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1.  NFIX Regulates Neural Progenitor Cell Differentiation During Hippocampal Morphogenesis 
Cerebral Cortex (New York, NY)  2012;24(1):261-279.
Neural progenitor cells have the ability to give rise to neurons and glia in the embryonic, postnatal and adult brain. During development, the program regulating whether these cells divide and self-renew or exit the cell cycle and differentiate is tightly controlled, and imbalances to the normal trajectory of this process can lead to severe functional consequences. However, our understanding of the molecular regulation of these fundamental events remains limited. Moreover, processes underpinning development of the postnatal neurogenic niches within the cortex remain poorly defined. Here, we demonstrate that Nuclear factor one X (NFIX) is expressed by neural progenitor cells within the embryonic hippocampus, and that progenitor cell differentiation is delayed within Nfix−/− mice. Moreover, we reveal that the morphology of the dentate gyrus in postnatal Nfix−/− mice is abnormal, with fewer subgranular zone neural progenitor cells being generated in the absence of this transcription factor. Mechanistically, we demonstrate that the progenitor cell maintenance factor Sry-related HMG box 9 (SOX9) is upregulated in the hippocampus of Nfix−/− mice and demonstrate that NFIX can repress Sox9 promoter-driven transcription. Collectively, our findings demonstrate that NFIX plays a central role in hippocampal morphogenesis, regulating the formation of neuronal and glial populations within this structure.
doi:10.1093/cercor/bhs307
PMCID: PMC3862270  PMID: 23042739
glia; glial fibrillary acidic protein; neural progenitor cell; nuclear factor one X; SOX9
2.  Social Perception in Autism Spectrum Disorders: Impaired Category Selectivity for Dynamic but not Static Images in Ventral Temporal Cortex 
Cerebral Cortex (New York, NY)  2012;24(1):37-48.
Studies of autism spectrum disorders (ASDs) reveal dysfunction in the neural systems mediating object processing (particularly faces) and social cognition, but few investigations have systematically assessed the specificity of the dysfunction. We compared cortical responses in typically developing adolescents and those with ASD to stimuli from distinct conceptual domains known to elicit category-related activity in separate neural systems. In Experiment 1, subjects made category decisions to photographs, videos, and point-light displays of people and tools. In Experiment 2, subjects interpreted displays of simple, geometric shapes in motion depicting social or mechanical interactions. In both experiments, we found a selective deficit in the ASD subjects for dynamic social stimuli (videos and point-light displays of people, moving geometric shapes), but not static images, in the functionally localized lateral region of the right fusiform gyrus, including the fusiform face area. In contrast, no group differences were found in response to either static images or dynamic stimuli in other brain regions associated with face and social processing (e.g. posterior superior temporal sulcus, amygdala), suggesting disordered connectivity between these regions and the fusiform gyrus in ASD. This possibility was confirmed by functional connectivity analysis.
doi:10.1093/cercor/bhs276
PMCID: PMC3862263  PMID: 23019245
Asperger's syndrome; autism; fusiform gyrus; MRI/fMRI; social cognition
3.  Functional Heterogeneity in Posterior Parietal Cortex Across Attention and Episodic Memory Retrieval 
Cerebral Cortex (New York, NY)  2012;24(1):49-66.
While attention is critical for event memory, debate has arisen regarding the extent to which posterior parietal cortex (PPC) activation during episodic retrieval reflects engagement of PPC-mediated mechanisms of attention. Here, we directly examined the relationship between attention and memory, within and across subjects, using functional magnetic resonance imaging attention-mapping and episodic retrieval paradigms. During retrieval, 4 functionally dissociable PPC regions were identified. Specifically, 2 PPC regions positively tracked retrieval outcomes: lateral intraparietal sulcus (latIPS) indexed graded item memory strength, whereas angular gyrus (AnG) tracked recollection. By contrast, 2 other PPC regions demonstrated nonmonotonic relationships with retrieval: superior parietal lobule (SPL) tracked retrieval reaction time, consistent with a graded engagement of top-down attention, whereas temporoparietal junction displayed a complex pattern of below-baseline retrieval activity, perhaps reflecting disengagement of bottom-up attention. Analyses of retrieval effects in PPC topographic spatial attention maps (IPS0-IPS5; SPL1) revealed that IPS5 and SPL1 exhibited a nonmonotonic relationship with retrieval outcomes resembling that in the SPL region, further suggesting that SPL activation during retrieval reflects top-down attention. While demands on PPC attention mechanisms vary during retrieval attempts, the present functional parcellation of PPC indicates that 2 additional mechanisms (mediated by latIPS and AnG) positively track retrieval outcomes.
doi:10.1093/cercor/bhs278
PMCID: PMC3862264  PMID: 23019246
dual attention theory; FMRI; familiarity; recollection; topographic mapping
4.  Homeostatic Control of Synaptic Activity by Endogenous Adenosine is Mediated by Adenosine Kinase 
Cerebral Cortex (New York, NY)  2012;24(1):67-80.
