Functional partitioning of sentence processing and emotional prosody in the right perisylvian cortex after perinatal stroke.

In healthy adults different language abilities-sentence processing versus emotional prosody-are supported by the left (LH) versus the right hemisphere (RH), respectively. However, after LH stroke in infancy, RH regions support both abilities with normal outcomes. We investigated how these abilities co-exist in RH regions after LH perinatal stroke by evaluating the overlap in the activation between two fMRI tasks that probed auditory sentence processing and emotional prosody processing. We compared the overlap for these two functions in the RH of individuals with perinatal stroke with the symmetry of these functions in the LH and RH of their healthy siblings. We found less activation overlap in the RH of individuals with LH perinatal stroke than would be expected if both functions retained their typical spatial layout, suggesting that their spatial segregation may be an important feature of a functioning language system.

One right can make a left: sentence processing in the right hemisphere after perinatal stroke.

When brain regions that are critical for a cognitive function in adulthood are irreversibly damaged at birth, what patterns of plasticity support the successful development of that function in an alternative location? Here we investigate the consistency of language organization in the right hemisphere (RH) after a left hemisphere (LH) perinatal stroke. We analyzed fMRI data collected during an auditory sentence comprehension task on 14 people with large cortical LH perinatal arterial ischemic strokes (left hemisphere perinatal stroke (LHPS) participants) and 11 healthy sibling controls using a "top voxel" approach that allowed us to compare the same number of active voxels across each participant and in each hemisphere for controls. We found (1) LHPS participants consistently recruited the same RH areas that were a mirror-image of typical LH areas, and (2) the RH areas recruited in LHPS participants aligned better with the strongly activated LH areas of the typically developed brains of control participants (when flipped images were compared) than the weakly activated RH areas. Our findings suggest that the successful development of language processing in the RH after a LH perinatal stroke may in part depend on recruiting an arrangement of frontotemporal areas reflective of the typical dominant LH.

Language and developmental plasticity after perinatal stroke.

The mature human brain is lateralized for language, with the left hemisphere (LH) primarily responsible for sentence processing and the right hemisphere (RH) primarily responsible for processing suprasegmental aspects of language such as vocal emotion. However, it has long been hypothesized that in early life there is plasticity for language, allowing young children to acquire language in other cortical regions when LH areas are damaged. If true, what are the constraints on functional reorganization? Which areas of the brain can acquire language, and what happens to the functions these regions ordinarily perform? We address these questions by examining long-term outcomes in adolescents and young adults who, as infants, had a perinatal arterial ischemic stroke to the LH areas ordinarily subserving sentence processing. We compared them with their healthy age-matched siblings. All participants were tested on a battery of behavioral and functional imaging tasks. While stroke participants were impaired in some nonlinguistic cognitive abilities, their processing of sentences and of vocal emotion was normal and equal to that of their healthy siblings. In almost all, these abilities have both developed in the healthy RH. Our results provide insights into the remarkable ability of the young brain to reorganize language. Reorganization is highly constrained, with sentence processing almost always in the RH frontotemporal regions homotopic to their location in the healthy brain. This activation is somewhat segregated from RH emotion processing, suggesting that the two functions perform best when each has its own neural territory.

Developmental changes in neural lateralization for visual-spatial function: Evidence from a line-bisection task.

Studies of hemispheric specialization have traditionally cast the left hemisphere as specialized for language and the right hemisphere for spatial function. Much of the supporting evidence for this separation of function comes from studies of healthy adults and those who have sustained lesions to the right or left hemisphere. However, we know little about the developmental origins of lateralization. Recent evidence suggests that the young brain represents language bilaterally, with 4-6-year-olds activating the left-hemisphere regions known to support language in adults as well as homotopic regions in the right hemisphere. This bilateral pattern changes over development, converging on left-hemispheric activation in late childhood. In the present study, we ask whether this same developmental trajectory is observed in a spatial task that is strongly right-lateralized in adults-the line bisection (or "Landmark") task. We examined fMRI activation among children ages 5-11 years as they were asked to judge which end of a bisected vertical line was longer. We found that young children showed bilateral activation, with activation in the same areas of the right hemisphere as has been shown among adults, as well as in the left hemisphere homotopic regions. By age 10, activation was right-lateralized. This strongly resembles the developmental trajectory for language, moving from bilateral to lateralized activation. We discuss potential underlying mechanisms and suggest that understanding the development of lateralization for a range of cognitive functions can play a crucial role in understanding general principles of how and why the brain comes to lateralize certain functions.

