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The mirror neuron system (MNS) has been proposed to play an important role in social cognition by providing a neural mechanism by which others' actions, intentions, and emotions can be understood. Here functional magnetic resonance imaging was used to directly examine the relationship between MNS activity and two distinct indicators of social functioning in typically-developing children (aged 10.1 years+/-7 months): empathy and interpersonal competence. Reliable activity in pars opercularis, the frontal component of the MNS, was elicited by observation and imitation of emotional expressions. Importantly, activity in this region (as well as in the anterior insula and amygdala) was significantly and positively correlated with established behavioral measures indexing children's empathic behavior (during both imitation and observation) and interpersonal skills (during imitation only). These findings suggest that simulation mechanisms and the MNS may indeed be relevant to social functioning in everyday life during typical human development.

Upper limb gestures, as well as transitive actions (i.e. acted upon an object) when either executed or observed affect speech. Broca's area seems to be involved in integration between the two motor representations of arm and mouth (Bernardis and Gentilucci, Neuropsychologia, 44:178-190, 2006, Gentilucci et al., Eur J Neurosci, 19:190-202, 2004a, Neuropsychologia, 42:1554-1567, 2004b, J Cogn Neurosci, 18:1059-1074, 2006). The relevance of these data is in relation with the hypothesis that language evolved from manual gestures, and was gradually transformed in speech by means of a system of dual motor commands to hand and mouth (Gentilucci and Corballis, Neurosci Biobehav, Rev 30:949-960, 2006). The present study aimed to verify whether this system of integration between gestures (and transitive actions) and speech is involved also in the language development of infants. Vocalizations of infants aged between 11 and 13 months were recorded during both manipulation of objects of different size and request arm gestures towards the same objects presented by the experimenter. Frequency in voice spectra increased when the infants manipulated or gestured to large objects in comparison with the same activities directed to small objects. These data suggest that intrinsic properties of an object evoking commands of manual interaction are used to identify that object, and to communicate.

Developmental differences (9- to 15-year-olds) in effective connectivity in left hemisphere regions were examined using dynamic causal modeling (DCM) of functional magnetic resonance imaging (fMRI) data. Children completed spelling tasks in the visual and auditory modalities in which they were asked to determine if two words were spelled the same from the first vowel onwards. Intrinsic (anatomical) connections were strongest from primary cortical regions to unimodal association areas - from Heschl's gyrus to superior temporal gyrus for the auditory spelling task and from calcarine to fusiform gyrus for the visual spelling task. The modulatory (experimental) effect for the visual spelling task from calcarine to superior temporal gyrus was stronger than all other effects from calcarine and this effect showed a developmental increase, suggesting automatic activation of phonology that increased with age. The modulatory effect from Heschl's gyrus to dorsal inferior frontal gyrus also showed a developmental increase, suggesting age-related increases in phonological segmentation in verbal working memory. All together, these results suggest that there are developmental increases in automatic access into brain regions involved in phonological processing in tasks that require orthographic processing.

Intrauterine growth restriction (IUGR) can increase susceptibility to perinatal hypoxic brain injury for reasons that are unknown. Previous studies of the neonatal IUGR brain have suggested that the cerebral mitochondrial capacity is reduced but the glycolytic capacity increased relative to normal weight (NW) neonates. In view of these two factors, we hypothesized that the generation of brain lactate during a mild hypoxic insult would be greater in neonatal IUGR piglets compared to NW piglets. Brain lactate/N-acetylaspartate (NAA) ratios and apparent diffusion coefficients (ADCs) were determined by proton magnetic resonance spectroscopy and imaging of the brain before, during and after hypoxia in seven neonatal piglets with asymmetric IUGR and six NW piglets. During hypoxia, IUGR piglets had significantly higher brain lactate/NAA ratios than NW piglets (P=0.046). The lactate response in the IUGR piglets correlated inversely with apoptosis in the thalamus and frontal cortex of the brain measured 4 h post hypoxia (Pearson's r=0.86, P<0.05). Apoptosis in IUGR piglets with high brain lactate was similar to that in the NW piglets whereas IUGR piglets with low brain lactate had significantly higher apoptosis than NW piglets (P=0.019). ADCs in the high lactate IUGR piglets were significantly lower during hypoxia than in all the other piglets. This signifies increased diffusion of water into brain cells during hypoxia, possibly in response to increased intracellular osmolality caused by high intracellular lactate concentrations. These findings support previous studies showing increased susceptibility to hypoxic brain injury in IUGR neonates but suggest that increased glycolysis during hypoxia confers neuroprotection in some IUGR piglets.

Ontogenetic treatment of rats with the dopamine D(2)-like receptor agonist quinpirole produces a significant increase in dopamine D(2) receptor sensitivity that persists throughout the animal's lifetime, a phenomenon known as D(2) priming. The present study was designed to investigate the effects of priming of the D(2) receptor on the expression of three different members of the regulator of G-protein signaling (RGS) family: Rgs4, Rgs9 and Rgs17. Male offspring were ontogenetically treated with quinpirole or saline from postnatal days (P)1-21 and raised to adulthood. On approximately P65, animals were given an acute quinipirole injection (0.1 mg/kg) and the number of yawns was recorded for 1 h after the injection. Yawning has been shown to be a behavioural event mediated by the dopamine D(2)/D(3) receptor. Animals ontogenetically treated with quinpirole demonstrated a significant 2.5-fold increase in yawning as compared to controls. Rgs transcripts were analysed through in situ hybridization several weeks later. Rats ontogenetically treated with quinpirole demonstrated a significant decrease in Rgs9 expression in the frontal cortex, but a more robust decrease in the striatum and nucleus accumbens as compared to controls. Regarding Rgs17, ontogenetic quinpirole produced a modest but significant increase in expression in the same brain areas. There were no significant differences in Rgs4 expression produced by drug treatment in any of the brain regions analysed. This study demonstrates that ontogenetic quinpirole treatment, which results in priming of the D(2) receptor, results in significant decreases in Rgs9, which has been shown to regulate G-protein coupling to D(2) receptors.

