rosen, B.R.;
and Caviness, V.S. Functional MRI localization of language in a 9-year-old child. Canadian Journal of
Neurological Sciences, 23:213-219, 1996.
Bilder, R.M.; Goldman, R.S.; Robinson, D.; Reiter, G.
Bell, L.; Bates, J.A.; Pappadopulos, E.; Willson, D.F.
Alvir, J.M.J.; Woerner, M.G.; Geisler, S.; Kane, J.M.
and Lieberman, J.A. Neuropsychology of first-episode
schizophrenia: Initial characterization and clinical correlates. American Journal of Psychiatry, 157:549-559,
2000.
Bjorklund, D.F., and Harnishfeger, K.K. The resources
construct in cognitive development: Diverse sources of
evidence and a theory of inefficient inhibition.
Developmental Review, 10:48-71, 1990.
Case, R. The role of the frontal lobes in the regulation of
cognitive development. Brain and Cognition, 20:51-73,
1992.
Casey, B.J.; Cohen, J.D.; Jezzard, P.; Turner, R.; Noll,
D.C.; Trainor, R.J.; Giedd, J.; Kaysen, D.; HertzPannier, L.; and Rapoport, J.L. Activation of prefrontal
cortex in children during a nonspatial working memory
task with functional MRI. Neurolmage, 2:221-229,
1995.
Casey, B.J.; Trainor, R.J.; Orendi, J.L.; Schubert, A.B.;
Nystrom, L.E.; Giedd, J.N.; Castellanos, F.X.; Haxby,
J.V.; Noll, D.C.; Cohen, J.D.; Forman, S.D.; Dahl, R.E.;
and Rapoport, J.L. A developmental functional MRI
study of prefrontal activation during performance of a
go-no-go task. Journal of Cognitive
Neuroscience,
9:835-847, 1997.
Schizophrenia Bulletin, Vol. 27, No. 3, 2001
Studies of Brain and Cognitive Maturation
Caviness, V.S.; Kennedy, D.N.; Bates, J.F.; and Makris,
N. The developing human brain: A morphometric
profile. In: Thatcher, R.W.; Reid Lyon, G.; Rumsey, J.;
and Krasnegor, N.A., eds. Developmental Neuroimaging:
Mapping the Development of Brain and Behavior. New
York: Academic Press, 1996. pp. 3-14.
Diamond, A., and Taylor, C. Development of an aspect of
executive control: Development of the abilities to remember what I said and to "do as I say, not as I do."
Developmental Psychobiology, 29:315-334, 1996.
Everting, S.; Dorris, M.C.; Klein, R.M.; and Munoz, D.P.
Role of primate superior colliculus in preparation and
execution of anti-saccades and pro-saccades. Journal of
Neuroscience, 19:2740-2754, 1999.
Censits, D.M.; Ragland, J.D.; Gur, R.C.; and Gur, R.E.
Neuropsychological evidence supporting a neurodevelopmental model of schizophrenia: A longitudinal study.
Schizophrenia Research, 24:289-298, 1997.
Everling, S., and Munoz, D.P. Neuronal correlates for
preparatory set associated with pro-saccades and anti-saccades in the primate frontal eye field. Journal of
Neuroscience, 20:387^100, 2000.
Changeux, J.-R, and Danchin, A. Selective stabilization of
developing synapses as a mechanism for the specification
of neuronal networks. Nature, 264:705-712, 1976.
Chelune, G.J., and Baer, R.A. Developmental norms for
the Wisconsin card sorting test. Journal of Clinical and
Experimental Neuropsychology, 8:219-228, 1986.
Fischer, B.; Biscaldi, M.; and Gezeck, S. On the development of voluntary and reflexive components in
human saccade generation. Brain
Research,
754:285-297, 1997.
Chen, Y.; Palafox, G.R; Nakayama, K.; Levy, D.L.;
Matthysse, S.; and Holzman, P.S. Motion perception in
schizophrenia. Archives of General
Psychiatry,
56:149-154, 1999.