Extracellular adenosine, a key regulator of neuronal excitability, is metabolized by astrocyte-based enzyme adenosine kinase (ADK). We hypothesized that ADK might be an upstream regulator of adenosine-based homeostatic brain functions by simultaneously affecting several downstream pathways. We therefore studied the relationship between ADK expression, levels of extracellular adenosine, synaptic transmission, intrinsic excitability, and brain-derived neurotrophic factor (BDNF)-dependent synaptic actions in transgenic mice underexpressing or overexpressing ADK. We demonstrate that ADK: 1) Critically influences the basal tone of adenosine, evaluated by microelectrode adenosine biosensors, and its release following stimulation; 2) determines the degree of tonic adenosine-dependent synaptic inhibition, which correlates with differential plasticity at hippocampal synapses with low release probability; 3) modulates the age-dependent effects of BDNF on hippocampal synaptic transmission, an action dependent upon co-activation of adenosine A2A receptors; and 4) influences GABAA receptor-mediated currents in CA3 pyramidal neurons. We conclude that ADK provides important upstream regulation of adenosine-based homeostatic function of the brain and that this mechanism is necessary and permissive to synaptic actions of adenosine acting on multiple pathways. These mechanistic studies support previous therapeutic studies and implicate ADK as a promising therapeutic target for upstream control of multiple neuronal signaling pathways crucial for a variety of neurological disorders.
doi:10.1093/cercor/bhs284
PMCID: PMC3862265  PMID: 22997174
adenosine; brain-derived neurotrophic factor; GABA; homeostasis; transgenic mice
5.  Gli3 Controls Corpus Callosum Formation by Positioning Midline Guideposts During Telencephalic Patterning 
Cerebral Cortex (New York, NY)  2012;24(1):186-198.
The corpus callosum (CC) represents the major forebrain commissure connecting the 2 cerebral hemispheres. Midline crossing of callosal axons is controlled by several glial and neuronal guideposts specifically located along the callosal path, but it remains unknown how these cells acquire their position. Here, we show that the Gli3 hypomorphic mouse mutant Polydactyly Nagoya (Pdn) displays agenesis of the CC and mislocation of the glial and neuronal guidepost cells. Using transplantation experiments, we demonstrate that agenesis of the CC is primarily caused by midline defects. These defects originate during telencephalic patterning and involve an up-regulation of Slit2 expression and altered Fgf and Wnt/β-catenin signaling. Mutations in sprouty1/2 which mimic the changes in these signaling pathways cause a disorganization of midline guideposts and CC agenesis. Moreover, a partial recovery of midline abnormalities in Pdn/Pdn;Slit2−/− embryos mutants confirms the functional importance of correct Slit2 expression levels for callosal development. Hence, Gli3 controlled restriction of Fgf and Wnt/β-catenin signaling and of Slit2 expression is crucial for positioning midline guideposts and callosal development.
doi:10.1093/cercor/bhs303
PMCID: PMC3862269  PMID: 23042737
corpus callosum; Fgf8; Gli3; Pdn; Slit2
6.  Meta-Analytic Connectivity Modeling Reveals Differential Functional Connectivity of the Medial and Lateral Orbitofrontal Cortex 
Cerebral Cortex (New York, NY)  2012;24(1):232-248.
The orbitofrontal cortex (OFC) is implicated in a broad range of behaviors and neuropsychiatric disorders. Anatomical tracing studies in nonhuman primates reveal differences in connectivity across subregions of the OFC, but data on the connectivity of the human OFC remain limited. We applied meta-analytic connectivity modeling in order to examine which brain regions are most frequently coactivated with the medial and lateral portions of the OFC in published functional neuroimaging studies. The analysis revealed a clear divergence in the pattern of connectivity for the medial OFC (mOFC) and lateral OFC (lOFC) regions. The lOFC showed coactivations with a network of prefrontal regions and areas involved in cognitive functions including language and memory. In contrast, the mOFC showed connectivity with default mode, autonomic, and limbic regions. Convergent patterns of coactivations were observed in the amygdala, hippocampus, striatum, and thalamus. A small number of regions showed connectivity specific to the anterior or posterior sectors of the OFC. Task domains involving memory, semantic processing, face processing, and reward were additionally analyzed in order to identify the different patterns of OFC functional connectivity associated with specific cognitive and affective processes. These data provide a framework for understanding the human OFC's position within widespread functional networks.
doi:10.1093/cercor/bhs308
PMCID: PMC3862271  PMID: 23042731
fMRI; network; orbital frontal; ventromedial prefrontal; ventrolateral prefrontal
7.  Neural Similarity Between Encoding and Retrieval is Related to Memory Via Hippocampal Interactions 
Cerebral Cortex (New York, NY)  2012;23(12):2818-2828.