Introduction: To describe the changes in the magnetic resonance (MR) signal of the perianterior horn structure (PAS) with increasing age, we studied 69 infants and children aged between 3 days and 9.4 years (average: 2.8 years) without any neurological deficits., Methods: T1- and T2-weighted images and FLAIR (fluid attenuation inversion recovery) images were obtained in the axial plane. Based on a comparison of the intensity of the PAS with that of the cortex in each sequence (T1-WI/FLAIR/T2-WI), we classified the signal-intensity patterns into four types: I, low/low/high; II, low/high/high; III, iso/high/high; IV, high/low/low., Results: Signal-intensity types I, II, III and IV were seen in 22, 8, 17, and 22 subjects, respectively, with younger subjects showing type I or II intensity patterns and older subjects showing type III or IV. In addition, T1-weighted and FLAIR images of subjects with a type I intensity pattern showed a rim of an isointensity component around the PAS that histologically coincided with migrating glial cells. The low-intensity area on FLAIR and T2-WI images of subjects with a type IV intensity pattern may represent myelinated fibers of the subcallosal fasciculus (ScF)., Conclusion: The intensity of the MR signals of the PAS changes with increasing age, and this change may reflect histological features. A better understanding of these characteristics may help us to clarify myelination abnormalities, particularly those related to the ScF in the frontal lobe in infants and children.

The functional neuroanatomy of language in the adult brain separates semantic and syntactic processes in the superior temporal gyrus (STG) and in the inferior frontal cortex. It is unknown whether a similar specialization is present in the developing brain. Semantic and syntactic aspects of sentence processing were investigated in 5- to 6-year-old children and in adults using functional magnetic resonance imaging. Although adults demonstrated function-specific activations in the STG and the frontal operculum, children showed a large activation overlap for these two language aspects in the STG. Compared to adults, they engaged additional areas in the left and right inferior frontal gyrus, which are known to support resource demanding processes. Thus, the language networks for semantic and syntactic processes are not yet specialized similarly to adults in the developing brain.

Theory of Mind (ToM) has been defined as our ability to predict behaviors of others in terms of their underlying intentions. While the developmental trajectory of ToM had been thought to be invariant across cultures, several ToM studies conducted outside the Anglo-American cultural or linguistic milieus have obtained mixed results. To examine effects of culture/language on the development of neural bases of ToM, we studied 12 American monolingual children and 12 Japanese bilingual children with second-order false-belief story and cartoon tasks, using functional magnetic resonance imaging (fMRI). While a few brain regions such as ventro-medial prefrontal cortex (vmPFC) and precuneus were recruited by both cultural/linguistic groups, several brain areas including inferior frontal gyrus (IFG) and temporo-parietal junction (TPJ) were employed in a culture/language-dependent manner during the ToM tasks. These results suggest that the neural correlates of ToM may begin to vary depending upon cultural/linguistic background from early in life.

During infancy and early childhood, children develop their ability to regulate their own emotions and behavior. This development of self-regulatory mechanisms has been considered to be the crucial link between genetic predisposition, early experience, and later adult functioning in society. This paper brings together the updated empirical findings related to the role of attention and the maturation of brain frontal areas in self-regulation. It reviews viewpoints and evidence of disciplines such as developmental psychology, cognitive neuroscience, social psychology, and neurobiology. It examines the causes of individual differences in self-regulation and the effects of those differences on the social and academic functioning of the individual. The consequences of failure in self-regulation are illustrated by focusing on the attention deficit/hyperactivity disorder (ADHD), including a detailed review of the animal models related to this disorder. Finally, some initial evidence suggesting the possibility of fostering self-regulation through training of attention is presented.

The cellular maturational processes behind cognitive development during childhood, including the development of working memory capacity, are still unknown. By using the most standard computational model of visuospatial working memory, we investigated the consequences of cellular maturational processes, including myelination, synaptic strengthening, and synaptic pruning, on working memory-related brain activity and performance. We implemented five structural developmental changes occurring as a result of the cellular maturational processes in the biophysically based computational network model. The developmental changes in memory activity predicted from the simulations of the model were then compared to brain activity measured with functional magnetic resonance imaging in children and adults. We found that networks with stronger fronto-parietal synaptic connectivity between cells coding for similar stimuli, but not those with faster conduction, stronger connectivity within a region, or increased coding specificity, predict measured developmental increases in both working memory-related brain activity and in correlations of activity between regions. Stronger fronto-parietal synaptic connectivity between cells coding for similar stimuli was thus the only developmental process that accounted for the observed changes in brain activity associated with development of working memory during childhood.

We studied developmental changes in the expression of non-phosphorylated neurofilament protein (NNF) (a marker of the structural maturation of pyramidal neurones) in the dorsolateral frontal cortex of marmoset monkeys, between embryonic day 130 and adulthood. Our focus was on cortical fields that send strong projections to extrastriate cortex, including the dorsal and ventral subdivisions of area 8A, area 46 and area 6d. For comparison, we also investigated the maturation of prefrontal area 9, which has few or no connections with visual areas. The timing of expression of NNF immunostaining in early life can be described as the result of the interaction of two developmental gradients. First, there is an anteroposterior gradient of maturation in the frontal lobe, whereby neurones in caudal areas express NNF earlier than those in rostral areas. Second, there is a laminar gradient, whereby the first NNF-immunoreactive neurones emerge in layer V, followed by those in progressively more superficial parts of layer III. Following a peak in density of NNF-immunopositive cell numbers in layer V at 2-3 months of age, there is a gradual decline towards adulthood. In contrast, the density of immunopositive cells in layer III continues to increase throughout the first postnatal year in area 6d and until late adolescence (> 1.5 years of age) in prefrontal areas. The present results support the view that the maturation of visual cognitive functions involves relatively late processes linked to structural changes in frontal cortical areas.

Decreased docosahexaenoic acid (DHA) and brain-derived neurotrophic factor (BDNF) have been implicated in bipolar disorder. It also has been reported that dietary deprivation of n-3 polyunsaturated fatty acids (PUFAs) for 15 weeks in rats, increased their depression and aggression scores. Here, we show that n-3 PUFA deprivation for 15 weeks decreased the frontal cortex DHA level and reduced frontal cortex BDNF expression, cAMP response element binding protein (CREB) transcription factor activity and p38 mitogen-activated protein kinase (MAPK) activity. Activities of other CREB activating protein kinases were not significantly changed. The addition of DHA to rat primary cortical astrocytes in vitro, induced BDNF protein expression and this was blocked by a p38 MAPK inhibitor. DHA's ability to regulate BDNF via a p38 MAPK-dependent mechanism may contribute to its therapeutic efficacy in brain diseases having disordered cell survival and neuroplasticity.

Objective: To investigate the effects of prematurity on sulcal formation., Methods: We evaluated the depth and volume of the primary olfactory sulcus (developed at 16 weeks' gestation) and the secondary orbital sulci (which start to develop at 28 weeks' gestation) in a sample of 22 adolescents with history of very-preterm birth (VPTB). We compared this preterm sample with a sample of subjects born at term and matched by age, gender, and sociocultural status. The Anatomist/BrainVISA 3.0.1 package was used to identify and quantify the sulci. In addition, voxel-based morphometry (VBM) was used to analyze possible reductions of gray and white matter in the orbitofrontal area., Results: Compared with controls, we found a significant reduction in the secondary sulci depth but not in the primary sulcus in the VPTB. VBM analysis showed reduced gray-matter volume in VPTB in the orbital region., Conclusions: Premature birth affects cerebral gyrification, and this impairment is not reversible during childhood. Identification of the specific factors involved in abnormal brain maturation may lead to effective interventions.