Fish, B.; Marcus, J.; Hans, S.L.; Auerbach, J.G.; and
Perdue, S. Infants at risk for schizophrenia: Sequelae of a
genetic neurointegrative defect. Archives of General
Psychiatry, 29:221-235, 1992.
Chugani, H.T. A critical period of brain development:
Studies of cerebral glucose utilization with PET.
Preventive Medicine, 27:184-188, 1998.
Franke, P.; Maier, W.; Hain, C ; and Klingler, T. Wisconsin
card sorting test: An indication or vulnerability to schizophrenia? Schizophrenia Research, 6:243-249, 1992.
Clementz, B.A.; McDowell, J.E.; and Zisook, S. Saccadic
system functioning among schizophrenia patients and
their first-degree biological relatives. Journal of Abnormal
Psychology, 103:277-287, 1994.
Fukushima, J.; Morita, N.; Fukushima, A.K.; Chiba, T.;
Tanaka, S.; and Yamashita, I. Voluntary control of saccadic eye movements in patients with schizophrenic and
affective disorders. Journal of Psychiatric Research,
24:9-24, 1990.
Cohen, J.D.; Barch, D.M.; Carter, C ; and ServanSchreiber, D. Context-processing deficits in schizophrenia: Converging evidence from three theoretically motivated cognitive tasks. Journal of Abnormal Psychology,
108:120-133, 1999.
Funahashi, S.; Bruce, C.J.; and Goldman-Rakic, P.S.
Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex. Journal of Neurophysiology,
61:331-349, 1989.
Fuster, J.M. The Prefrontal Cortex. New York: Raven
Press, 1997.
Gelenbe, E.; Feng, Y; and Krishnan, K.R.R. Neural network methods for volumetric magnetic resonance imaging
of the human brain. Proceedings
of the IEEE,
84:1488-1496, 1996.
Crawford, T.J.; Haeger, B.; Kennard, C ; Reveley, M.A.;
and Henderson, L. Saccadic abnormalities in psychotic
patients. I. Neuroleptic-free psychotic patients.
Psychological Medicine, 25:461^171, 1995.
Darby, D.G.; Nobre, A.C.; Thangaraj, V.; Edelman, R.;
Mesulam, M.M.; and Warach, S. Cortical activation in the
human brain during lateral saccades using EPISTAR functional magnetic resonance imaging. Neurolmage,
3:53-62, 1996.
Giedd, J.N.; Blumenthal, J.; Jeffries, N.O.; Castellanos,
F.X.; Liu, H.; Zijdenbos, A.; Paus, T.; Evans, A.C.; and
Rapoport, J.L. Brain development during childhood and
adolescence: A longitudinal MRI study. Nature
Neuroscience, 2:861-863,1999.
Dempster, F.N. Resistance to Interference: Developmental
changes in a basic processing mechanism. In: Howe,
M.L., and Pasnak, R., eds. Emerging Themes in Cognitive
Development,
Volume I: Foundations. New York:
Springer-Verlag, 1993. pp. 3-27.
Goldberg, T.E.; Hyde, M.; Kleinman, J.E.; and
Weinberger, D.R. Course of schizophrenia:
Neuropsychological evidence for a static encephalopathy.
Schizophrenia Bulletin, 19(4):797-804, 1993.
Diamond, A., and Goldman-Rakic, P.S. Comparison of
human infants and rhesus monkeys on Piaget's AB task:
Evidence for dependence on dorsolateral prefrontal cortex. Experimental Brain Research, 74:24-40, 1989.
Goldman-Rakic, P.S. Parallel systems in the cerebral
cortex: the topography of cognition. In: Arbib, M.A.,
and Robinson, J.A., eds. Natural and Artificial Parallel
451
Schizophrenia Bulletin, Vol. 27, No. 3, 2001
B. Luna and J.A. Sweeney
Computation.
New York: MIT Press, 1990. pp.
155-176.