Development of bilateral parietal activation for complex visual-spatial function: Evidence from a visual-spatial construction task.

The neural representation of visual-spatial functions has traditionally been ascribed to the right hemisphere, but little is known about these representations in children, including whether and how lateralization of function changes over the course of development. Some studies suggest bilateral activation early in life that develops toward right-lateralization in adulthood, while others find evidence of right-hemispheric dominance in both children and adults. We used a complex visual-spatial construction task to examine the nature of lateralization and its developmental time course in children ages 5-11 years. Participants were shown two puzzle pieces and were asked whether the pieces could fit together to make a square; responses required either mental translation of the pieces (Translation condition) or both mental translation and rotation of the pieces (Rotation condition). Both conditions were compared to a matched Luminance control condition that was similar in terms of visual content and difficulty but required no spatial analysis. Group and single-subject analyses revealed that the Rotation and Translation conditions elicited strongly bilateral activation in the same parietal and occipital locations as have been previously found for adults. These findings show that visual-spatial construction consistently elicits robust bilateral activation from age 5 through adulthood. This challenges the idea that spatial functions are all right-lateralized, either during early development or in adulthood. More generally, these findings provide insights into the developmental course of lateralization across different spatial skills and how this may be influenced by the computational requirements of the particular functions involved.

The neural basis of language development: Changes in lateralization over age.

We have long known that language is lateralized to the left hemisphere (LH) in most neurologically healthy adults. In contrast, findings on lateralization of function during development are more complex. As in adults, anatomical, electrophysiological, and neuroimaging studies in infants and children indicate LH lateralization for language. However, in very young children, lesions to either hemisphere are equally likely to result in language deficits, suggesting that language is distributed symmetrically early in life. We address this apparent contradiction by examining patterns of functional MRI (fMRI) language activation in children (ages 4 through 13) and adults (ages 18 through 29). In contrast to previous studies, we focus not on lateralization per se but rather on patterns of left-hemisphere (LH) and right-hemisphere (RH) activation across individual participants over age. Our analyses show significant activation not only in the LH language network but also in their RH homologs in all of the youngest children (ages 4 through 6). The proportion of participants showing significant RH activation decreases over age, with over 60% of adults lacking any significant RH activation. A whole-brain correlation analysis revealed an age-related decrease in language activation only in the RH homolog of Broca's area. This correlation was independent of task difficulty. We conclude that, while language is left-lateralized throughout life, the RH contribution to language processing is also strong early in life and decreases through childhood. Importantly, this early RH language activation may represent a developmental mechanism for recovery following early LH injury.

What you say versus how you say it: Comparing sentence comprehension and emotional prosody processing using fMRI.

While language processing is often described as lateralized to the left hemisphere (LH), the processing of emotion carried by vocal intonation is typically attributed to the right hemisphere (RH) and more specifically, to areas mirroring the LH language areas. However, the evidence base for this hypothesis is inconsistent, with some studies supporting right-lateralization but others favoring bilateral involvement in emotional prosody processing. Here we compared fMRI activations for an emotional prosody task with those for a sentence comprehension task in 20 neurologically healthy adults, quantifying lateralization using a lateralization index. We observed right-lateralized frontotemporal activations for emotional prosody that roughly mirrored the left-lateralized activations for sentence comprehension. In addition, emotional prosody also evoked bilateral activation in pars orbitalis (BA47), amygdala, and anterior insula. These findings are consistent with the idea that analysis of the auditory speech signal is split between the hemispheres, possibly according to their preferred temporal resolution, with the left preferentially encoding phonetic and the right encoding prosodic information. Once processed, emotional prosody information is fed to domain-general emotion processing areas and integrated with semantic information, resulting in additional bilateral activations.

Revisiting the Landmark Task as a tool for studying hemispheric specialization: What's really right?

