SYSTEMS-LEVEL BRAIN DEVELOPMENT

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and the McKnight Foundation (D.F.) and the Erasmus
University Rotterdam, a Vidi grant from Netherlands
Organization for Scientific Research, and Human
Frontier Science Program grants (M.B.).
10.1126/science.1115807

VIEWPOINT

Language Acquisition and Brain Development
Kuniyoshi L. Sakai
Language acquisition is one of the most fundamental human traits, and it is obviously
the brain that undergoes the developmental changes. During the years of language
acquisition, the brain not only stores linguistic information but also adapts to thegrammatical regularities of language. Recent advances in functional neuroimaging havesubstantially contributed to systems-level analyses of brain development. In thisViewpoint, I review the current understanding of how the ‘‘final state’’ of language
acquisition is represented in the mature brain and summarize new findings on corticalplasticity for second language acquisition, focusing particularly on the function of thegrammar center.
A child acquires any natural languages withina few years, without the aid of analyticalthinking and without explicit Bgrammar[ in-struction as usually taught in school. The
origin of grammatical rules should thus beascribed to an innate system in the humanwww.sciencemag.org

SCIENCEVOL 310brain (1). The knowledge of and competence
for human language is acquired throughvarious means and modality types. Linguists
regard speaking, signing, and language comprehension as primary faculties of language,i.e., innate or inherent and biologically determined, whereas they regard reading and writing as secondary abilities. Indeed, the native or
first language (L1) is acquired during the firstyears of life through such primary faculties
while children are rapidly expanding their
linguistic knowledge (2). In contrast, reading
and writing are learned with much conscious

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tex plasticity, which are—with few exceptions(81)—poorly understood. Although complex,a mechanistic, cellular-level explanation of
S1 map plasticity appears increasingly tractable
and would constitute a major step toward
understanding cortical information storage.