Previous studies have shown that developmental changes in the structure and function of prefrontal regions can continue throughout childhood and adolescence. Our recent results suggested a role for the left inferior frontal cortex in modulating task-dependent shifts in effective connectivity when adults focus on orthographic versus phonological aspects of presented words. Specifically, the top-down influence of the inferior frontal cortex determined whether incoming word-form information from the fusiform gyrus would have a greater impact on the parietal areas involved in orthographic processing or temporal areas involved in phonological processing (Bitan, T., Booth, J.R., Choy, J., Burman, D.D., Gitelman, D.R. and Mesulam, M.-M., 2005. Shifts of Effective Connectivity within a Language Network during Rhyming and Spelling. J. Neurosci. 25, 5397-5403.). In the current study, we find that children displayed an identical pattern of task-dependent functional activations within this network. In comparison to adults, however, children had significantly weaker top-down modulatory influences emanating from the inferior frontal area. Adult language processing may thus involve greater top-down cognitive control compared to children, resulting in less interference from task-irrelevant information.

Background: Although animal studies have demonstrated frontal white matter and behavioral changes resulting from prenatal cocaine exposure, no human studies have associated neuropsychological deficits in attention and inhibition with brain structure. We used diffusion tensor imaging to investigate frontal white matter integrity and executive functioning in cocaine-exposed children., Methods: Six direction diffusion tensor images were acquired using a Siemens 3T scanner with a spin-echo echo-planar imaging pulse sequence on right-handed cocaine-exposed (n = 28) and sociodemographically similar non-exposed children (n = 25; mean age: 10.6 years) drawn from a prospective, longitudinal study. Average diffusion and fractional anisotropy were measured in the left and right frontal callosal and frontal projection fibers. Executive functioning was assessed using two well-validated neuropsychological tests (Stroop color-word test and Trail Making Test)., Results: Cocaine-exposed children showed significantly higher average diffusion in the left frontal callosal and right frontal projection fibers. Cocaine-exposed children were also significantly slower on a visual-motor set-shifting task with a trend toward lower scores on a verbal inhibition task. Controlling for gender and intelligence, average diffusion in the left frontal callosal fibers was related to prenatal exposure to alcohol and marijuana and an interaction between cocaine and marijuana exposure. Performance on the visual-motor set-shifting task was related to prenatal cocaine exposure and an interaction between cocaine and tobacco exposure. Significant correlations were found between test performance and fractional anisotropy in areas of the frontal white matter., Conclusions: Prenatal cocaine exposure, alone and in combination with exposure to other drugs, is associated with slightly poorer executive functioning and subtle microstructural changes suggesting less mature development of frontal white matter pathways. The relative contribution of postnatal environmental factors, including characteristics of the caregiving environment and stressors associated with poverty and out-of-home placement, on brain development and behavioral functioning in polydrug-exposed children awaits further research.

Objectives: The purpose of this work was to assess the long-term impact of childhood lead exposure on the neurosubstrate of language function and brain organization., Methods: Young adults from the Cincinnati Lead Study were recruited to undergo functional magnetic resonance image scanning while performing a verb generation task. These subjects have been followed from birth through early childhood with extensive documentation of lead exposure, neuropsychology, and behavior. Forty-two subjects provided useful imaging data. The locale, strength, and the correlation between brain language activation and childhood blood lead concentration were studied., Results: After adjusting for potential confounders, the activation in left frontal cortex, adjacent to Broca's area, and left middle temporal gyrus, including Wernicke's area, were found to be significantly associated with diminished activation in subjects with higher mean childhood blood lead levels, whereas the compensatory activation in the right hemisphere homolog of Wernicke's area was enhanced in subjects with higher blood lead levels., Conclusion: This study indicates that childhood lead exposure has a significant and persistent impact on brain reorganization associated with language function.

Frontal horn cysts (FHCs) are elliptical, smooth, thin-walled cysts adjacent to the tip of the anterior horns of the lateral ventricles. Among 3,545 terms or near term healthy babies who underwent cranial ultrasound examination in our hospital over a 2-year 5-month period, 18 were found to have FHCs (17 typical and one atypical; seven bilateral and 11 unilateral, of which seven were on the left and four on the right). The female to male ratio was 2:1. The incidence of FHCs in normal term babies was thus 0.5%. Six children had resolution of the cyst within 1 month, and 6 more had resolution on repeat scan from 2 to 11 months of age. Four children did not have subsequent ultrasonography to document resolution, but they had normal growth and development. Two were lost to follow up. The infant with an atypical FHC had an enlarged left frontal horn cyst with a midline shift on follow up, but he had normal development. Our study suggests that FHC may be a normal physiologic variant or a benign pathologic condition that can be expected to resolve spontaneously within a few months. It is reasonable to follow typical FHC by cranial ultrasound examinations at 1 or 2 and 6 months of age. In the case of an atypical cyst, more frequent follow up and further image studies like CT or MRI are necessary.

Purpose: This study explores the relationship between age and resting-state regional cerebral blood flow (rCBF) in regions associated with higher order language skills using a population of normal children, adolescents, and young adults., Method: rCBF was measured in 33 normal participants between the ages of 7 and 19 years using single photon emission computed tomography. Participants' ages were regressed on rCBF values (normalized to whole-brain CBF) in 2 ways: (a) within anatomically defined, language-related regions of interest (ROIs) including Wernicke's area, Broca's area, angular gyrus, planum temporale, and Heschl's gyrus and (b) within clusters of voxels found to be significantly related to age in voxel-wise analyses., Results: rCBF in all anatomically defined ROIs except Heschl's gyrus declined as a function of age. Additionally, voxel-wise analyses revealed clusters where rCBF declined with age in left inferior parietal, left superior temporal, and right middle temporal regions-areas often implicated in higher order language functions., Conclusions: These data suggest that ongoing maturation (e.g., dendritic pruning) in higher order cognitive areas (e.g., angular gyrus) continues into adolescence, as reflected by declining rCBF, while the primary auditory area (Heschl's gyrus) has become a stable neuronal population by age 7 years.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is used as a general pediatric anesthetic. Recent data suggest that anesthetic drugs may cause neurodegeneration during development. The purpose of this study was to determine the robustness of ketamine-induced developmental neurotoxicity using rhesus monkey frontal cortical cultures and also to determine if dysregulation of NMDA receptor subunits promotes ketamine-induced cell death. Frontal cortical cells collected from the neonatal monkey were incubated for 24 h with 1, 10, or 20 microM ketamine alone or with ketamine plus either NR1 antisense oligonucleotides or the nuclear factor kB translocation inhibitor, SN-50. Ketamine caused a marked reduction in the neuronal marker polysialic acid neural cell adhesion molecule and mitochondrial metabolism, as well as an increase in DNA fragmentation and release of lactate dehydrogenase. Ketamine-induced effects were blocked by NR1 antisenses and SN-50. These data suggest that NR1 antisenses and SN-50 offer neuroprotection from the enhanced degeneration induced by ketamine in vitro.