A fundamental principle in memory research is that memory is a function of the similarity between encoding and retrieval operations. Consistent with this principle, many neurobiological models of declarative memory assume that memory traces are stored in cortical regions, and the hippocampus facilitates the reactivation of these traces during retrieval. The present investigation tested the novel prediction that encoding–retrieval similarity can be observed and related to memory at the level of individual items. Multivariate representational similarity analysis was applied to functional magnetic resonance imaging data collected during encoding and retrieval of emotional and neutral scenes. Memory success tracked fluctuations in encoding–retrieval similarity across frontal and posterior cortices. Importantly, memory effects in posterior regions reflected increased similarity between item-specific representations during successful recognition. Mediation analyses revealed that the hippocampus mediated the link between cortical similarity and memory success, providing crucial evidence for hippocampal–cortical interactions during retrieval. Finally, because emotional arousal is known to modulate both perceptual and memory processes, similarity effects were compared for emotional and neutral scenes. Emotional arousal was associated with enhanced similarity between encoding and retrieval patterns. These findings speak to the promise of pattern similarity measures for evaluating memory representations and hippocampal–cortical interactions.
doi:10.1093/cercor/bhs258
PMCID: PMC3827709  PMID: 22967731
emotional memory; episodic memory; functional neuroimaging; multivariate pattern analysis
8.  The Role of the Anterior Cingulate Cortex in Choices based on Reward Value and Reward Contingency 
Cerebral Cortex (New York, NY)  2012;23(12):2884-2898.
Although several studies have emphasized the role of the anterior cingulate cortex (ACC) in associating actions with reward value, its role in guiding choices on the basis of changes in reward value has not been assessed. Accordingly, we compared rhesus monkeys with ACC lesions and controls on object- and action-based reinforcer devaluation tasks. Monkeys were required to associate an object or an action with one of two reward outcomes, and we assessed the monkey's shift in choices of objects or actions after changes in the value of 1 outcome. No group differences emerged on either task. For comparison, we tested the same monkeys on their ability to make choices guided by reward contingency in object- and action-based reversal learning tasks. Monkeys with ACC lesions were impaired in using rewarded trials to sustain the selection of the correct object during object reversal learning. They were also impaired in using errors to guide choices in action reversal learning. These data indicate that the role of the ACC is not restricted to linking specific actions with reward outcomes, as previously reported. Instead, the data suggest a more general role for the ACC in using information about reward and nonreward to sustain effective choice behavior.
doi:10.1093/cercor/bhs266
PMCID: PMC3827710  PMID: 22944530
action-reversal; monkey; object-reversal; reward value
9.  Dopamine Asymmetries Predict Orienting Bias in Healthy Individuals 
Cerebral Cortex (New York, NY)  2012;23(12):2899-2904.
Pseudoneglect is traditionally viewed as reflecting right hemisphere specialization for processing spatial information, resulting in orienting toward the contralateral, left, hemispace. Recent evidence suggests that healthy individuals differ from each other in both direction and magnitude of orienting bias, and moreover, the bias displayed by a person is consistent across time, suggesting that it may represent a trait of the individual. Animal studies reveal consistent orienting bias within an individual, which reflects asymmetry in dopaminergic brain systems. We measured basal D2-like receptor binding using positron emission tomography and the high-affinity ligand [F-18]fallypride, to test the hypothesis that asymmetry in dopaminergic neurotransmission in healthy humans modulates the orienting bias in humans. As predicted, we found that individual differences in the direction and magnitude of the orienting bias were strongly associated with the pattern of asymmetric binding of dopamine (DA) D2 receptors in the striatum, as well as clusters in the frontal and temporal cortex. These findings show for the first time that orienting bias reflects individual differences in the lateralization of DA systems in the healthy human brain.
doi:10.1093/cercor/bhs277
PMCID: PMC3827711  PMID: 22941721
asymmetry; dopamine; individual differences; PET; spatial attention
10.  Metabolic Maturation of the Human Brain From Birth Through Adolescence: Insights From In Vivo Magnetic Resonance Spectroscopy 
Cerebral Cortex (New York, NY)  2012;23(12):2944-2955.