Gordon, C.T.; Frazier, J.A.; McKenna, K.; Giedd, J.;
Zametkin, A.; Zahn, T.; Hommer, D.; Hong, W.; Kaysen,
D.; and Albus, K.E. Childhood-onset schizophrenia: An
NIMH study in progress. Schizophrenia
Bulletin,
20(4):697-712, 1994.
Hans, S.L.; Marcus, J.; Nuechterlein, K.H.; Asarnow,
R.F.; Styr, B.; and Auerbach, J.G. Neurobehavioral
deficits at adolescence in children at risk for schizophrenia: The Jerusalem infant development study. Archives of
General Psychiatry, 56:741-748, 1999.
Hertz-Pannier, L.; Gaillard, W.D.; Mott, S.H.; Cuenod,
C.A.; Bookheimer, S.Y.; Weinstein, S.; Conry, J.; Papero,
P.H.; Schiff, S.J.; Le Bihan, D.; and Theodore, W.H.
Noninvasive assessment of language dominance in children and adolescents with functional MRI: A preliminary
study. Neurology, 48:1003-1012, 1997.
Keshavan, M.S.; Anderson, S.; and Pettegrew, J.W. Is
schizophrenia due to excessive synaptic pruning in the
prefrontal cortex? The Feinberg hypothesis revisited.
Journal of Psychiatric Research, 28:239-265, 1994.
Keshavan, M.S.; Pettegrew, J.W.; Panchalingam, K.S.;
Kaplan, D.; and Bozik, E. Phosphorus 31 magnetic resonance spectroscopy detects altered brain metabolism
before onset of schizophrenia. Archives of General
Psychiatry, 48:1112-1113, 1991.
Kim, S.G.; Ugurbil, K.; and Strick, PL. Activation of a
cerebellar output nucleus during cognitive processing.
Science, 265:949-951, 1994.
Klingberg, T.; Vaidya, C.J.; Gabrieli, J.D.E.; Moseley,
M.E.; and Hedehus, M. Myelination and organization of
the frontal white matter in children: A diffusion tensor
MRI study. Neuroreport, 10:2817-2821, 1999.
Leigh, R.J., and Zee, D.S. The Neurology of Eye
Movements. New York: Oxford University Press, 1999.
Hikosaka, O., and Wurtz, R.H. Visual and oculomotor
functions of monkey substantia nigra pars reticulata. III.
Memory-contingent visual and saccade responses.
Journal of Neurophysiology, 49:1268-1284, 1983.
Hoff, A.L.; Riordan, H.; O'Donnell, D.W.; Morris, L.; and
Delisi, L.E. Neuropsychological functioning of firstepisode schizophreniform patients. American Journal of
Psychiatry, 149:898-903, 1992.
Hudspeth, W.J., and Pribram, K.H. Stages of brain and
cognitive maturation. Journal of Educational Psychology,
82:881-884, 1990.
Huttenlocher, PR. Morphometric study of human cerebral
cortex development. Neuropsychologia, 28:517-527, 1990.
Hyde, T.M.; Ziegler, J.C.; and Weinberger, D.R.
Psychiatric disturbances in metachromatic leukodystrophy. Archives of Neurology, 49:401-406, 1992.
Jernigan, T.L.; Trauner, D.A.; Hesselink, J.R.; and Tallal,
P.A. Maturation of human cerebrum observed in vivo during adolescence. Brain, 114:2037-2049, 1991.
Levin, H.S.; Culhane, K.A.; Hartmann, J.; Evankovich,
K.; and Mattson, A.J. Developmental changes in performance on tests of purported frontal lobe functioning.
Developmental Neuropsychology, 7:377-395, 1991.
Levy, D.L., and Holzman, PS. Eye tracking dysfunction
and schizophrenia: An overview with special reference to
the genetics of schizophrenia. International Review of
Psychiatry, 9:365-371, 1997.
Levy, D.L.; Mendell, N.R.; LaVancher, C.A.; Brownstein,
J.; Krastoshevsky, O.; Teraspulsky, L.; McManus, K.S.;
Lo, Y.; Bloom, R.; Matthysse, S.; and Holzman, P S .