Persisting alterations in monoaminergic innervation patterns have been observed following various environmental manipulations and neuro-psychopharmacological treatments during fetal or early postnatal life. The present study investigates the question how differences in initial growth conditions at birth might interfere with subsequent development of both serotonergic and noradrenergic innervation in the rat frontal cortex (FC) and brain stem. For this purpose, newborn rat littermates were divided into two groups, a low and a high birth weight group, and the densities of both serotonin (5-HT) and norepinephrine (NE) transporters in the FC and brain stem were analyzed at adulthood. 5-HT transporter density in the FC was significantly higher in the high birth weight group as compared with the low birth weight group. No significant differences were observed between both groups in the density of 5-HT transporters in the brain stem and in the densities of NE transporters in FC and brain stem. It is discussed that differences in birth weight may affect the postnatal development of 5-HT projections to the frontal cortex.

Working memory capacity increases throughout childhood and adolescence, which is important for the development of a wide range of cognitive abilities, including complex reasoning. The spatial-span task, in which subjects retain information about the order and position of a number of objects, is a sensitive task to measure development of spatial working memory. This review considers results from previous neuroimaging studies investigating the neural correlates of this development. Older children and adolescents, with higher capacity, have been found to have higher brain activity in the intraparietal cortex and in the posterior part of the superior frontal sulcus, during the performance of working memory tasks. The structural maturation of white matter has been investigated by diffusion tensor magnetic resonance imaging (DTI). This has revealed several regions in the frontal lobes in which white matter maturation is correlated with the development of working memory. Among these is a superior fronto-parietal white matter region, located close to the grey matter regions that are implicated in the development of working memory. Furthermore, the degree of white matter maturation is positively correlated with the degree of cortical activation in the frontal and parietal regions. This suggests that during childhood and adolescence, there is development of networks related to specific cognitive functions, such as visuo-spatial working memory. These networks not only consist of cortical areas but also the white matter tracts connecting them. For visuo-spatial working memory, this network could consist of the superior frontal and intraparietal cortex.

Multiple changes occur in the aging brain, leading to age-related emotional disorders. A growing body of recent evidence suggests that the cortical delta-opioid receptor system plays a critical role in anxiety- and depressive-like behaviors in the rodent. In this study, we show that aging mice promoted anxiety-like behaviors as characterized by both the light-dark and elevated plus-maze tests, and they exhibit an increase in astrocytes in the cingulate cortex due to the dysfunction of cortical delta-opioid receptor systems. As well as aging mice, mice with a dysfunction of the delta-opioid receptor system induced by chronic treatment with the selective delta-opioid receptor antagonist naltrindole, revealed astrogliosis in the cingulate cortex, which was associated with anxiety. We also found that the microinjection of cultured astrocytes into the cingulate cortex of young mice enhanced the expression of anxiety-like behavior. Our results indicate that the aging process promotes astrogliosis in the cingulate cortex through the dysfunction of cortical delta-opioid receptors. This phenomenon may lead to emotional disorders including aggravated anxiety during normal aging.

Mismatch negativity (MMN) is an event-related potential reflecting automatic attention-related information processing marking the detection of auditory change. The bilateral scalp distribution develops by 14 years of age, and is elicited with adult latencies by 17 years. But consistent with reports of continued brain maturation after adolescence, we show here that features of the temporal and frontal lobe dipole sources also continue to develop in the third decade of life. This has consequences for studies of the developmental course of MMN anomalies, from childhood into adulthood, in attention-deficit/hyperactivity disorder. Two groups of healthy subjects with mean ages of 17 and 30 years were presented with a 3-tone auditory oddball. The duration-deviant MMN was recorded during attention to a visual discrimination (auditory-passive condition) and an active auditory discrimination. MMN amplitudes were smaller in the older subjects and the MMN lasted longer over the right hemisphere. Latencies and moments of the four dipoles in the temporal and frontal lobes did not distinguish the two subject-groups. But both temporal lobe sources were located significantly more ventrally and further left in the young adult than in the adolescent subjects. The left cingular source moved posteriorly and the right inferior frontal source moved antero-medially in the older subjects. Brain development in the third decade may cause the two frontal sources to move apart on the rostro-caudal axis but the temporal lobe sources to move left on the lateral and down on the dorsoventral axes. Thus special care is necessary in interpreting putative dysfunctional neurobiological changes in developmental attention-deficit disorders where as-yet-unspecified sub-groups may show a late developmental lag, partial lag, or no lag at all, associated with other impairments.

Both the motor system and the frontal executive control system show a late maturation in humans which continues into school-age and even adolescence. We investigated the maturation of preparation processes towards a fast motor reaction in 74 healthy right-handed children aged 6 to 18 years and analyzed the topography of the late component of contingent negative variation (lCNV) in a 64-electrode high density sensor array. While adolescents from about 12 years on showed a bilaterally distributed centro-parietal maximum like adults do, younger children almost completely missed the negativity over the left central area contralaterally to the side of the anticipated movement. The reason, as revealed by current source density, was that only adolescents showed significant evoked activity of the left pre-/primary motor and supplementary/cingulate motor areas, while in contrast both age groups displayed significant current sinks over the right (ipsilateral) centro-temporal area and right posterior parietal cortex. Spatio-temporal source analysis confirmed that negativity over the right posterior parietal area could not be explained by a projection via volume conduction from frontal areas involved in motor preparation but represented an independent component with a different maturational course most likely related to sensory attention. Significant event-related desynchronization of alpha-power over the contralateral sensorimotor cortex was found in the younger age group, indicating that also 6- to 11-year-old children were engaged in motor preparation. Thus, the missing current sink over the contalateral sensorimotor cortex during late CNV in 6- to 11-year-old children might reflect the immaturity of a specific subcomponent of the motor preparation system which is related to evoked (late CNV) but not induced activity (alpha-ERD).

In this study, the neural mechanisms of novelty detection in children and adults were examined by means of novelty-elicited event-related potentials. The gross morphology of the event-related potentials elicited by complex, novel stimuli was similar in children and adults, suggesting that processing of novel acoustic information is essentially similar across the age groups. The more frontally distributed P3 components and the larger late frontal negativities in children than in adults suggest an age-related change in activity in the frontal part of the brain. This is consistent with the findings showing that the structural maturation of the frontal cortex does not appear to be completed until late adolescence.