Between birth and late adolescence, the human brain undergoes exponential maturational changes. Using in vivo magnetic resonance spectroscopy, we determined the developmental profile for 6 metabolites in 5 distinct brain regions based on spectra from 309 children from 0 to 18 years of age. The concentrations of N-acetyl-aspartate (an indicator for adult-type neurons and axons), creatine (energy metabolite), and glutamate (excitatory neurotransmitter) increased rapidly between birth and 3 months, a period of rapid axonal growth and synapse formation. Myo-inositol, implicated in cell signaling and a precursor of membrane phospholipid, as well as an osmolyte and astrocyte marker, declined rapidly during this period. Choline, a membrane metabolite and indicator for de novo myelin and cell membrane synthesis, peaked from birth until approximately 3 months, and then declined gradually, reaching a plateau at early childhood. Similarly, taurine, involved in neuronal excitability, synaptic potentiation, and osmoregulation, was high until approximately 3 months and thereafter declined. These data indicate that the first 3 months of postnatal life are a critical period of rapid metabolic changes in the development of the human brain. This study of the developmental profiles of the major brain metabolites provides essential baseline information for future analyses of the pediatric health and disease.
doi:10.1093/cercor/bhs283
PMCID: PMC3888212  PMID: 22952278
human brain maturation; magnetic resonance spectroscopy; metabolism; myelination
11.  Quantification and Discrimination of Abnormal Sulcal Patterns in Polymicrogyria 
Cerebral Cortex (New York, NY)  2012;23(12):3007-3015.
Polymicrogyria (PMG) is a malformation of cortical development characterized by an irregular gyral pattern and its diagnosis and severity have been qualitatively judged by visual inspection of imaging features. We aimed to provide a quantitative description of abnormal sulcal patterns for individual PMG brains using our sulcal graph-based analysis and examined the association with language impairment. The sulcal graphs were constructed from magnetic resonance images in 26 typical developing and 18 PMG subjects and the similarity between sulcal graphs was computed by using their geometric and topological features. The similarities between typical and PMG groups were significantly lower than the similarities measured within the typical group. Furthermore, more lobar regions were determined to be abnormal in most patients when compared with the visual diagnosis of PMG involvement, suggesting that PMG may have more global effects on cortical folding than previously expected. Among the PMG, the group with intact language development showed sulcal patterns more closely matched with the typical than the impaired group in the left parietal lobe. Our approach shows the potential to provide a quantitative means for detecting the severity and extent of involvement of cortical malformation and a greater understanding of genotype–phenotype and clinical-imaging features correlations.
doi:10.1093/cercor/bhs292
PMCID: PMC3888213  PMID: 22989584
cortical malformation; graph matching; polymicrogyria; sulcal pattern
12.  Axo-Dendritic Overlap and Laminar Projection Can Explain Interneuron Connectivity to Pyramidal Cells 
Cerebral Cortex (New York, NY)  2012;23(12):2790-2802.
Neocortical GABAergic interneurons have important roles in the normal and pathological states of the circuit. Recent work has revealed that somatostatin-positive (SOM) and parvalbumin-positive (PV) interneurons connect promiscuously to pyramidal cells (PCs). We investigated whether Peters' rule, that is, the spatial overlap of axons and dendrites, could explain this unspecific connectivity. We reconstructed the morphologies of P11–17 mouse SOM and PV interneurons and their PC targets, and performed Monte Carlo simulations to build maps of predicted connectivity based on Peters' rule. We then compared the predicted with the real connectivity maps, measured with 2-photon uncaging experiments, and found no statistical differences between them in the probability of connection as a function of distance and in the spatial structure of the maps. Finally, using reconstructions of connected SOM-PCs and PV-PCs, we investigated the subcellular targeting specificity, by analyzing the postsynaptic position of the contacts, and found that their spatial distributions match the distribution of postsynaptic PC surface area, in agreement with Peters' rule. Thus, the spatial profile of the connectivity maps and even the postsynaptic position of interneuron contacts could result from the mere overlap of axonal and dendritic arborizations and their laminar projections patterns.
doi:10.1093/cercor/bhs210
PMCID: PMC3968298  PMID: 22941716
GABA; microcircuit; Peters' rule; synapse
13.  The Doublesex Homolog Dmrt5 is Required for the Development of the Caudomedial Cerebral Cortex in Mammals 
Cerebral Cortex (New York, NY)  2012;23(11):2552-2567.