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quired in their own developmental courses andsemantic decision tasks even when the same
effort and repetition, usually at school. Thisthat the timing and duration of their sensitive
speech stimuli are used (15). On the otherability may be influenced by cultural rather
periods differ. In this viewpoint, I will first
hand, activations in the left AG/SMG andthan biological factors. However, the exisclarify the fundamental linguistic factors andfrontal regions are less consistent among thetence of developmental dyslexics indicates
their possible representation in the maturelexico-semantic tasks tested by a number ofthat reading ability requires specific neuralbrain as revealed by brain mapping techfunctional imaging studies. Lexico-semantic
mechanisms (3), and a link between poorniques. The major linguistic factors aretasks may involve various cognitive factors
reading and impaired auditory resolution
phonology and lexico-semantics at the wordother than semantic processing, and thus difhas been suggested (4). It is therefore crulevel and sentence comprehension and syntax
ferent cortical regions might be recruited decial to understand how distinct linguistic faculat the sentence and discourse level, which cerpending on the particular strategy used by theties develop in the brain throughout various
tainly interact with each other (Fig. 2A). A
participants.
ages. Figure 1 illustrates the typical develcritical question is whether these factors
opment of L1 faculties. This correlates with
Sentence Comprehension
correspond to distinct regions of the brain.
a massive increase in brain volume during
I will then focus on advances in functional
the first years. Speech in infants develops
Sentences convey not only lexico-semantic
imaging studies of L2 acquisition, indicatfrom babbling at around 6 to 8 months of age,
information for each word but sentence meaning activation changes in particular regions
to the one-word stage at 10 to 12 months, anding based on syntactic structures. Semantic
then to the two-word stage aroundprocessing at the sentence level2 years. Note that sign systems
differs from a simple summation
are spontaneously acquired byof lexico-semantic processing forboth deaf and hearing infants ineach word. For example, thea similar developmental course
meaning of ‘‘John thinks that(5), starting from manual silent
David praises his son’’ clearly
Bbabbling[ (6). However, thesediffers from that of ‘‘John thinks
obvious developmental changes
that his son praises David,’’ alrefer to language output. Speechthough the lexical items involved
perception and even grammaticalin each of these sentences areknowledge develops much earidentical. Therefore, the processlier, within the first months aftering of syntactic structures plays abirth (7, 8).
critical role in the selective inteA clear contrast among lingration of lexico-semantic inforguistic factors exists between L1
mation into sentence meaning.
and a second language (L2). The
We proposed that the left inferior
L2 ability does not seem to takefrontal gyrus (IFG) region exany determined steps of developtending from the triangular part
ment, and it shows enormous in(F3t or BA 45) to the orbital part
dividual variation. Whether L2(F3O or BA 47) is the putative
relies on the same dedicatedregion for the selection and inmechanism of L1 is thus a matter Fig. 1. Brain growth and first language (L1) acquisition. Human brain tegration of semantic informaof debate (9). An L2 can be mas- weight is presented as a function of age, where 100 in the ordinate tion, which are separable fromtered at any time in life, though corresponds to the mean adult value (10). Approximate times of simple lexico-semantic processthe L2 ability rarely becomes milestones in normal speech development are also indicated.
ing (16) (Fig. 2B, green region).
comparable to that of L1 if it is
We directly compared corticalof the brain during the course of language
acquired beyond the hypothesized ‘‘sensitive
activations in tasks involving comprehension
development.
period[ from early infancy until puberty (È12of sentences with those in lexical decision
years old). The notion of a sensitive periodtasks and found discourse-level selective acPhonology and Lexico-Semantics
for language acquisition comes from the loss
tivation in the left F3t/F3O under both audiRecent functional magnetic resonance imaging
of flexibility for cerebral reorganization due
tory and visual conditions. We also clarified
to acquired aphasia after puberty (10). The
that the functional connectivity between the(fMRI) and positron emission tomography(PET) studies have indicated that auditory
concept of the sensitive period has been exleft F3t/F3O and a region in the left precenphonological processing is associated withtended to L2 acquisition in that English protral sulcus is significantly enhanced during
activation in the posterior superior tempoficiency declines after the age of 7 years when
the sentence task but not during the lexicoral gyrus (STG) [Brodmann’s area (BA) 22],Chinese or Korean speakers move to thesemantic task (17). In the neuroimaging field,
whereas lexico-semantic processing is typiUnited States (11). This hypothesis has recentthere is a growing emphasis on structural andcally associated with activation in the left
ly been challenged by an event-related brain
functional connectivity to clarify how distribextra-sylvian temporoparietal regions, includpotential (ERP) study. Adults who learned auted but interacting populations of neurons
ing the angular gyrus and supramarginal gyrus
miniature artificial language showed a simiwork in a coordinated fashion during language(AG/SMG) (Fig. 2A) (13). However, studies
lar ERP response to a syntactic anomaly asprocessing.
on phonological versus lexico-semantics havenative speakers do (12). It may also be posA recent fMRI study showed that thereported many additional regions, including
sible that different linguistic abilities are acprocessing of American Sign Language (ASL)
the inferior frontal regions, and phonologicalrecruited the bilateral cortical areas of both
Department of Basic Science, Graduate School of Arts
processing may have varied levels of abstracdeaf native signers and hearing native signand Sciences, University of Tokyo, Komaba, Tokyo
tion within distinct subregions (14). We haveers, whereas the processing of written En153-8902, Japan. Core Research of Evolutional
shown that bilateral STG activation is moreglish was left-lateralized (18). Note that for
Science and Technology (CREST), Japan Science andenhanced in phonological decision and voicethe deaf signers, ASL is the L1 and written
Technology Agency, Kawaguchi-shi 332-0012, Japan.
pitch comparison tasks than in syntactic andEnglish the L2. Another fMRI study reported
E-mail: sakai@mind.c.u-tokyo.ac.jp816

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SYSTEMS-LEVEL BRAIN DEVELOPMENT