Disinhibition in antisaccade performance in schizophrenia. In: Lenzenweger, M.F., and Dworkin, R.H., eds.
Origins and Development of Schizophrenia: Advances in
Experimental Psychopathology. American Psychological
Association Press, 1998. pp. 185-210.
Lewis, D.A. Development of the prefrontal cortex during
adolescence: Insights into vulnerable neural circuits in
schizophrenia. Neuropsychopharmacology, 16:385-398,
1997.
Katsanis, J.; Iacono, W.G.; and Harris, M. Development
of oculomotor functioning in preadolescence, adolescence, and adulthood. Psychophysiology, 35:64-72, 1998.
Katsanis, J.; Kortenkamp, S.; Iacono, W.G.; and Grove,
W.M. Antisaccade performance in patients with schizophrenia and affective disorder. Journal of Abnormal
Psychology, 106:468-472, 1997.
Luciana, M., and Nelson, C. The functional emergence of
prefrontally-guided working memory systems in four- to
eight-year-old children. Neuropsychologia, 36:273-293,
1998.
Kennard, C , and Rose, F.C. Physiological Aspects of
Clinical Neuro-ophthalmology.
Chicago: Year Book
Medical Publishers, Inc., 1988.
Luna, B.; Garver, K.E.; and Sweeney, J.A. Development
in cognitive and sensorimotor systems from late childhood to adulthood. Proceedings of the 30th Annual
Meeting of the Society for Neuroscience; 2000 Nov 4—9th,
New Orleans, LA., 1338, 2000.
Kennedy, D.N.; Lange, N.; Makris, N.; Bates, J.; Meyer,
J.; and Caviness, V.S. Gyri of the human neocortex: An
MRI-based analysis of volume and variance. Cerebral
Cortex, 8:373-384, 1998.
Luna, B., and Sweeney, J.A. Cognitive functional magnetic resonance imaging at very-high-field: Eye movement control. Topics in Magnetic Resonance Imaging,
10:3-15, 1999.
452
Studies of Brain and Cognitive Maturation
Schizophrenia Bulletin, Vol. 27, No. 3, 2001
Petit, L.; Clark, V.P.; Ingeholm, J.; and Haxby, J.V.
Dissociation of saccade-related and pursuit-related activation in human frontal eye fields as revealed by fMRI.
Journal of Neurophysiology, 77:3386-3390, 1997.
Luna, B.; Thulborn, K.R.; Munoz, D.P.; Merriam, E.P.;
Garver, K.E.; Minshew, N.J.; Keshavan, M.S.; Genovese,
C.R.; Eddy, W.F.; and Sweeney, J.A. Maturation of widely
distributed brain function subserves cognitive development. Neurolmage, 13:786-793, 2001.
Pfefferbaum, A.; Mathalon, D.H.; Sullivan, E.V.; Rawles,
J.M.; Zipursky, R.B.; and Lim, K.O. A quantitative magnetic resonance imaging study of changes in brain morphology from infancy to late adulthood. Archives of
Neurology, 51:874-887, 1994.
Luna, B.; Thulborn, K.R.; Strojwas, M.H.; McCurtain,
B.J.; Berman, R.A.; Genovese, C.R.; and Sweeney, J.A.
Dorsal cortical regions subserving visually-guided saccades in humans: An fMRI study. Cerebral Cortex,
8:40-47, 1998.
Pfefferbaum, A.; Sullivan, E.V.; Hedehus, M.; Lim, K.O.;
Adalsteinsson, E.; and Moseley, M. Age-related decline in
brain white matter anisotropy measured with spatially
corrected echo-planar diffusion tensor imaging. Magnetic
Resonance in Medicine, 44:259-268, 2000.
Marcus, J.; Hans, S.L.; Auerbach, J.G.; and Auerbach,
A.G. Children at risk for schizophrenia: The Jerusalem
infant development study. Archives of General Psychiatry,
50:797-809,1993.
