It is hypothesized that
adolescent development involves a redistribution of cerebral functions
from lower subcortical structures to higher regions of the prefrontal
cortex to provide greater self-control over emotional behavior. We
further hypothesized that this redistribution is likely to be moderated
by sex-specific hormonal changes. To examine developmental sex
differences in affective processing, 19 children and adolescents
underwent fMRI while viewing photographs of faces expressing fear.
Males and females differed in the pattern of their amygdala vs
prefrontal activation during adolescent maturation. With age, females
showed a progressive increase in prefrontal relative to amygdala
activation in the left hemisphere, whereas males failed to show a
significant age related difference. There appear to be sex differences
in the functional maturation of affect-related prefrontal–amygdala
circuits during adolescence.
Emotional experience is
regulated by an integrated functional system that includes the
neocortex and numerous subcortical limbic nuclei. Of these structures,
the amygdala has consistently emerged as one of the most critical for
ascribing emotional significance to stimuli and influencing affective
responsiveness and emotional learning [1,2].
Neuroimaging studies of adults have shown that the amygdala often
produces increased activation during the perception of fearful facial
expressions [3,4]. Furthermore, a recent fMRI study by Hariri and colleagues 
suggests that the prefrontal cortex, particularly on the right, may
provide humans with the capacity to modulate emotional responses by
attenuating activity within the amygdalae. In contrast to the growing
literature on the neurobehavioral processing of affect in adults, there
is relatively little information available regarding the development of
emotional circuits during maturation from childhood through the
adolescent years. The transitional period of puberty involves
significant changes in physical and cognitive functioning, which are
paralleled by equally striking transformations in affective processing.
Normal adolescent development involves a shift from characteristically
childlike emotional reactions toward greater self-regulation, social
awareness, and the capacity for voluntary modification of emotional
displays. During adolescent maturation, there is a progressive increase
in myelinated axonal projections to the prefrontal lobes [6–8],
consistent with evidence that the prefrontal lobes are generally among
the latest cerebral structures to reach full development .
Recent neuroimaging studies have demonstrated that maturation during
the adolescent period is mirrored by age-related increases in
functional activation within the frontal lobes .
These findings suggest that adolescent maturation may involve a
developmental transition within the brain whereby executive control is
transferred from immature subcortical systems to frontal lobe cortical
networks characteristic of the adult brain, particularly within the
left prefrontal cortex.
Our understanding of the
development of the adolescent brain is complicated by the fluctuations
of reproductive hormones that may result in sexually dimorphic cerebral
structure and function .
Structural neuroimaging studies have shown that by early adolescence,
the brains of males and females show significant morphological
differences. In particular, adolescent females have disproportionately
larger volumes of the hippocampus, pallidum, and caudate but have
significantly smaller amygdala volumes compared to males , while males show significantly greater growth of the left amygdala relative to females during adolescence .
By adulthood, females appear to have a significantly larger percentage
of gray matter within the dorsolateral prefrontal cortex relative to
males . It is likely that
such structural dimorphism is manifested in differences in behavior
between the sexes. One of the most well documented sex differences in
behavior is the consistent finding that males display more frequent and
severe aggressive behavior than females, particularly during the
adolescent and young adult years .
Thus, a comprehensive model of frontal-subcortical development of
affective processing must account for the sex differences observed in
emotional behavior and brain structure.
In general, while maturation
affords the individual greater control over emotional behavior, the
neurobiological processes that underlie this regulatory capacity and
their developmental sequence are not fully understood. One possibility
is that with maturational development, the prefrontal cortex acquires a
greater capacity to modulate the activity of the subcortical circuits
involved in emotional processing. While this hypothesis appears to be
supported in a recent study of adults ,
it has not been examined developmentally. To test this hypothesis,
children and adolescents were presented with a facial affect perception
task while undergoing fMRI. We hypothesized that chronological age
would be associated with a progressive increase in frontal modulation
of amygdala activity as evidenced by relatively increased activation
within the dorsolateral prefrontal cortex (DLPFC) and decreased
activation within the amygdala. Furthermore, given the known behavioral
and morphometric differences within the amygdala of males and females,
we expected that these effects would be moderated by sex.
MATERIALS AND METHODS
Participants included 19
healthy children and adolescent volunteers (13 right- and six
left-handed by self-report), ranging in age from 9 to 17 years (mean (±
s.d.) 13.5 ± 2.1). The sample included nine males and 10 females, all
of whom were provided monetary compensation for participation. The
subjects had no known history of psychiatric illness or severe medical
problems, and all had normal visual acuity. All subjects and their
parents or guardian(s) provided written informed consent prior to
participation in the study.