bilateral cortical activation for the processing of British Sign Language (BSL), but without evidence of enhanced right-hemisphererecruitments in sign language when compared with an audio-visual speech condition(19). It is, therefore, a considerable challenge
to clarify ‘‘what’s right and what’s left.’’ Because sign-language aphasia is due primarily to left-hemisphere lesions (20), it should
be clarified whether comprehension of sentences is functionally lateralized in sign andspeech. By using tasks involving comprehension of sentences and sentential nonword
detection, we compared different groups andstimulus conditions (21). Under the sign condition with sentence stimuli in Japanese Sign
Language (JSL), we tested two groups ofparticipants: deaf signers of JSL and hearing
bilinguals of JSL and Japanese. Under the
speech condition, we tested hearing monolinguals of Japanese with auditory Japanese
stimuli alone or with an audio-visual presentation of Japanese and JSL stimuli. Acrossall four conditions, there were consistently
left-dominant activations involving frontal andtemporo-parietal regions. Furthermore, irrespective of the modalities of sign and speech,
activations selective to the comprehension ofsentences were found primarily in the left regions, including the left F3t/F3O; only the left
F3t/F3O showed no main effects of modality
condition. These results indicate amodal commonality in the functional dominance of theleft cortical regions for comprehension of sentences as well as the essential and universal
role of the left F3t/F3O in processing linguistic information from both signed and spoken
sentences.

Syntax: The Grammar Center
Although there has been much speculation
concerning subdivisions for various aspectsof sentence processing and consensus is stilllacking, there is accumulating evidence thatthe opercular and triangular parts (F3op/F3t
or BAs 44 and 45) of the left IFG and the leftlateral premotor cortex (BAs 6, 8, and 9;
mainly in BA 8) are selectively related togrammatical processing (15, 22–26). The leftlateral premotor cortex is located at the junction of the precentral sulcus and the inferior
frontal sulcus and is just dorsal to the left
F3op/F3t. I propose that these left frontal
regions can be regarded as the ‘‘grammar
center,’’ reflecting the universal nature ofgrammatical processing. Is there a specialized (domain-special) neural system for grammatical processing that is separable fromother domain-general cognitive systems? We
examined cortical activation by directly comparing brain activations in syntactic decisiontasks with those in verbal short-term memorytasks (26). The left dorsal IFG (a part of
F3op/F3t) as well as the left lateral premotor cortex showed selective activation for
syntactic decision tasks when they weredirectly compared with a verbal short-term
memory task (Fig. 2B, red regions). The
activation of these regions is related toprocesses of analyzing syntactic structures,and it cannot be explained either by taskdifficulty or by verbal short-term memory
components. The human left frontal cortex isthus uniquely specialized in the syntactic
processes of sentence comprehension, without any counterparts in other animals.
There is great controversy regarding thelimits of noninvasive imaging techniques
as a tool for human studies; for example,
such correlation methods are insufficient toshow causal relationships between corticalactivations and linguistic functions. To establish a causal link between the grammar
center and syntactic processing, we usedtranscranial magnetic stimulation (TMS) anda minimal-pair paradigm in which either asyntactic or semantic factor differed between
stimulus pairs (27). Event-related paired TMS

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Functional Changes of the Grammar
Center During L2 Acquisition
How can the function of the grammar center be modified during the acquisition of
new languages? There are at least two major factors that may affect the cortical activation change: the proficiency level (PL)of L2 and the age of acquisition (AOA). It
has been reported that L1 (AOA before
about 6 years) and L2 (AOA after about 7
years) are represented differentially in cortical areas (28), whereas other studies havereported that they have common neural substrates during sentence comprehension tasks(29). An fMRI study supports the AOA effect on cortical activations, showing thatthe left IFG activation for grammatical processing in L2 is greater than that in L1 (30).
However, another fMRI study claims thatthe degree of exposure to language affects
the left IFG activation, even if the AOA ismatched (31). It has also been pointed outthat the left frontal and extrastriate regions
are differentially modulated, either by age
or task performance among children (aged
7 to 10) and adults (32). However, the age
and PL effects on cortical activations areoften confounded with the demands requiredin each language task and the resultant task
performance, and it remains unknown whether these factors are actually separable fromeach other.
Given these uncertainties, we tried toclarify the relative contributions of age, PL,
language task demands, and task performance to modulating activations in the left
IFG. We examined whether learning of English past-tense verbs as L2 knowledge altered
the brain activations of 13-year-old students (native Japanese speakers) studying
English for the first time (33). We targeted
twins as participants (six monozygotic and
one dizygotic twin pairs), because it is intriguing to ask whether the shared factors oftwins actually influence their language abil-