Regional patterning of the cerebral cortex is initiated by morphogens secreted by patterning centers that establish graded expression of transcription factors within cortical progenitors. Here, we show that Dmrt5 is expressed in cortical progenitors in a high-caudomedial to low-rostrolateral gradient. In its absence, the cortex is strongly reduced and exhibits severe abnormalities, including agenesis of the hippocampus and choroid plexus and defects in commissural and thalamocortical tracts. Loss of Dmrt5 results in decreased Wnt and Bmp in one of the major telencephalic patterning centers, the dorsomedial telencephalon, and in a reduction of Cajal–Retzius cells. Expression of the dorsal midline signaling center-dependent transcription factors is downregulated, including Emx2, which promotes caudomedial fates, while the rostral determinant Pax6, which is inhibited by midline signals, is upregulated. Consistently, Dmrt5−/− brains exhibit patterning defects with a dramatic reduction of the caudomedial cortex. Dmrt5 is increased upon the activation of Wnt signaling and downregulated in Gli3xt/xt mutants. We conclude that Dmrt5 is a novel Wnt-dependent transcription factor required for early cortical development and that it may regulate initial cortical patterning by promoting dorsal midline signaling center formation and thereby helping to establish the graded expression of the other transcription regulators of cortical identity.
doi:10.1093/cercor/bhs234
PMCID: PMC3792737  PMID: 22923088
choroid plexus; cortical hem; Emx2; telencephalon; Wnt/Bmp
14.  Coupling Diffusion Imaging with Histological and Gene Expression Analysis to Examine the Dynamics of Cortical Areas across the Fetal Period of Human Brain Development 
Cerebral Cortex (New York, NY)  2012;23(11):2620-2631.
As a prominent component of the human fetal brain, the structure of the cerebral wall is characterized by its laminar organization which includes the radial glial scaffold during fetal development. Diffusion tensor imaging (DTI) is useful to quantitatively delineate the microstructure of the developing brain and to clearly identify transient fetal layers in the cerebral wall. In our study, the spatio-temporal microstructural changes in the developing human fetal cerebral wall were quantitatively characterized with high-resolution DTI data of postmortem fetal brains from 13 to 21 gestational weeks. Eleven regions of interest for each layer in the entire cerebral wall were included. Distinctive time courses of microstructural changes were revealed for 11 regions of the neocortical plate. A histological analysis was also integrated to elucidate the relationship between DTI fractional anisotropy (FA) and histology. High FA values correlated with organized radial architecture in histological image. Expression levels of 17565 genes were quantified for each of 11 regions of human fetal neocortex from 13 to 21 gestational weeks to identify transcripts showing significant correlation with FA change. These correlations suggest that the heterogeneous and regionally specific microstructural changes of the human neocortex are related to different gene expression patterns.
doi:10.1093/cercor/bhs241
PMCID: PMC3792738  PMID: 22933464
development; diffusion tensor imaging; gene expression; histology; human fetal brain
15.  Neural Substrates of Executive Dysfunction in Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): a Brain Potential Study 
Cerebral Cortex (New York, NY)  2012;23(11):2657-2666.
Executive dysfunction in fragile X-associated tremor/ataxia syndrome (FXTAS) has been suggested to mediate other cognitive impairments. In the present study, event-related potentials and neuropsychological testing were combined to investigate the brain mechanisms underlying the executive dysfunction in FXTAS. Thirty-two-channel electroencephalography was recorded during an auditory “oddball” task requiring dual responses. FXTAS patients (N= 41, mean age= 62) displayed prolonged latencies of N1 and P3 and reduced amplitudes of P2 and P3, whereas their N2 measures remained within the normal range, indicating relatively preserved early-stage auditory attention but markedly impaired late-stage attention and working memory updating processes (as indexed by P3). Topographical mapping revealed a typical parietal P3 peak preceded by a prominent fronto-central P3 in normal control subjects (N= 32), whereas FXTAS patients had decreased parietal P3 amplitude and diminished fronto-central positivities with a delayed onset (∼50 ms later than controls, P < 0.002). The P3 abnormalities were associated with lower executive function test (e.g., BDS-2) scores. Smaller P3 amplitudes also correlated with increased CGG repeat length of fragile X mental retardation 1 (FMR1) gene and higher FMR1 mRNA levels. These results indicate that abnormal fronto-parietal attentional network dynamics underlie executive dysfunction, the cardinal feature of cognitive impairment in FXTAS.
doi:10.1093/cercor/bhs251
PMCID: PMC3792740  PMID: 22918986
attention; executive function; FMR1; P300; working memory
16.  POU-III Transcription Factors (Brn1, Brn2, and Oct6) Influence Neurogenesis, Molecular Identity, and Migratory Destination of Upper-Layer Cells of the Cerebral Cortex 
Cerebral Cortex (New York, NY)  2012;23(11):2632-2643.