This study assessed microstructural development in four regions of the human cerebral cortex during preterm maturation using diffusion tensor imaging (DTI), compared to the macrostructural development of cortical gyration evaluated using three-dimensional volumetric T1-weighted MR imaging. Thirty-seven premature infants of estimated gestational age (EGA) ranging from 25 to 38 weeks were prospectively enrolled and imaged in an MR-compatible neonatal incubator with a high-sensitivity neonatal head coil. Cortical gyration was measured quantitatively as the ratio of gyral height to width on the volumetric MR images in four regions bilaterally (superior frontal, superior occipital, precentral, and postcentral gyri). Mean diffusivity (D(av)), fractional anisotropy (FA-the fraction of D(av) that is anisotropic), and the three DTI eigenvalues (components of diffusivity radial and tangential to the pial surface of cortex) were measured in the same cortical regions. Cortical gyration scores, FA, and radial diffusivity were all significantly correlated with EGA (P < 0.0001). However, in multivariate analysis, no significant relationship (P > 0.05) was found between DTI parameters and cortical gyration beyond their common association with estimated gestational age. Pre- and postcentral gyri had significantly lower anisotropy than the superior occipital and superior frontal gyri (P < 0.05), indicating that DTI is sensitive to regional heterogeneity in cortical development. Maturational changes in the DTI eigenvalues of cortical gray matter were found to differ from those that have previously been described in developing white matter, with a significant age-related decline in the radial diffusivity (P < 0.0001) but not in the tangential diffusivities (P > 0.05).

Purpose: The temporal lobe seems particularly susceptible to seizure activity. Mesial temporal lobe structures, including the hippocampus, have the lowest seizure thresholds in the brain. Conversely, thresholds in the frontal neocortex are significantly higher. The development of intact, isolated preparations of hippocampus and neocortex in vitro allows for study into mechanisms governing seizure threshold., Methods: Epileptiform discharges in isolated mouse neocortical blocks were compared with the contralateral intact hippocampus, isolated from the same brain, by using the low-Mg2+, 4 aminopyridine (4-AP), and low-Ca2+ in vitro seizure models. The pharmacology of low Mg(2+)-induced ictal-like events (ILEs) generated in the hippocampus and neocortex was then compared by using glutamatergic antagonists DL-2-amino-5-phosphonovaleric acid (APV) and 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), and the Ca2+ channel antagonist, nifedipine., Results: Neocortical blocks generated both recurrent, spontaneous ILEs and interictal-like events under low-Mg2+ artificial CSF (aCSF) perfusion, distinct from those generated in the hippocampus. ILEs from the hippocampus displayed lower thresholds and longer durations as compared with isolated neocortical blocks. Similar results were obtained during 4-AP perfusion. Perfusion with low-Ca2+ ACSF did not produce stereotypical ILEs in the neocortical block, producing instead recurrent, slow depolarizations. Both ILEs and recurrent, slow depolarizations were produced in the hippocampus. Application of APV and nifedipine exacerbated low Mg(2+)-induced ILEs in the hippocampus but not the neocortex, indicating a distinct pharmacology for partial seizures of different brain regions., Conclusions: The developing mouse hippocampus demonstrates increased ictogenesis compared with the developing neocortex in vitro, consistent with clinical observations and in vivo experimental models.

Repeated episodes of spontaneous large-scale neuronal bursting and calcium influx in the developing brain can potentially affect such fundamental processes as circuit formation and gene expression. Between postnatal day 3 (P3) and P7, the immature cortex can express one such form of activation whereby a wave of neuronal activity propagates through cortical networks, generating massive calcium influx. We previously showed that this activity could be triggered by brief stimulation of muscarinic receptors. Here, we show, by monitoring large cortical areas at low magnification, that although all areas respond to muscarinic agonists to some extent, only some areas are likely to generate the coordinated wave-like activation. The waves can be triggered repeatedly in frontal areas where, as we also show, waves occur spontaneously at a low frequency. In parietal and occipital areas, no such waves are seen. This selectivity may be related in part to differences in the cortical distribution of dopaminergic signaling, because we find that activation of dopamine receptors enables the response. Because M1 muscarinic receptors are typically coupled with G-alpha(q)/11, we investigated whether other receptors known to couple with this G-protein (group I glutamate metabotropic receptors, neurotensin type 1) could similarly elicit wave-like activation in responsive cortical areas. Our results suggest that multiple neurotransmitter systems can enable this form of activation in the frontal cortex. The findings suggest that a poorly recognized, developmentally regulated form of strong network activation found predominantly in the frontal cortex could potentially exert a profound influence on brain development.

The development of the frontopolar cortex (FPC) through late childhood and adolescence was investigated using measures of cortical thickness. T(1)-weighted structural MRIs from 35 typically developing participants aged 8-20 years were used to construct 3D models of the brain, from which cortical thickness was measured. There was a significant inverse association between age and cortical thickness, such that cortical thickness decreased as age increased between 8 and 20 years. There was no effect of laterality or gender on cortical thickness.

Although past research has provided an initial examination of maturational trends of frontal lobe functioning, it has not yielded a unifying developmental model. The purpose of this study was to generate a model representing the maturation of frontal lobe function as determined principally through neuropsychological tests. A meta-analytic review of the literature on the development of frontal lobe functioning was conducted. Journal articles were identified through an initial search of PsycInfo, Medline, and ERIC for the years 1984-2004 using key words executive function*, frontal function*, development*, and age. Analyses of effect size differences across age groups assisted in determining the developmental patterns for commonly used measures of frontal functioning by providing a common metric of growth. Age-related increases across the different frontal functions were averaged providing overall age-related increases in performance. A plot was made of the development of frontal lobe functioning using the mean effect size of change in performance across age groups. The model of the development of frontal lobe functioning suggests a staging of development that begins in early childhood with the maturation of frontal functioning and continues, although at a decreased rate, into adolescence and early adulthood.

In this study we explored whether a postnatal doubling of the total number of neurons occurs in the human Brodmann areas 44 and 45 (Broca's area). We describe the most recent error prediction formulae and their application for the modern stereological estimators for volume and number of neurons. We estimated the number of neurons in 3D optical disector probes systematically random sampled throughout the entire Brodmann areas (BA) 44 and 45 in developing and young adult cases. In the relatively small number of male and female cases studied no substantial postnatal increase in total number of neurons occurred in areas 44 and 45; the volume of these areas reached adult values around 7 years. In addition, we did find indications that a shift from a right-over-left to a left-over-right asymmetry may occur in the volume of BA 45 during postnatal development. No major asymmetry in total number of neurons in BA 44 and 45 was detected.