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Fig. 2. (A) Possible network of fundamental linguistic functions in the brain. The exact correspondences between the left (L) brain regions and linguistic factors are still under study. (B) The
grammar center and other left frontal regions critically involved in sentence processing. The green
region (the left F3t/F3O) is selectively activated in the comprehension of sentences (16, 17),
whereas the red regions (the left lateral premotor cortex, the left dorsal IFG, and the left F3op/F3t)
are specifically involved in syntactic processing (15, 26) and can be regarded as the grammar center.

pulses over the left F3op/F3t selectively reduced reaction times in explicit syntactic decisions but not in explicit semantic decisions,suggesting the selective physiological effects of facilitation or priming. This effectwas observed during syntactic decisions regarding both normal and anomalous sentences and when magnetic stimulation was
administered to the left F3op/F3t at a specific time (150 ms from a verb stimulus).
Even if the ‘‘normal’’ sentences were physically identical stimuli, TMS showed the differential effects on the normal sentences thatparalleled the effects on anomalous sentences,
depending on the types of explicit linguistic
decisions being made. These results indicatethat the left F3op/F3t plays an essential roleas the grammar center of human sentence
processing.

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I NDDE EVVE EL LOOP PMME ENNTT

Fig. 3. Functional changes of the grammar center
during second language (L2) acquisition. (A) Pasttense task-selective activation in L2 (EPi, the English
past-tense task with irregular verbs) after classroom
training for participants age 13 years (33). (B) Pasttense task-selective activation in L1 (JP, the Japanese
past-tense task) for participants age 13 years. (C)Past-tense task-selective activation in L2 (EPi) forthe lower PL subgroup of participants age 19 years(34). (D) Past-tense task-selective activation in L2(EPi) for the higher PL subgroup of participants age
19 years. (E) Possible activation changes in the brain
during L2 acquisition and consolidation.

PL improvements at the earlystages of L2 acquisition andbecomes lower when a higher
proficiency in L2 is attained.
These results may reflect a moregeneral law of activation changes
during language development.
Cortical activations increase initially at the onset of acquisition,
followed by the maintenance of
the activations and then a fall in
activations during consolidationof linguistic competence (Fig.
3E). On the other hand, thedevelopmental changes in regional cerebral blood flow andcerebral metabolic rates are
known to manifest initially as
an increase and later, after about
the age of 9, as a decrease (35).
Because such metabolic differences between children andadults might affect the acquisition, analysis, and interpretationof fMRI data in group analyses,
an appropriate task control isnecessary to compensate for the
global physiological changes inthe brain. Moreover, if the general law stated above is applicable, a brain region may
show higher, lower, or comparable activation, depending on
which developmental stages
are compared.

Outlookities and neural substrates. For 2 months, thestudents participated in intensive training
in English verbs as part of their standard
classroom education. The twins completed
two sets of fMRI sessions, one before (day1) and one after (day 2) training. When an
English past-tense (EP) task was contrasted
with an English verb-matching (EM) task
for day 2, activations were found primarily
in the left IFG (Fig. 3A); these activations
had been absent in the same contrast forday 1. The contrast between Japanese pasttense (JP) and Japanese verb-matching (JM)
tasks resulted in the same left IFG activation(Fig. 3B), which is in agreement with theuniversal nature of grammatical processing.
These results suggest that cortical plasticity
for L2 acquisition is guided toward L1 specialization of the left IFG, at least at the age of13, despite notable differences between L1 andL2 in the students’ linguistic knowledge and intheir performance in making past-tense forms.
The activation increases of the left dorsal IFG
across days 1 and 2 showed a highly significant correlation within each pair of twins.

818

This suggests that the functional changes specifically observed in the left IFG were susceptible to shared genetic and environmental
factors for each twin in a surprisingly predictive manner. The activation increases in theleft IFG predicted the extent to which theindividual participants improved their knowledge of the past tense. In a subsequent fMRI
study, we tested participants aged 19 who hadstudied English for 6 years, thereby comparing
the cortical activations involved in the abovementioned EP and EM tasks (34). The activation in the left dorsal IFG was lower,
corresponding to a higher PL (Fig. 3, C andD), suggesting that the PL plays a major rolein the activation of this region. On the other
hand, the left F3t/F3O activation in Japanese(L1) of participants aged 13 was significantly
greater than that for those aged 19, despite thematched performances in L1. We conclude
that the grammar center subserves specificlinguistic functions that are critically required
when mastering any language.
Combining these task-selective activation
changes, left dorsal IFG activation increases with