Matsue, Y.; Saito, H.; Osakabe, K.; Awata, S.; Ueno, T;
Matsuoka, H.; Chiba, H.; Fuse, Y.; and Sato, M. Smooth
pursuit eye movements and voluntary control of saccades
in the antisaccade task in schizophrenic patients. Japanese
Journal of Psychiatry and Neurology, 48:13-22, 1994.
Pierrot-Deseilligny, C. Cortical control of saccades in
man. Acta Neurologica Belgica, 91:63-79, 1991.
Merriam, E.P.; Thase, M.E.; Haas, G.L.; Keshavan, M.S.;
and Sweeney, J.A. Prefrontal cortical dysfunction in
depression determined by Wisconsin Card Sorting Test
38:94-109, 1968.
performance. American Journal of
Pollack, M.; Levenstein, S.; and Klein, D.F. A three-year
posthospital follow-up of adolescent and adult schizo-
phrenics. American Journal of
Orthopsychiatry,
Rademacher, J.; Caviness, V.S.; Steinmetz, H.; and
Galaburda, A.M. Topographical variation of the human
primary cortices: Implications for neuroimaging, brain
mapping, and neurobiology. Cerebral Cortex, 3:313-329,
1993.
Psychiatry,
156:780-782, 1999.
Middleton, FA., and Strick, PL. Cerebellar output: Motor
and cognitive channels. Trends in Cognitive Sciences,
2:348-353, 1998.
Ridderinkhof, K.R., and van der Molen, M.W. Mental
resources, processing speed, and inhibitory control: A
developmental perspective. Biological
Psychology,
45:241-261, 1997.
Miller, L.K. Eye-movement latency as a function of age,
stimulus uncertainty, and position in the visual field.
Perceptual and Motor Skills, 28:631-636, 1969.
Riley, E.M.; McGovern, D.; Mockler, D.; Doku, V.C.K.;
O'Ceallaigh, S.; Fannon, D.G.; Tennakoon, L.;
Santamaria, M.; Soni, W.; Morris, R.G.; and Sharma, T.
Neuropsychological functioning in first-episode psychosis—evidence of specific deficits. Schizophrenia
Research, 43:47-55, 2000.
Munoz, D.P.; Broughton, J.; Goldring, J.; and Armstrong,
I. Age-related performance of human subjects on saccadic
eye movement tasks. Experimental Brain Research,
217:1-10, 1998.
O'Driscoll, G.A.; Alpert, N.M.; Matthysse, S.W.; Levy,
D.L.; Rauch, S.L.; and Holzman, P S . Functional neuroanatomy of antisaccade eye movements investigated
with positron emission tomography. Proceedings of the
National Academy of Sciences of the United States of
America, 92:925-929, 1995.
Robbins, T.W. The case for frontostriatal dysfunction in
schizophrenia. Schizophrenia Bulletin, 16(3):391-402,
1990.
Rosenberg, D.R.; Averbach, D.H.; O'Hearn, K.O.;
Seymour, A.B.; Birmaher, B.; and Sweeney, J.A.
Oculomotor response inhibition abnormalities in pediatric
obsessive compulsive disorder. Archives of General
Psychiatry, 54:831-838, 1997.
Park, S., and Holzman, PS. Schizophrenics show spatial
working memory deficits. Archives of General Psychiatry,
49:975-982, 1992.
Park, S.; Holzman, PS.; and Goldman-Rakic, PS. Spatial
working memory deficits in the relatives of schizophrenic
patients. Archives of General Psychiatry, 52:821-828,
1995.
Ross, R.G.; Radant, A.D.; and Hommer, D.W. A developmental study of smooth pursuit eye movements in normal
children from 7 to 15 years of age. Journal of the
American Academy of Child and Adolescent Psychiatry,
32:783-791, 1993.