In recent decades, the general trend in the criminal justice system in the USA has been to narrow the range of insanity defences available, with an increasing dependence solely on the M'Naghten rule. This states that innocence by reason of insanity requires that the perpetrator could not understand the nature of their criminal act, or did not know that the act was wrong, by reason of a mental illness. In this essay, I question the appropriateness of this, in light of contemporary neuroscience. Specifically, I focus on the role of the prefrontal cortex (PFC) in cognition, emotional regulation, control of impulsive behaviour and moral reasoning. I review the consequences of PFC damage on these endpoints, the capacity for factors such as alcohol and stress to transiently impair PFC function, and the remarkably late development of the PFC (in which full myelination may not occur until early adulthood). I also consider how individual variation in PFC function and anatomy, within the normative range, covaries with some of these endpoints. This literature is reviewed because of its relevance to issues of criminal insanity; specifically, damage can produce an individual capable of differentiating right from wrong but who, nonetheless, is organically incapable of appropriately regulating their behaviour.

Several studies have shown that memory circuits can be reorganised as a function of age. Brain magnetic activity evoked by a memory task was recorded in 19 healthy elderly subjects divided into two groups, a young-elder group (mean age of 62) and senior-elder group (mean age of 76). The young-elder group showed greater activity over the left medial temporal lobe in the late latency windows (between 400 and 800 ms) than the senior-elder group. The senior-elder group showed an initial increased activity (between 150 and 400 ms) over the complex of motor areas, followed by an increased activity in the left temporo-parietal cortex at the late latency window. These results revealed a reorganization of brain networks supporting memory in the eldest subjects. Furthermore, these circuits are reorganised in a time-dependent manner, meaning the rehearsal articulatory process active in the early time window followed by a phonological storage and recognition process in the late latency window.

In the human brain, myelination of axons continues until early adulthood and is thought to be important for the development of cognitive functions during childhood. We used diffusion tensor MR imaging and calculated fractional anisotropy, an indicator of myelination and axonal thickness, in children aged between 8 and 18 years. Development of working memory capacity was positively correlated with fractional anisotropy in two regions in the left frontal lobe, including a region between the superior frontal and parietal cortices. Reading ability, on the other hand, was only correlated with fractional anisotropy in the left temporal lobe, in the same white matter region where adults with reading disability are known to have lower fractional anisotropy. Both the temporal and the frontal regions were also correlated with age. These results show that maturation of white matter is an important part of brain maturation during childhood, and that maturation of relatively restricted regions of white matter is correlated with development of specific cognitive functions.

The objective of this study was to measure myelination of frontal lobe changes in infants and young children. Twenty-four cases of infants and children (age range 12-121 months) were evaluated by a quantitative assessment of T2-weighted MR image features. Reliable quantitative changes between white and gray matter correlated with developmental age in a group of children with no neurological findings. Myelination appears to be an increasing exponential function with the greatest rate of change occurring over the first 3 years of life. The quantitative changes observed were in accordance with previous qualitative judgments of myelination development. Children with periventricular leukomalacia (PVL) showed delays in achieving levels of myelination when compared to normal children and adjusted for chronological age. The quantitative measure of myelination development may prove to be useful in assessing the stages of development and helpful in the quantitative descriptions of white matter disorders such as PVL.

Introduction and Development: Frontal lobe, more specifically prefrontal cortex, is one of the brain regions that undergoes more protracted ongoing development. The wider the developmental window of one brain structure, the more vulnerable the functions related to it. Hence, executive functions, which are mediated by prefrontal networks, seems to be specially vulnerable during childhood. Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders. Functional neuroimaging techniques have shown a dysfunction in a fronto-striatal network in this disorder, that is likely subserving deficits in executive processes, such as in response inhibition., Discussion: This review focuses on contributions of neuroimaging techniques, with high spatial (SPECT, PET and fMRI), temporal (ERP) and spatio-temporal (MEG) resolution, to the neurofunctionality of ADHD.

Benzodiazepines (BZs) acting as modulators of GABA(A) receptors (GABA(A)Rs) are an important group of drugs for the treatment of anxiety disorders. However, a large inter-individual variation in BZ sensitivity occurs in the human population with some anxiety disorder patients exhibiting diminished sensitivity to BZ and reduced density of GABA(A)Rs. The mechanism underlying BZ treatment resistance is not known, and it is not possible to predict whether an anxiety patient will respond to BZ. 5-hydroxytryptamine1A receptor (5-HT1AR) null mice (R-/-) on the Swiss-Webster (SW) background reproduce several features of BZ-resistant anxiety; they exhibit anxiety-related behaviors, do not respond to BZ, have reduced BZ binding, and have decreased expression of the major GABA(A)R subunits alpha1 and alpha2. Here, we show that R-/- mice on the C57Bl6 (B6) background also have anxiety phenotype, but they respond to BZ and have normal GABA(A)R subunit expression. This indicates that the 5-HT1AR-mediated regulation of GABA(A)R alpha subunit expression is subject to genetic modification. Hybrid SW/B6-R-/- mice also exhibit BZ-resistant anxiety, suggesting that SW mice carry a genetic modifier, which mediates the effect of the 5-HT1AR on the expression of GABA(A)Ralpha subunits. In addition, we show that this genetic interaction in SW mice operates early in postnatal life to influence the expression of GABA(A)R alpha subunits at the transcriptional level. These data indicate that BZ-resistant anxiety results from a developmental arrest of GABA(A)R expression in SW-R-/- mice, and a similar mechanism may be responsible for the BZ insensitivity of some anxiety patients.

Tracking the functional development of specific regions of the prefrontal cortex in children using event-related potentials (ERPs) is challenging for both technical and conceptual reasons. In this paper we outline our strategy for studying frontal lobe development and present preliminary results from children aged 7-17 years and young adults using ERPs functionally associated with anterior cingulate and prefrontal cortex, especially the orbitofrontal, ventral, and medial portions. Our analysis of contingent negative variation, error-related negativity, and novelty P300 data show that the ERPs associated with these regions are still maturing into late adolescence, and that their amplitude has significant correlations with behavioral capacities.

The primary objective in this paper is to present a framework to understand the structure of consciousness. We argue that consciousness has been difficult to define because there are different kinds of consciousness, hierarchically organized, which need to be differentiated. Our framework is based on evidence from adult focal lesion research. The different types of consciousness are associated with distinct brain regions, with the higher levels of consciousness related to self-awareness and theory of mind (both facets of consciousness), with an emphasis on the role of the frontal lobes. The secondary objective is to use this structure to suggest hypotheses about the potential effect of frontal dysfunction at various developmental stages, and including both congenital and acquired brain injury.