Functional neuroimaging data
were collected on a 1.5 T GE Signa MRI scanner (General Electric
Systems, Milwaukee, WI) equipped with a whole-body echo-planar imaging
system (Advanced NMR, Inc., Wilmington, MA) and a quadrature head coil.
BOLD contrast images were acquired using an echo-planar gradient echo
pulse sequence (TR = 3 s, TE = 40 ms. For functional imaging, 50
sequential images were collected in each of 12 axial slices of 6 mm
thickness, with a 64 × 128 acquisition matrix, and an in-plane
resolution of 3 × 3 mm. Head movement was restricted by comfortable
placement of foam padding around the head.
Fearful face activation paradigm:
Visual stimuli consisted of six fearful faces selected from the stimulus set of Ekman and Friesen .
Face stimuli were generated on a Macintosh computer and were projected
onto a translucent screen placed at the subject's feet using a
magnetically shielded LCD video projector. The screen was visible via a
mirror mounted to the head coil. Each 150 s scanning sequence consisted
of five alternating 30 s stimulus/rest periods. The experimental
paradigm has been used previously and is described in greater detail
elsewhere . During baseline
and rest periods, subjects were asked to visually fixate on a small
white circle located in the center of the screen. Each stimulus period
presented three face photographs. In order to assess participation, all
subjects were asked to report the affect displayed following each
Image processing and analysis:
All images were corrected for in-plane and translational motion .
Matched T1 axial images were inspected to determine the single slice
for each subject that included the largest area of both amygdala.
Regions of interest (ROIs) for each amygdala were selected with
reference to an anatomic atlas .
Each ROI was comprised of four pixels, each pixel 3 × 3 mm, sampled
from one axial slice, and placements were made based on gyral
boundaries and structural landmarks visible on MR images. The amygdala
ROI's were placed in medial aspects of the amygdala on an axial slice
that included the subcallosal area (Brodmann's area 25) and the
inferior regions of the middle and superior temporal gyrus (see Fig. 1,
left). Two ROI's were placed in the dorsolateral prefrontal cortex
(Brodmann's areas 46 and 9), localized anterior to the cingulate cortex
at the approximate level of the genu of the corpus collosum (see Fig. 1, right).
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Axial slices acquired in a 14-year-old female subject illustrating
relative changes in signal intensity during the viewing of fearful
facial affect. Left: activation of the left and right amygdala. Right:
activation in left and right dorsolateral prefrontal cortex (DLPFC)
regions of interest.
Measures of signal intensity
were derived by averaging the MR signal measured in all pixels in each
ROI for each time point during the task activation period. The MR
signal was then normalized to each subject's baseline average, derived
from the mean of the first seven images, and converted into a metric
representing the percent change in MR signal from baseline. Signal
responses were averaged for the two activation periods for each ROI. To
determine the relationship between developmental maturation and
amygdala activity, the mean increase in MR signal during the viewing of
the fearful faces was correlated with age for each ROI separately using
a Pearson product-moment correlation.
Age and amygdala activation:
presents the scatterplots showing the relationship between
chronological age and the percentage change in MR signal for the left
and right amygdala separately. As evident from Fig. 2a,
chronological age and BOLD signal change were negatively associated,
indicating a decrease in functional activation within the left amygdala
as age increased from late childhood through adolescence (r = -0.45, p = 0.05). In contrast, it is clear from the scatterplot in Fig. 2b
that there was no significant linear relationship between chronological
age and MR signal change within the right amygdala (r = -0.04, p = 0.89).
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Fig. 2. Correlations between chronological age and normalized signal intensity for the amygdala. Scatter-plots for the total sample (n = 19) show a significant correlation between age and activation in the (a) left amygdala (r = -0.45, p = 0.05), but not for the (b)
right amygdala (r = -0.04, ns). When examined separately by sex, males
did not demonstrate a significant correlation between age and signal
intensity in either the (c) left (r = -0.39, ns) or (d) right amygdala (r = -0.04, ns), but females showed a significant correlation for the (e) left (r = -0.63, p = 0.05), but not (f) right amygdala (r = 0.12, ns).
The relationship between age
and amygdala activation was further explored by conducting separate
analyses by gender. For male participants, there was no significant
association between chronological age and signal intensity within
either the left (r = -0.39, p = 0.30) or right (r = -0.04, p
= 0.93) amygdala. In contrast, female participants demonstrated a
significant negative correlation between chronological age and signal
intensity within the left (r = -0.63, p
= 0.05), but not the right (r = 0.12, p = 0.75) amygdala. When the
magnitudes of the correlations were compared across gender using
Fisher's r-to-z transformation, the two groups did not differ
significantly for either the right or the left amygdala.