Paus, T; Babenko, V.; and Radii, T. Development of an
ability to maintain verbally instructed central gaze fixation studied in 8 to 10 year old children. International
Journal of Psychophysiology, 10:53-61, 1990.
Ross, R.G.; Radant, A.D.; Young, D.A.; and Hommer,
D.W. Saccadic eye movements in normal children from 8
to 15 years of age: A developmental study of visuospatial
453
Schizophrenia Bulletin, Vol. 27, No. 3, 2001
B. Luna and J.A. Sweeney
attention. Journal of Autism and Developmental
Disorders, 24:413-431, 1994.
Rosse, R.B.; Schwartz, B.L.; Kim, S.Y.; and Deutsch, S.I.
Correlation between antisaccade and Wisconsin Card
Sorting Test performance in schizophrenia. American
Journal of Psychiatry, 150:333-335, 1993.
Rubia, K.; Overmeyer, S.; Taylor, E.; Brammer, M.;
Williams, S.C.R.; Simmons, A.; Andrew, C ; and
Bullmore, E.T. Functional frontalisation with age:
Mapping neurodevelopmental trajectories with fMRI.
Neuroscience and Biobehavioral Reviews, 24:13-19,
2000.
Rubin, P.; Holm, A.; Moller-Madsen, S.; Videbech, P.;
Hertel, C ; Povlsen, U.J.; and Hemmingsen, R.
Neuropsychological deficit in newly diagnosed patients
with schizophrenia or schizophreniform disorder. Ada
Psychiatrica Scandinavica, 92:35^3, 1995.
Sweeney, J.A.; Luna, B.; Haas, G.L.; Keshavan, M.S.;
Mann, J.J.; and Thase, M.E. Pursuit tracking impairments
in schizophrenia and mood disorders: Step-ramp studies
with unmedicated patients. Biological
Psychiatry,
46:671-680, 1999.
Sweeney, J.A.; Luna, B.; Srinivasagam, N.M.; Keshavan,
M.S.; Schooler, N.R.; Haas, G.L.; and Carl, J.R. Eye
tracking abnormalities in schizophrenia: Evidence for
dysfunction in the frontal eye fields. Biological
Psychiatry, 44:698-708, 1998.
Sweeney, J.A.; Mintun, M.A.; Kwee, S.; Wiseman, M.B.;
Brown, D.L.; Rosenberg, D.R.; and Carl, J.R. A positron
emission tomography study of voluntary saccadic eye
movements and spatial working memory. Journal of
Neurophysiology, 75:454-468, 1996.
Thaker, G.K.; Cassady, S.; Adami, H.; Moran, M.; and
Ross, D.E. Eye movements in spectrum personality disorders: Comparison of community subjects and relatives of
schizophrenic patients. American Journal of Psychiatry,
153:362-368, 1996.
Rund, B.R. A review of longitudinal studies of cognitive
functions in schizophrenia patients. Schizophrenia
Bulletin, 24(3):425-435, 1998.
Sawaguchi, T., and Goldman-Rakic, P.S. Dl dopamine
receptors in prefrontal cortex: Involvement in working
memory. Science, 251:947-950, 1991.
Saykin, A.J.; Gur, R.C.; Gur, R.E.; Mozley, P.D.; Mozley,
L.H.; Resnick, S.M.; Kester, D.B.; and Stafiniak, P.
Neuropsychological function in schizophrenia: A selective
impairment in memory and learning. Archives of General
Psychiatry, 48:618-624, 1991.
Selemon, L.D., and Goldman-Rakic, P.S. The reduced
neuropil hypothesis: A circuit based model of schizophrenia. Biological Psychiatry, 45:17-25, 1999.
Sowell, E.R., and Jernigan, T.L. Further MRI evidence of
late brain maturation: Limbic volume increases and
changing asymmetries during childhood and adolescence.
Developmental Neuropsychology, 14:599-617, 1998.
Thatcher, R.W. Maturation of the human frontal lobes:
Physiological evidence for staging. Developmental
Neuropsychology, 7:397^19, 1991.