The "Landmark Task" (LT) is a line bisection judgment task that predominantly activates right parietal cortex. The typical version requires observers to judge bisections for horizontal lines that cross their egocentric midline and therefore may depend on spatial attention as well as spatial representation of the line segments. To ask whether the LT is indeed right-lateralized regardless of spatial attention (for which the right hemisphere is known to be important), we examined LT activation in 26 neurologically healthy young adults using vertical (instead of horizontal) stimuli, as compared with a luminance control task that made similar demands on spatial attention. We also varied task difficulty, which is known to affect lateralization in both spatial and language tasks. Despite these changes to the task, we observed right-lateralized parietal activations similar to those reported in other LT studies, both at group level and in individual lateralization indices. We conclude that LT activation is robustly right-lateralized, perhaps uniquely so among commonly-studied spatial tasks. We speculate that the unique properties of the LT reside in its requirement to judge relative magnitudes of the two line segments, rather than in the more general aspects of spatial attention or visual-spatial representation.

Bilateral parietal activations for complex visual-spatial functions: Evidence from a visual-spatial construction task.

In this paper, we examine brain lateralization patterns for a complex visual-spatial task commonly used to assess general spatial abilities. Although spatial abilities have classically been ascribed to the right hemisphere, evidence suggests that at least some tasks may be strongly bilateral. For example, while functional neuroimaging studies show right-lateralized activations for some spatial tasks (e.g., line bisection), bilateral activations are often reported for others, including classic spatial tasks such as mental rotation. Moreover, constructive apraxia has been reported following left- as well as right-hemisphere damage in adults, suggesting a role for the left hemisphere in spatial function. Here, we use functional neuroimaging to probe lateralization while healthy adults carry out a simplified visual-spatial construction task, in which they judge whether two geometric puzzle pieces can be combined to form a square. The task evokes strong bilateral activations, predominantly in parietal and lateral occipital cortex. Bilaterality was observed at the single-subject as well as at the group level, and regardless of whether specific items required mental rotation. We speculate that complex visual-spatial tasks may generally engage more bilateral activation of the brain than previously thought, and we discuss implications for understanding hemispheric specialization for spatial functions.

Identification of genes regulated by the cepIR quorum-sensing system in Burkholderia cenocepacia by high-throughput screening of a random promoter library.

The Burkholderia cenocepacia cepIR quorum-sensing system regulates expression of extracellular proteases, chitinase, and genes involved in ornibactin biosynthesis, biofilm formation, and motility. In a genome-wide screen we identified cepIR-regulated genes by screening a random promoter library of B. cenocepacia K56-2 constructed in a luminescence reporter detection plasmid for differential expression in response to N-octanoyl-l-homoserine lactone (OHL). Eighty-nine clones were identified; in 58 of these clones expression was positively regulated by cepIR, and in 31 expression was negatively regulated by cepIR. The expression profiles of the 89 promoter clones were compared in the cepI mutant K56-dI2 in medium supplemented with 30 pM OHL and K56-2 to confirm that the presence of OHL restored expression to wild-type levels. To validate the promoter library observations and to determine the effect of a cepR mutation on expression of selected genes, the mRNA levels of nine genes whose promoters were predicted to be regulated by cepR were quantitated by quantitative reverse transcription-PCR in the wild type and cepI and cepR mutants. The expression levels of all nine genes were similar in the cepI and cepR mutants and consistent with the promoter-lux reporter activity. The expression of four selected cepIR-regulated gene promoters was examined in a cciIR mutant, and two of these promoters were also regulated by cciIR. This study extends our understanding of genes whose expression is influenced by cepIR and indicates the global regulatory effect of the cepIR system in B. cenocepacia.

Identification of potential CepR regulated genes using a cep box motif-based search of the Burkholderia cenocepacia genome.