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Noninvasive imaging techniques have already been applied to study the ‘‘initial state’’of brain activations reflecting speech perception in infants (36, 37). In the future,
participants at various developmental stages
will be systematically tested by functional
imaging studies with language and/or general cognitive tasks. Regional cerebral volume
and tissue concentration differences have also
been characterized by voxel-based morphometry, and this technique may elucidate structural development of the brain in a larger
population, extending the study of adult human brains (38). Indeed, twin studies have contributed to reveal genetic factors for brain
structure, more significantly those influencing
language areas in the left hemisphere (39).
Longitudinal studies of both structure andfunction of brains may further reveal theirdevelopmental tendencies in general, as wellas individual differences. Moreover, theobservation of functional changes during
recovery from neurological conditions, suchas dyslexia and aphasia, will help facilitate
remediation and rehabilitation in both children and adults. As to the normal development of the brain, further research is still

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References and Notes
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Univ. Press, Cambridge, UK, 2002).
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3. A. A. Beaton, Dyslexia, Reading, and the Brain: A
Sourcebook of Psychological and Biological Research(Psychology Press, Hove, UK, 2004).
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5. G. Morgan, B. Woll, Eds., Direction in Sign Language
Acquisition (Benjamins, Amsterdam, 2002).
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413, 35 (2001).

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Areas (‘‘Higher-Order Brain Functions,’’ 17022013)
and for the 21st Century COE (Center of Excellence)
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10.1126/science.1113530

VIEWPOINTSex Differences in the Brain:
Implications for Explaining Autism
Simon Baron-Cohen,* Rebecca C. Knickmeyer, Matthew K. Belmonte
Empathizing is the capacity to predict and to respond to the behavior of agents (usuallypeople) by inferring their mental states and responding to these with an appropriate
emotion. Systemizing is the capacity to predict and to respond to the behavior of
nonagentive deterministic systems by analyzing input-operation-output relations andinferring the rules that govern such systems. At a population level, females are stronger
empathizers and males are stronger systemizers. The ‘‘extreme male brain’’ theory posits
that autism represents an extreme of the male pattern (impaired empathizing andenhanced systemizing). Here we suggest that specific aspects of autistic neuroanatomy
may also be extremes of typical male neuroanatomy.
Leaving aside political correctness, there iscompelling evidence for sexual dimorphism inthe brain, cognition, and behavior (1). In thisViewpoint, we review the evidence at all threelevels. Classic autism and Asperger syndrome(AS) are the two clearest subgroups on theautistic spectrum of conditions, and both affect males more often than females. We conjecture that understanding sex differences inAutism Research Centre, Cambridge University, Department of Psychiatry, Douglas House, 18b Trumpington
Road, Cambridge CB2 2AH, UK.
*To whom correspondence should be addressed.
E-mail: sb205@cam.ac.uk

the general population has implications forunderstanding the causes of autism-spectrum
conditions.

The E-S Theory of Psychological Sex
Differences
Although males and females do not differ ingeneral intelligence, specific cognitive tasks
reveal sex differences. Differences favoringmales are seen on the mental rotation test (2),spatial navigation including map reading (3),targeting (4), and the embedded figures test(5), although there are conflicting studies regarding the latter (6). Males are also more
likely to play with mechanical toys as chil-www.sciencemag.org

SCIENCEVOL 310dren (7), and as adults, they score higher onengineering and physics problems (8). In
contrast, females score higher on tests ofemotion recognition (9), social sensitivity(10), and verbal fluency (11). They start totalk earlier than boys do (12) and are more
likely to play with dolls as children (7). Effectsizes range from small (Cohen’s d 0 0.2 foremotion recognition) to large (Cohen’s d 0 1.3
to 1.9 for targeting), with a substantial degreeof overlap between male and female distributions, even for effects considered large by theconventions of psychology. All of these differences exist at the level of populations, notindividuals; from such population differences,no inferences can or should be made about
individuals.
Although these population differences partially arise from experiential factors, experiments in animals suggest a biologicalfoundation. Male rats perform significantly
better than females do on the radial arm andMorris water maze (13). This sex difference iseliminated by castrating males or by treating
females with testosterone neonatally (14).

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