Age and DLPFC activation:
The correlation plots between chronological age and DLPFC activation are presented in Fig. 3.
When DLPFC activation was considered for each hemisphere individually,
there was no significant relationship between chronological age and
left (r = 0.28, p = 0.25) or right (r = 0.17, p = 0.48) prefrontal cortical activation.
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Fig. 3. Correlations between chronological age and normalized signal intensity for the DLPFC. Data for the combined sample (n = 19) did not reveal a significant correlation between age and activation in the (a) left DLPFC (r = 0.28, ns) or (b)
right DLPFC (r = 0.17, ns). However, when examined separately by sex,
males demonstrated a significant correlation between age and signal
intensity in the (c) left (r = -0.67, p = 0.05), but not the (d)
right DLPFC (r = 0.49, ns). Females, in contrast, showed a
non-significant trend toward increased activation of the DLPFC with age
for the (e) left (r = 0.54, p = 0.11), but not the (f) right (r = 0.13, ns).]
When male subjects were
analyzed independently, there emerged a significant negative
correlation between age and signal intensity within the left DLPFC (r =
-0.67, p = 0.05). Activation within
the right prefrontal cortex was not significantly associated with age
in the sample of males (r = 0.49, p = 0.18). In contrast, female subjects showed a non-significant trend toward greater left DLPFC with age (r = 0.54, p = 0.11), while no significant association was evident within the right DLPFC (r = 0.13, p
= 0.72). Correlations between chronological age and DLPFC signal
intensity were significantly different in magnitude between males and
females on the left (z = 2.54, p = 0.01), but not on the right (z = 0.73, p = 0.47).
Age and DLPFC–amygdala difference:
To examine the relationship
between frontal and amygdala activity during adolescent brain
development, we subtracted the normalized signal intensity of the
amygdala from the signal intensity of the ipsilateral DLPFC of each
hemisphere to yield a difference score. As evident in Fig. 4a, the left DLPFC–left amygdala difference score for the total sample correlated significantly with chronological age (r = 0.56, p
= 0.01), indicating a progressive age-related disparity between
relatively greater activation within the left prefrontal region and
decreased activation within the left amygdala over the adolescent
years. In contrast, Fig. 4b shows that the right DLPFC–right amygdala difference score was not significantly related to chronological age (r = 0.16, p = 0.50).
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Correlations between chronological age and the difference score between
the ipsilateral DLPFC-amygdala signal intensity. Overall, for the
combined sample (n = 19), there was a significant correlation between the DLPFC–amygdala difference on the (a) left (r = 0.56, p = 0.01), but not for the (b)
right (r = 0.16, ns). For males considered as a group, there was no
significant correlation between age and DLPFC–amygdala difference
scores for the (c) left (r = -0.43, ns) or the (d)
right (r = 0.40, ns). Females, in contrast, showed a significant
correlation between the DLPFC-amygdala difference score on the (e) left (r = 0.73, p = 0.02), but not the (f) right (r = 0.08, ns).
We evaluated the relationship
between age and the DLPFC–amygdala difference scores separately by
gender. In the sample of males, the difference between DLPFC and
amygdala did not correlate significantly with age for either the left
(r =s-0.43, p = 0.25) or the right (r = 0.40, p
= 0.29) hemisphere. Similar analyses for the females, in contrast,
yielded a significant association between chronological age and the
DLPFC-amygdala difference score for the left (r = 0.73, p = 0.02) but not the right (r = 0.08, p
= 0.83) hemisphere. Again, comparison of the magnitude of correlations
obtained for males and females revealed a significant difference
between genders on the left (z = 2.50, p = 0.01) but not on the right (z = 0.62, p = 0.54).
The present results suggest
that there are functional changes within the amygdala and DLPFC during
the perception of affective facial stimuli that correlate with
maturational development during adolescence. In our child and
adolescent sample as a whole, greater chronological age was associated
with decreased functional activation of the left amygdala during the
viewing of photographs of faces expressing fearful affect. Further
analyses revealed that this relationship reached statistical
significance only for the females. In contrast, activation within the
right amygdala was not linearly related to chronological age for either
sex. These findings complement other studies of adolescents  and adults [3,4]
that find activation within the amygdala in response to fearful faces.
Our results further suggest that maturational development is associated
with a decline in left amygdala responsiveness to fearful affective
expressions. These findings are consistent with our initial hypothesis
that age-related maturation would be associated with progressively
greater modulation of amygdala activation by the prefrontal cortex.