Thomas, K.M.; King, S.W.; Franzen, PL.; Welsh, T.F.;
Berkowitz, A.L.; Noll, D.C.; Birmaher, V.; and Casey, B.J.
A developmental functional MRI study of spatial working
memory. Neurolmage, 10:327-338, 1999.
Thompson, P.M.; Giedd, J.N.; Woods, R.P.; MacDonald,
D.; Evans A.C.; and Toga, A.W. Growth patterns in the
developing brain detected by using continuum mechanical
tensor maps. Nature, 404:190-193, 2000.
Vaidya, C.J.; Austin, G.; Kirkorian, G.; Ridlehuber,
H.W.; Desmond, J.E.; Glover, G.H.; and Gabrieli,
J.D.E. Selective effects of methylphenidate in attention
deficit hyperactivity disorder: A functional magnetic
resonance study. Proceedings of the National Academy
of Sciences of the United States of America,
95:14494-14499, 1998.
Staal, W.G.; Hijman, R.; Pol, H.E.H.; and Kahn, R.S.
Neuropsychological dysfunctions in siblings discordant for
schizophrenia. Psychiatry Research, 95:227-235, 2000.
Stapleton, S.; Kiriakopoulos, E.; Mikulis, D.; Drake, J.;
Hoffman, H.; Humphreys, R.; Hwang, P.; Otsubo, H.;
Holowka, S.; Logan, W.; and Rutka, J. Combined utility
of functional MRI, cortical mapping, and frameless
stereotaxy in the resection of lesions in eloquent areas of
brain in children. Pediatric Neurosurgery, 26:68-82,
1997.
Waddington, J.L.; Torrey, E.F.; Crow, T.J.; and Hirsch,
S.R. Schizophrenia, neurodevelopment and disease.
Archives of General Psychiatry, 48:271-273, 1991.
Weinberger, D.R.; Berman, K.F.; and Zee, R.F.
Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia: I. Regional cerebral blood flow evidence. Archives of General Psychiatry, 43:114-124, 1986.
Weinberger, D.R., and Lipska, B.K. Cortical maldevelopment, anti-psychotic drugs, and schizophrenia: A search for
common ground. Schizophrenia Research, 16:87-110,1995.
Strick, PL. How do the basal ganglia and cerebellum gain
access to the cortical motor areas? Behavioural Brain
Research, 18:107-123, 1985.
Stuss, D.T. Biological and psychological development of
executive function. Brain and Cognition, 20:8-23, 1992.
Welsh, M.C.; Pennington, B.F.; and Groisser, D.B. A normative-developmental study of executive function: A win-
454
Schizophrenia Bulletin, Vol. 27, No. 3, 2001
Studies of Brain and Cognitive Maturation
our colleagues Matcheri Keshavan, Gretchen Haas, and
David Lewis, with whom we discussed relevant ideas on
multiple occasions and conducted studies related to ideas
developed in this article.
dow on prefrontal function in children. Developmental
Neuropsychology, 7:131-149, 1991.
Wilson, S.P., and Kipp, K. The development of efficient
inhibition: Evidence from directed-forgetting tasks.
Developmental Review, 18:86-123, 1998.
The Authors
Yakovlev, P.I., and Lecours, A.R. Regional Development of
the Brain in Early Life. Oxford: Blackwell Scientific, 1967.
Beatriz Luna, Ph.D., is Assistant Professor of Psychiatry,
University of Pittsburgh School of Medicine, Western
Psychiatric Institute and Clinic, Neurobehavioral Studies
Program, Pittsburgh, PA. John A. Sweeney, Ph.D., is
Professor of Psychiatry, Neurology, and Psychology;
University of Illinois at Chicago; School of Medicine;
Neurocognitive Assessment and Brain Imaging Program;
Chicago, IL.
Acknowledgments
Supported by MH42969, MH01433, MH01727,
MH45156, MH62134, HD35469, NS35949, and the
National Alliance for Research on Schizophrenia and
Depression. We would also like to express appreciation to
455