The upper layers (II–IV) are the most prominent distinguishing feature of mammalian neocortex compared with avian or reptilian dorsal cortex, and are vastly expanded in primates. Although the time-dependent embryonic generation of upper-layer cells is genetically instructed within their parental progenitors, mechanisms governing cell-intrinsic fate transitions remain obscure. POU-homeodomain transcription factors Pou3f3 and Pou3f2 (Brn1 and Brn2) are known to label postmitotic upper-layer cells, and are redundantly required for their production. We find that the onset of Pou3f3/2 expression actually occurs in ventricular zone (VZ) progenitors, and that Pou3f3/2 subsequently label neural progeny switching from deep-layer Ctip2+ identity to Satb2+ upper-layer fate as they migrate to proper superficial positions. By using an Engrailed dominant-negative repressor, we show that sustained neurogenesis after the deep- to upper-layer transition requires the proneual action of Pou3fs in VZ progenitors. Conversely, single-gene overexpression of any Pou3f in early neural progenitors is sufficient to specify the precocious birth of Satb2+ daughter neurons that extend axons to the contralateral hemisphere, as well as exhibit robust pia-directed migration that is characteristic of upper-layer cells. Finally, we demonstrate that Pou3fs influence multiple stages of neurogenesis by suppressing Notch effector Hes5, and promoting the expression of proneural transcription factors Tbr2 and Tbr1.
doi:10.1093/cercor/bhs252
PMCID: PMC3792741  PMID: 22892427
development; differentiation; In utero electroporation; Neurogenesis; Upper layer
17.  Differential Wiring of Layer 2/3 Neurons Drives Sparse and Reliable Firing During Neocortical Development 
Cerebral Cortex (New York, NY)  2012;23(11):2690-2699.
Sensory information is transmitted with high fidelity across multiple synapses until it reaches the neocortex. There, individual neurons exhibit enormous variability in responses. The source of this diversity in output has been debated. Using transgenic mice expressing the green fluorescent protein coupled to the activity-dependent gene c-fos, we identified neurons with a history of elevated activity in vivo. Focusing on layer 4 to layer 2/3 connections, a site of strong excitatory drive at an initial stage of cortical processing, we find that fluorescently tagged neurons receive significantly greater excitatory and reduced inhibitory input compared with neighboring, unlabeled cells. Differential wiring of layer 2/3 neurons arises early in development and requires sensory input to be established. Stronger connection strength is not associated with evidence for recent synaptic plasticity, suggesting that these more active ensembles may not be generated over short time scales. Paired recordings show fosGFP+ neurons spike at lower stimulus thresholds than neighboring, fosGFP− neurons. These data indicate that differences in circuit construction can underlie response heterogeneity amongst neocortical neurons.
doi:10.1093/cercor/bhs257
PMCID: PMC3792743  PMID: 22918982
AMPA receptors; activity-dependent gene expression; critical period; somatosensory; subnetworks
18.  Mapping Region-Specific Longitudinal Cortical Surface Expansion from Birth to 2 Years of Age 
Cerebral Cortex (New York, NY)  2012;23(11):2724-2733.
The human cerebral cortex develops rapidly and dynamically in the first 2 years of life. It has been shown that cortical surface expansion from term infant to adult is highly nonuniform in a cross-sectional study. However, little is known about the longitudinal cortical surface expansion during early postnatal stages. In this article, we generate the first longitudinal surface-based atlases of human cortical structures at 0, 1, and 2 years of age from 73 healthy subjects. On the basis of the surface-based atlases, we study the longitudinal cortical surface expansion in the first 2 years of life and find that cortical surface expansion is age related and region specific. In the first year, cortical surface expands dramatically, with an average expansion of 1.80 times. In particular, regions of superior and medial temporal, superior parietal, medial orbitofrontal, lateral anterior prefrontal, occipital cortices, and postcentral gyrus expand relatively larger than other regions. In the second year, cortical surface still expands substantially, with an average expansion of 1.20 times. In particular, regions of superior and middle frontal, orbitofrontal, inferior temporal, inferior parietal, and superior parietal cortices expand relatively larger than other regions. These region-specific patterns of cortical surface expansion are related to cognitive and functional development at these stages.
doi:10.1093/cercor/bhs265
PMCID: PMC3792744  PMID: 22923087
cortical surface expansion; longitudinal cortical development; longitudinal surface-based atlas; infant cortical folding
19.  Independence of Early Speech Processing from Word Meaning 
Cerebral Cortex (New York, NY)  2012;23(10):2370-2379.