While we expected that the
modulation of amygdala activation would result in greater activation
within the prefrontal region for the sample as a whole ,
we were also interested in examining the potential moderating effects
of gender on the development of these affect-related circuits. We found
that males and females demonstrated significantly different
trajectories of left DLPFC responsiveness over the adolescent period.
Although females demonstrated a non-significant trend toward greater
left DLPFC activation with increasing age, the trajectory for the males
was reversed, with reduced left DLPFC signal intensity associated with
greater age. The difference in the observed trajectories between the
males and females was significant and suggests that adolescent
maturation may involve sexually dimorphic development of prefrontal
cortex-amygdala circuits involved in affective processing. The sexually
dissociated trajectories in functional activity that we observed are
likely to be related to the responsiveness of these structures to
sex-specific hormones during adolescent development [6,12].
As we have recently reported ,
the identification of facial affect requires the ability to extract
visuospatial and figural information, as well as the ability to
concentrate, attend, and recall affective categories presented. The
challenge paradigms in the current study are therefore dependent on
both emotional and cognitive processing, making it impossible to
isolate a single component function that may be responsible for the
activation differences observed. However, studies describing the
neurobiologic correlates of emotional processing have highlighted
attentional components including orienting, response choice and
sustained attention suggesting that the differences in affective
processing seen in the current study may in part be due to differences
in attentional capacity or strategy between males and females. This
interpretation is supported by recent studies that have reported sex
differences in visual attention, vigilance and boredom [20,21].
It has been hypothesized that
maturation into adulthood involves a progressive frontalization of
cognitive and emotional regulation .
This perspective suggests that as the adolescent child develops, the
prefrontal lobes gain progressively greater inhibitory control over
emotional responses involving the amygdala and other limbic structures [5,19,22].
Our data suggest, however, that developmental redistribution of
cerebral functions may occur differently for males and females. With
age, the relative activation of the amygdala within the female sample
became progressively lower than that of the DLPFC. This relationship
was reversed in the males, indicating that greater age was associated
with a trend toward less prefrontal relative to amygdala activation.
The present findings suggest that during adolescence, males and females
demonstrate divergent neurobiological strategies in the processing of
fearful facial affect.
The left-lateralized nature of
the maturational change is also noteworthy, as it raises the
possibility of differential affective functioning of the amygdalae. Our
findings are also in accord with electroencephalographic studies of
frontal asymmetry patterns that find left frontal hypoactivation to be
associated with negative affect or withdrawal related emotion 
and relative increased left frontal activation to be associated with
positive or approach related emotions and a reduced risk of
psychopathology . Other
functional neuroimaging studies have found greater left amygdala
responsiveness during facial perception and encoding tasks , particularly those involving affective processes [26,27].
Studies using PET have shown increased left amygdala metabolism in
family history positive depressive patients when tested during a
euthymic state . There is
also some evidence that affective disorders may involve a disinhibition
of the left amygdala by dysfunctional modulatory systems [19,28].
Thus, negative affective processing is often associated with increased
left amygdala activation, and reduced left prefrontal activation.
Given that our results are
preliminary and were obtained with a relatively small sample,
conclusions based on these findings must be viewed as tentative until
replicated with larger groups of subjects. Future studies would benefit
from the inclusion a comparison group of adults so that the trajectory
of amygdala response may be examined beyond the adolescent years.
Secondly, functional imaging studies have consistently shown that the
amygdala rapidly habituates to affective stimuli, resulting in reduced
BOLD signal in studies that employ a blocked stimulus presentation
paradigm [3,29]. As our study
included a blocked presentation, we may have minimized our ability to
detect amygdala activation, and future studies may benefit from the use
of event related designs. Another potential limitation was that the
ROIs used in the present study were limited to four pixels selected
from a single coronal slice for each region. It is therefore possible
that some regions that are critical for emotional regulation and
processing were not adequately sampled. We believe, however, that the
sampling of individual ROIs within each individual is the most
anatomically correct approach given the age related differences in
brain sizes across our sample. Finally, our challenge task was designed
specifically to activate the amygdala and not the DLPFC. Future studies
should use multiple tasks that separately activate amygdala and DLPFC
in order to provide converging evidence of developmental changes in the
activation of each region.