In recent years, an exciting thrust in the developmental research literature has been the focus on "executive" functions (EF). However, the emphasis has been on the more purely cognitive aspects of EF operative in abstract reasoning and problem solving-aspects associated mainly with dorsolateral frontal regions. Although the literature on adult neuropsychology has seen an emerging and growing interest in the study of processes more related to orbitofrontal cortex (OFC), including emotion and personality, research on the development of EF has lagged behind. This special issue of Brain and Cognition is intended to redress this imbalance by bringing together researchers who are studying the nature and development of orbitofrontal function from a wide variety of perspectives.

In the axon terminals of the locus coeruleus (LC) neurons, a high level of axonal branching was occurred in the middle-aged brain, and the increased branching was maintained in the aged brain. In the present study, we hypothesized that neurotrophic support is necessary for the morphological age-related changes seen in the noradrenergic innervations from the LC to frontal cortex. Through immunohistochemical and quantitative image analyses, we examined the age-dependent effects of brain-derived neurotrophic factor (BDNF) on the noradrenergic axon terminals in the frontal cortex of F344 rats. We continuously infused BDNF into the frontal cortex of young (6-months-old), middle-aged (13-months-old), or aged (25-months-old) rats. Exogenous BDNF infusion caused a marked increase in the density of noradrenergic axons in the aged brain, but no trophic action of BDNF was observed in the young and middle-aged brain. Neutralization of endogenous BDNF with a specific function-blocking antibody to BDNF led to a reduction in noradrenergic axons in the frontal cortex of 19-month-old rats. The present results suggest that BDNF is not involved in the augmentation of noradrenergic innervations in the aging brain, but it is necessary for the maintenance of noradrenergic innervations in the aged brain.

Rett syndrome (RS) is caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2) and is characterized by arrested postnatal neurodevelopment. We followed the expression of MeCP2 protein in various brain structures of normal rat from birth to 2 years of age. By measuring the amount of protein using the Western blot technique, or by determining the percentage of immunoreactive cells, significant heterogeneity in MeCP2 distribution among various brain areas was observed. Highest expression was found in olfactory bulb and in frontal cortex. In contrast, little expression was detected in caudate-putamen, septum and hippocampus. Except in the olfactive nuclei, very few cells showed detectable MeCP2 protein at birth. The number increased during the first week of age, especially in cortex and nucleus accumbens. Rather than playing a global role in gene transcription, the heterogeneous distribution of MeCP2 transcription factor favors the idea that it has a specialized function in neurons.

Dopamine D1 receptors have been implicated in various neurodevelopmental disorders, including attention-deficit/hyperactivity disorder. However, little is known about potential late maturational changes of the motor inhibitory and stimulatory role of these receptors. Here, we investigated the effects of a full and selective D1 receptor agonist, SKF-81297, on motor activity and expression of the plasticity-associated gene, c-fos, in the prefrontal cortex and striatum of juvenile and adolescent male rats. In general, SKF-81297 produced a biphasic effect on motor activity (locomotor and rearing activity), which consisted of an initial short inhibition followed by a long-lasting stimulation. These effects were dose- and age- dependent. The inhibitory phase was more pronounced in adolescent than in juvenile rats whereas the opposite was true for the stimulatory phase. During the initial inhibitory phase of the drug, c-fos mRNA expression was increased in the prefrontal cortex of juvenile rats but reduced in adolescent rats. There was also an increase in c-fos mRNA expression in the medial-dorsal striatum and olfactory tubercle, which was more evident in juvenile rats. In contrast, during the stimulatory phase, c-fos mRNA expression was increased in both the dorsal and ventral striatum, especially in the nucleus accumbens, as well as in the prefrontal cortex, in both age groups. The increase of c-fos mRNA in the dorsal striatum, however, was more pronounced in juvenile rats. These results indicate the presence of two distinct D1 receptor populations within the frontal-striatal circuitry, which have opposite effects on motor activity, and which have different maturational profiles.

Executive functions were studied in 14 early and continuously treated PKU subjects (age 10.8 years, range 8-13) in comparison with controls matched for IQ, sex, age and socioeconomic status. Brain MRI examination was normal in all PKU patients. Neuropsychological evaluation included Wisconsin Card Sorting Test, Rey-Osterreith Complex Figure Test, Elithorn's Perceptual Maze Test, Weigl's Sorting Test, Tower of London, Visual Search and Motor Motor Learning Test. Whatever the IQ, PKU subjects performed worse than controls in tests exploring executive functions. Subgrouping the PKU subjects according to the quality of dietary control for the entire follow-up period (using 400 micromol/L as cut-off value for blood phenylalanine (Phe) concentration) showed that patients with worse dietary control performed more poorly than both the PKU group with the best dietary control and the control group. However, a mild impairment of executive functions was still found in PKU patients with a good dietary control (Phe <400 micromol/L) compared to controls. Concerning the PKU group as a whole, no linear correlation was found between neuropsychological performance and historical and concurrent biochemical parameters. We conclude that (a) PKU patients, even when treated early, rigorously and continuously, show an impairment of frontal lobe functions; (b) a protracted exposure to moderately high levels of Phe can affect frontal lobe functions independently of the possible effect of the same exposure on IQ; (c) in order to reduce the risk of frontal lobe dysfunction, the target of dietary therapy should be to maintain blood Phe concentration below 400 micromol/L.

The present study was designed to determine whether the changes that occur during aging in the expression of the N-methyl-D-aspartate (NMDA) receptor and two NMDA receptor subunits, zeta1 and epsilon2, are a continuation of developmental processes and whether protein and mRNA expression patterns of the subunits are similar across the lifespan. The prefrontal/frontal cortex of C57BL/6 mice of eight different ages (7-8, 13-15, 30-32, 49-53, and 70-72 days and 4.5, 11, and 25 months of age) were used to examine NMDA-displaceable [(3)H]glutamate binding and mRNA in tissue sections and mRNA and protein from homogenates. The lateral prefrontal/frontal cortex of C57BL/6 mice showed more significant declines in density of agonist binding to NMDA receptors during both development and aging than the medial cortex. Changes in mRNA expression for the epsilon2 subunit across the lifespan appeared to be related to the changes in NMDA receptor binding in the lateral cortex, even though the protein expression of the epsilon2 subunit did not show the same pattern of expression as the mRNA during development. The changes in epsilon2 subunit mRNA expression during adult aging may be a continuation of developmental processes, but there was also evidence that expression levels plateaued during early adulthood. The developmental expression of the zeta1subunit in the prefrontal/frontal cortex was influenced by gender and there was no significant effect of adult aging on either the protein or mRNA expression of this subunit. Determining how the expression of the NMDA receptor and its subunits change throughout the lifespan can help us to better understand the processes affecting the receptor during aging. These results should be useful for designing interventions into the aging process to repair or prevent changes in the NMDA receptor and its associated functions, such as learning and memory.