We combined magnetoencephalography (MEG) with magnetic resonance imaging and electrocorticography to separate in anatomy and latency 2 fundamental stages underlying speech comprehension. The first acoustic-phonetic stage is selective for words relative to control stimuli individually matched on acoustic properties. It begins ∼60 ms after stimulus onset and is localized to middle superior temporal cortex. It was replicated in another experiment, but is strongly dissociated from the response to tones in the same subjects. Within the same task, semantic priming of the same words by a related picture modulates cortical processing in a broader network, but this does not begin until ∼217 ms. The earlier onset of acoustic-phonetic processing compared with lexico-semantic modulation was significant in each individual subject. The MEG source estimates were confirmed with intracranial local field potential and high gamma power responses acquired in 2 additional subjects performing the same task. These recordings further identified sites within superior temporal cortex that responded only to the acoustic-phonetic contrast at short latencies, or the lexico-semantic at long. The independence of the early acoustic-phonetic response from semantic context suggests a limited role for lexical feedback in early speech perception.
doi:10.1093/cercor/bhs228
PMCID: PMC3767959  PMID: 22875868
ECoG; MEG; N400; speech processing
20.  Functional Connection Between Posterior Superior Temporal Gyrus and Ventrolateral Prefrontal Cortex in Human 
Cerebral Cortex (New York, NY)  2012;23(10):2309-2321.
The connection between auditory fields of the temporal lobe and prefrontal cortex has been well characterized in nonhuman primates. Little is known of temporofrontal connectivity in humans, however, due largely to the fact that invasive experimental approaches used so successfully to trace anatomical pathways in laboratory animals cannot be used in humans. Instead, we used a functional tract-tracing method in 12 neurosurgical patients with multicontact electrode arrays chronically implanted over the left (n = 7) or right (n = 5) perisylvian temporal auditory cortex (area PLST) and the ventrolateral prefrontal cortex (VLPFC) of the inferior frontal gyrus (IFG) for diagnosis and treatment of medically intractable epilepsy. Area PLST was identified by the distribution of average auditory-evoked potentials obtained in response to simple and complex sounds. The same sounds evoked little if there is any activity in VLPFC. A single bipolar electrical pulse (0.2 ms, charge-balanced) applied between contacts within physiologically identified PLST resulted in polyphasic evoked potentials clustered in VLPFC, with greatest activation being in pars triangularis of the IFG. The average peak latency of the earliest negative deflection of the evoked potential on VLPFC was 13.48 ms (range: 9.0–18.5 ms), providing evidence for a rapidly conducting pathway between area PLST and VLPFC.
doi:10.1093/cercor/bhs220
PMCID: PMC3767955  PMID: 22879355
auditory evoked potential; electrical stimulation; functional connectivity
21.  Lateral Prefrontal Cortex is Organized into Parallel Dorsal and Ventral Streams Along the Rostro-Caudal Axis 
Cerebral Cortex (New York, NY)  2012;23(10):2457-2466.
Anatomical connectivity differences between the dorsal and ventral lateral prefrontal cortex (PFC) of the non-human primate strongly suggests that these regions support different functions. However, after years of study, it remains unclear whether these regions are functionally distinct. In contrast, there has been a groundswell of recent studies providing evidence for a rostro-caudal functional organization, along the lateral as well as dorsomedial frontal cortex. Thus, it is not known whether dorsal and ventral regions of lateral PFC form distinct functional networks and how to reconcile any dorso-ventral organization with the medio-lateral and rostro-caudal axes. Here, we used resting-state connectivity data to identify parallel dorsolateral and ventrolateral streams of intrinsic connectivity with the dorsomedial frontal cortex. Moreover, we show that this connectivity follows a rostro-caudal gradient. Our results provide evidence for a novel framework for the intrinsic organization of the frontal cortex that incorporates connections between medio-lateral, dorso-ventral, and rostro-caudal axes.
doi:10.1093/cercor/bhs223
PMCID: PMC3767956  PMID: 22879354
cognitive control; connectivity; dorsolateral; intrinsic; prefrontal cortex; resting state; ventrolateral
22.  Functional Significance of Atypical Cortical Organization in Spina Bifida Myelomeningocele: Relations of Cortical Thickness and Gyrification with IQ and Fine Motor Dexterity 
Cerebral Cortex (New York, NY)  2012;23(10):2357-2369.
The cortex in spina bifida myelomeningocele (SBM) is atypically organized, but it is not known how specific features of atypical cortical organization promote or disrupt cognitive and motor function. Relations of deviant cortical thickness and gyrification with IQ and fine motor dexterity were investigated in 64 individuals with SBM and 26 typically developing (TD) individuals, aged 8–28 years. Cortical thickness and 3D local gyrification index (LGI) were quantified from 33 cortical regions per hemisphere using FreeSurfer. Results replicated previous findings, showing regions of higher and lower cortical thickness and LGI in SBM relative to the TD comparison individuals. Cortical thickness and LGI were negatively associated in most cortical regions, though less consistently in the TD group. Whereas cortical thickness and LGI tended to be negatively associated with IQ and fine motor outcomes in regions that were thicker or more gyrified in SBM, associations tended to be positive in regions that were thinner or less gyrified in SBM. The more deviant the levels of cortical thickness and LGI—whether higher or lower relative to the TD group—the more impaired the IQ and fine motor outcomes, suggesting that these cortical atypicalities in SBM are functionally maladaptive, rather than adaptive.