The present data suggest that
the left amygdala responds to affective photographs of fearful facial
stimuli in children and adolescents, but further suggests that the
amount of activation decreases across the adolescent maturational
period. Moreover, the decrease in amygdala activity was moderated by
sex, with only females showing a significant decline over the
adolescent period. In addition, over the adolescent period, there is a
sex-dependent change in the degree of DLPFC activity, with females
showing a progressive increase, and males a progressive decrease in
left prefrontal signal intensity. Overall, females show a trend toward
greater responsiveness of the prefrontal lobes relative to the amygdala
with maturation, while males demonstrate the reverse pattern with age.
These findings support a developmental model whereby cerebral
maturation is associated with progressively greater control over
emotional behavior via prefrontal cortical systems that modulate lower
limbic responses, but further suggest that the rate of development of
this affective system and the ultimate expression of emotional behavior
may be significantly influenced by sex-specific developmental factors.
1. Davis M. J Neuropsychiatry Clin Neurosci 1997 9, 382–402. [Context Link]
2. LeDoux J. The Emotional Brain. New York: Simon and Shuster; 1996. [Context Link]
3. Breiter HC, Etcoff NL, Whalen PJ. et al. Neuron 1996 17, 875–887. [Context Link]
4. Morris JS, Frith CD, Perrett DI. et al. Nature 1996 383, 812–815. [Context Link]
5. Hariri AR, Bookheimer SY, Mazziotta JC. Neuroreport 2000 11, 43–48. [Context Link]
6. Caviness VS, Jr., Kennedy DN, Richelme C. et al. Cereb Cortex 1996 6, 726–736. [Context Link]
7. Pfefferbaum A, Mathalon DH, Sullivan EV. et al. Arch Neurol 1994 51, 874–887. [Context Link]
8. Reiss AL, Abrams MT, Singer HS. et al. Brain 1996 119, 1763–1774. [Context Link]
9. Huttenlocher PR. Neuropsychologia 1990 28, 517–527. [Context Link]
10. Rubia K, Overmeyer S, Taylor E. et al. Neurosci Biobehav Rev 2000 24, 13–19. [Context Link]
11. Pilgrim C, Hutchison JB. Neuroscience 1994 60, 843–855. [Context Link]
12. Giedd JN, Vaituzis AC, Hamburger SD. et al. J Comp Neurol 1996 366, 223–230. [Context Link]
13. Schlaepfer TE, Harris GJ, Tien AY. et al. Psychiatry Res 1995 61, 129–135. [Context Link]
14. Halpern DF. Sex Differences in Cognitive Abilities. Hillsdale, NJ: Lawrence Erlbaum Associates; 1992. [Context Link]
15. Ekman P, Friesen WV. Pictures of Facial Affect. Palo Alto, CA: Consulting Psychologists Press; 1976. [Context Link]
16. Baird AA, Gruber SA, Fein DA. et al. J Am Acad Child Adolesc Psychiatry 1999 38, 195–199. [Context Link]
17. Maas LC, Frederick BD, Renshaw PF. Magn Reson Med 1997 37, 131–139. [Context Link]
18. Schnitzlein H, Murtagh F. Imaging Anatomy of the Head and Spine. Munich: Urban and Schwartzberg; 1990. [Context Link]
19. Yurgelun-Todd DA, Gruber SA, Kanayama G et al. Bipolar Disorders in press. [Context Link]
20. Davidson H, Cave KR, Sellner D. Neuropsychologia 2000 38, 508–519. [Context Link]
21. Prinzel LJ, Freeman FG. Percept Mot Skills 1997 85, 1195–1202. [Context Link]
22. Damasio AR. Brain Res Brain Res Rev 1998 26, 83–86. [Context Link]
23. Davidson RJ. Cogn Emotion 1998 12, 307–330. [Context Link]
24. Tomarken AJ, Davidson RJ. J Abnorm Psychol 1994 103, 339–349. [Context Link]
25. Killgore WDS, Casasanto DJ, Yurgelun-Todd DA. et al. Neuroreport 2000 11, 2259–2263. [Context Link]
26. Phillips ML, Young AW, Scott SK. et al. Proc R Soc Lond B Biol Sci 1998 265, 1809–1817. [Context Link]
27. Schneider F, Grodd W, Weiss U. et al. Psychiatry Res 1997 76, 75–82. [Context Link]
28. Drevets WC. Ann N Y Acad Sci 1999 877, 614–637. [Context Link]
29. Whalen PJ, Rauch SL, Etcoff NL. et al. J Neurosci 1998 18, 411–418. [Context Link]
Adolescence; Affect; Amygdala; Development; Dorsolateral prefrontal
cortex; Emotion; Face perception; Fear; fMRI; Neuroimaging; Sex
Accession Number: 00001756-200102120-00047