BACKGROUND: The Burkholderia cenocepacia CepIR quorum sensing system has been shown to positively and negatively regulate genes involved in siderophore production, protease expression, motility, biofilm formation and virulence. In this study, two approaches were used to identify genes regulated by the CepIR quorum sensing system. Transposon mutagenesis was used to create lacZ promoter fusions in a cepI mutant that were screened for differential expression in the presence of N-acylhomoserine lactones. A bioinformatics approach was used to screen the B. cenocepacia J2315 genome for CepR binding site motifs. RESULTS: Four positively regulated and two negatively regulated genes were identified by transposon mutagenesis including genes potentially involved in iron transport and virulence. The promoter regions of selected CepR regulated genes and site directed mutagenesis of the cepI promoter were used to predict a consensus cep box sequence for CepR binding. The first-generation consensus sequence for the cep box was used to identify putative cep boxes in the genome sequence. Eight potential CepR regulated genes were chosen and the expression of their promoters analyzed. Six of the eight were shown to be regulated by CepR. A second generation motif was created from the promoters of these six genes in combination with the promoters of cepI, zmpA, and two of the CepR regulated genes identified by transposon mutagenesis. A search of the B. cenocepacia J2315 genome with the new motif identified 55 cep boxes in 65 promoter regions that may be regulated by CepR. CONCLUSION: Using transposon mutagenesis and bioinformatics expression of twelve new genes have been determined to be regulated by the CepIR quorum sensing system. A cep box consensus sequence has been developed based on the predicted cep boxes of ten CepR regulated genes. This consensus cep box has led to the identification of over 50 new genes potentially regulated by the CepIR quorum sensing system.

Identification of N-acylhomoserine lactones in mucopurulent respiratory secretions from cystic fibrosis patients.

Pseudomonas aeruginosa and species of the Burkholderia cepacia complex are the primary bacterial pathogens contributing to lung disease in patients with cystic fibrosis. Quorum sensing systems using N-acyl homoserine lactone (AHL) signal molecules are involved in the regulation of a number of virulence factors in these species. Extracts of mucopurulent respiratory secretions from 13 cystic fibrosis patients infected with P. aeruginosa and/or strains of the B. cepacia complex were fractionated using reverse-phase fast pressure liquid chromatography and analyzed for the presence of AHLs using a traI-luxCDABE-based reporter that responds to AHLs with acyl chains ranging between 4 and 12 carbons. Using this assay system, a broad range of AHLs were detected and identified despite being present at low concentrations in limited sample volumes. N-(3-oxo-dodecanoyl)-l-homoserine lactone, N-(3-oxo-decanoyl)-l-homoserine lactone and N-octanoyl-l-homoserine lactone (OHL) were the AHLs most frequently identified. OHL and N-decanoyl-l-homoserine lactone were detected in nanomolar concentrations compared to picomolar amounts of the 3-oxo-derivatives of the AHLs identified.

Role of Bacillus thuringiensis Cry1 delta endotoxin binding in determining potency during lepidopteran larval development.

Five economically important crop pests, Manduca sexta, Pieris brassicae, Mamestra brassicae, Spodoptera exigua, and Agrotis ipsilon, were tested at two stages of larval development for susceptibility to Bacillus thuringiensis toxins Cry1Ac, Cry1Ca, Cry1J, and Cry1Ba. Bioassay results for M. sexta showed that resistance to all four Cry toxins increased from the neonate stage to the third-instar stage; the increase in resistance was most dramatic for Cry1Ac, the potency of which decreased 37-fold. More subtle increases in resistance during larval development were seen in M. brassicae for Cry1Ca and in P. brassicae for Cry1Ac and Cry1J. By contrast, the sensitivity of S. exigua did not change during development. At both larval stages, A. ipsilon was resistant to all four toxins. Because aminopeptidase N (APN) is a putative Cry1 toxin binding protein, APN activity was measured in neonate and third-instar brush border membrane vesicles (BBMV). With the exception of S. exigua, APN activity was found to be significantly lower in neonates than in third-instar larvae and thus inversely correlated with increased resistance during larval development. The binding characteristics of iodinated Cry1 toxins were determined for neonate and third-instar BBMV. In M. sexta, the increased resistance to Cry1Ac and Cry1Ba during larval development was positively correlated with fewer binding sites in third-instar BBMV than in neonate BBMV. The other species-instar-toxin combinations did not reveal positive correlations between potency and binding characteristics. The correlation between binding and potency was inconsistent for the species-instar-toxin combinations used in this study, reaffirming the complex mode of action of Cry1 toxins.