doi:10.1093/cercor/bhs226
PMCID: PMC3767957  PMID: 22875857
atypical cortical organization; cortical thickness; gyrification; neurobehavioral function; spina bifida
23.  The Development of Hub Architecture in the Human Functional Brain Network 
Cerebral Cortex (New York, NY)  2012;23(10):2380-2393.
Functional hubs are brain regions that play a crucial role in facilitating communication among parallel, distributed brain networks. The developmental emergence and stability of hubs, however, is not well understood. The current study used measures of network topology drawn from graph theory to investigate the development of functional hubs in 99 participants, 10–20 years of age. We found that hub architecture was evident in late childhood and was stable from adolescence to early adulthood. Connectivity between hub and non-hub (“spoke”) regions, however, changed with development. From childhood to adolescence, the strength of connections between frontal hubs and cortical and subcortical spoke regions increased. From adolescence to adulthood, hub–spoke connections with frontal hubs were stable, whereas connectivity between cerebellar hubs and cortical spoke regions increased. Our findings suggest that a developmentally stable functional hub architecture provides the foundation of information flow in the brain, whereas connections between hubs and spokes continue to develop, possibly supporting mature cognitive function.
doi:10.1093/cercor/bhs227
PMCID: PMC3767958  PMID: 22875861
adolescents; brain networks; development; functional connectivity; graph theory
24.  Category-Specific Neural Oscillations Predict Recall Organization During Memory Search 
Cerebral Cortex (New York, NY)  2012;23(10):2407-2422.
Retrieved-context models of human memory propose that as material is studied, retrieval cues are constructed that allow one to target particular aspects of past experience. We examined the neural predictions of these models by using electrocorticographic/depth recordings and scalp electroencephalography (EEG) to characterize category-specific oscillatory activity, while participants studied and recalled items from distinct, neurally discriminable categories. During study, these category-specific patterns predict whether a studied item will be recalled. In the scalp EEG experiment, category-specific activity during study also predicts whether a given item will be recalled adjacent to other same-category items, consistent with the proposal that a category-specific retrieval cue is used to guide memory search. Retrieved-context models suggest that integrative neural circuitry is involved in the construction and maintenance of the retrieval cue. Consistent with this hypothesis, we observe category-specific patterns that rise in strength as multiple same-category items are studied sequentially, and find that individual differences in this category-specific neural integration during study predict the degree to which a participant will use category information to organize memory search. Finally, we track the deployment of this retrieval cue during memory search: Category-specific patterns are stronger when participants organize their responses according to the category of the studied material.
doi:10.1093/cercor/bhs229
PMCID: PMC3767960  PMID: 22875859
category clustering; episodic memory; free recall; neural integration; pattern classification
25.  Modeling Ketamine Effects on Synaptic Plasticity During the Mismatch Negativity 
Cerebral Cortex (New York, NY)  2012;23(10):2394-2406.
This paper presents a model-based investigation of mechanisms underlying the reduction of mismatch negativity (MMN) amplitudes under the NMDA-receptor antagonist ketamine. We applied dynamic causal modeling and Bayesian model selection to data from a recent ketamine study of the roving MMN paradigm, using a cross-over, double-blind, placebo-controlled design. Our modeling was guided by a predictive coding framework that unifies contemporary “adaptation” and “model adjustment” MMN theories. Comparing a series of dynamic causal models that allowed for different expressions of neuronal adaptation and synaptic plasticity, we obtained 3 major results: 1) We replicated previous results that both adaptation and short-term plasticity are necessary to explain MMN generation per se; 2) we found significant ketamine effects on synaptic plasticity, but not adaptation, and a selective ketamine effect on the forward connection from left primary auditory cortex to superior temporal gyrus; 3) this model-based estimate of ketamine effects on synaptic plasticity correlated significantly with ratings of ketamine-induced impairments in cognition and control. Our modeling approach thus suggests a concrete mechanism for ketamine effects on MMN that correlates with drug-induced psychopathology. More generally, this demonstrates the potential of modeling for inferring on synaptic physiology, and its pharmacological modulation, from electroencephalography data.
doi:10.1093/cercor/bhs238
PMCID: PMC3767962  PMID: 22875863
Bayesian model selection; dynamic causal modeling; effective connectivity; mismatch negativity; NMDA receptor

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