The aim of this study was to explore whether there are networks of regions where maturation of white matter and changes in brain activity show similar developmental trends during childhood. In a previous study, we showed that during childhood, grey matter activity increases in frontal and parietal regions. We hypothesized that this would be mediated by maturation of white matter. Twenty-three healthy children aged 8-18 years were investigated. Brain activity was measured using the blood oxygen level-dependent (BOLD) contrast with functional magnetic resonance imaging (fMRI) during performance of a working memory (WM) task. White matter microstructure was investigated using diffusion tensor imaging (DTI). Based on the DTI data, we calculated fractional anisotropy (FA), an indicator of myelination and axon thickness. Prior to scanning, WM score was evaluated. WM score correlated independently with FA values and BOLD response in several regions. FA values and BOLD response were extracted for each subject from the peak voxels of these regions. The FA values were used as covariates in an additional BOLD analysis to find brain regions where FA values and BOLD response correlated. Conversely, the BOLD response values were used as covariates in an additional FA analysis. In several cortical and sub-cortical regions, there were positive correlations between maturation of white matter and increased brain activity. Specifically, and consistent with our hypothesis, we found that FA values in fronto-parietal white matter correlated with BOLD response in closely located grey matter in the superior frontal sulcus and inferior parietal lobe, areas that could form a functional network underlying working memory function.

The amygdala, which plays a critical role in emotional learning and social cognition, is structurally and functionally sexually dimorphic in humans. We used magnetic neuroimaging and molecular genetic analyses with healthy subjects and patients possessing X-chromosome anomalies to find dosage-sensitive genes that might influence amygdala development. If such X-linked genes lacked a homologue on the Y-chromosome they would be expressed in one copy in normal 46,XY males and two copies in normal 46,XX females. We showed by means of magnetic neuroimaging that 46,XY males possess significantly increased amygdala volumes relative to normal 46,XX females. However, females with Turner syndrome (45,X) have even larger amygdalae than 46,XY males. This finding implies that haploinsufficiency for one or more X-linked genes influences amygdala development irrespective of a direct or indirect (endocrinological) mechanism involving the Y-chromosome. 45,X females also have increased grey matter volume in the orbitofrontal cortex bilaterally, close to a region implicated in emotional learning. They are as poor as patients with bilateral amygdalectomies in the recognition of fear from facial expressions. We attempted to localize the gene(s) responsible for these deficits in X-monosomy by means of a deletion mapping strategy. We studied female patients possessing structural X-anomalies of the short arm. A genetic locus (no greater than 4.96 Mb in size) at Xp11.3 appears to play a key role in amygdala and orbitofrontal structural and (by implication) functional development. Females with partial X-chromosome deletions, in whom this critical locus is deleted, have normal intelligence. Their fear recognition is as poor as that of 45,X females and their amygdalae are correspondingly enlarged. This 4.96 Mb region contains, among others, the genes for monoamine oxidase A (MAOA) and B (MAOB), which are involved in the oxidative deamination of several neurotransmitters, including dopamine and serotonin. Abnormal activity of these neurotransmitters has been implicated in the aetiology of several neurodevelopmental disorders in which social cognitive deficits are prominent. These associated deficits include a specific lack of fear recognition from facial expressions. We show that the thrombocytic activity of MAOB is proportionate to the number of X-chromosomes, and hypothesize that haploinsufficiency of this enzyme in 45,X females predisposes to their deficits in social cognition.

Functional imaging and clinical studies in children and adults have provided evidence of developmental changes in the hemispheric specialization for language. Whereas cytoarchitectonic asymmetry has been demonstrated in Broca's region of adults, the anatomical correlates of developmental changes in language dominance are largely unknown. In the present postmortem study of 34 human brains (ages ranging from 3.5 months to 85 years), the cytoarchitecture of areas 44 and 45 as the putative anatomical correlates of Broca's region, their developmental changes, and interhemispheric asymmetry were analyzed. Asymmetry as estimated by Euclidean distances between feature vectors of cytoarchitectonic profiles of left and right areas 44 and 45 was already found in 1-year-old infants. Asymmetry tended to increase with age, which was significant in area 45, but not in area 44. An adult-like, left-larger-than-right asymmetry in the volume fraction of cell bodies [gray level index (GLI)] was reached at approximately 5 years in area 45 and 11 years in area 44. These time points indicate a delayed development of the cytoarchitectonic asymmetry in Broca's region in comparison with that of the primary motor cortex. It may be hypothesized that the delayed maturation is the microstructural basis of the development of language abilities and the influence of language practice on cytoarchitecture during childhood. Interhemispheric asymmetry in the cytoarchitecture of areas 44 and 45 continues to change throughout life. We conclude that the cytoarchitectonic asymmetry of areas 44 and 45 is a result of microstructural plasticity that endures throughout almost the whole lifespan., (Copyright 2003 Wiley-Liss, Inc.)

The clinical and neuropathologic aspects of Rett syndrome suggest that an arrest of brain development produces the phenotype, but it is not understood how the gene implicated in Rett syndrome, methyl-CpG protein 2 (MeCP2), is regulated during brain development. In this study, the ontogeny of MeCP2 is examined in the developing human brain and in the female Rett syndrome brain to evaluate the relationship between MeCP2 expression and brain development in health and disease, respectively. Immunocytochemistry using an antibody to the C-terminal region of the protein was performed in paraffin sections of the developing brain to define the age and the sites of MeCP2 protein expression. In development, there is no MeCP2 expression in the germinal matrix or in the progenitor cells. At 10 to 14 weeks' gestation, the neurons of the brain stem and the Cajal-Retzius and subplate neurons of the cortex express MeCP2. By midgestation, some neurons of the basal ganglia express MeCP2, and at late gestation, the most mature cortical neurons in the lower cortical layers are positive. The postnatal cortex continues to increase its expression of neuronal MeCP2. In the Rett syndrome brain, fewer neurons express MeCP2 than in the normal brain. This reduction is most apparent in the brain stem and thalamus. The neurons of the cerebral cortex show the least reduction. We conclude that the regulation of MeCP2 abundance is related to human brain development, being expressed in neurons when they appear mature. In Rett syndrome, however, the expression pattern of MeCP2 does not completely resemble that of the normal immature brain, suggesting that the maintenance of MeCP2 might be determined in specific neurons by factors other than those controlling maturation. In the developing brain, synaptic activity and plasticity could be necessary to maintain MeCP2 in selected neuronal populations.