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Nitric oxide (NO) signalling has been implicated in the pathogenesis of several mental illnesses; however, its specific contribution remains unclear. We investigated whether peripheral NO concentration is associated with specific diagnoses, and whether there is a correlation with genetic variation in NO synthase (NOS) genes. We included 185 participants in the study; 52 healthy controls, 43 major depressive disorder (MDD) patients, 41 bipolar disorder (BPD) patients, and 49 schizophrenia (SCZ) patients. Clinical, genetic, and biochemical data were collected at admission to a psychiatric hospital and at discharge. Serum was used to quantify concentration of the stable NO metabolites nitrite and nitrate. Individuals were genotyped for the NOS1 exon 1f variable number of tandem repeats 1 (VNTR1) polymorphism, and single nucleotide polymorphisms (SNPs) in the NOS1, NOS1AP and NOS3 genes. At admission, SCZ patients were found to have significantly higher peripheral NO metabolite (NOx-) concentrations compared to healthy controls, MDD and BPD patients. NOS1 exon 1f VNTR1 short allele carriers were found to have significantly increased NOx- concentration. Moreover, this result was still significant in patients even at discharge. The data also revealed that patients who did not remit in their depressive symptoms had significantly increased NOx- concentration compared to remitters at discharge, supported by the finding of a significant positive correlation between depression symptom severity and NOx- concentration. Taken together, it is possible that elevated peripheral NOx- concentration is associated with increased severity of psychopathology, potentially due to NOS1 exon1f VNTR1 genotype. Our results further implicate NO signalling in mental illness pathogenesis, supporting its possible use as a peripheral biomarker, and imply that NOS genotype may play a significant role in regulating peripheral NOx- concentration.

Objective:Sensorimotor gating is experimentally operationalized by the prepulse inhibition (PPI) of the startle response (SR). Previous studies suggest high test-retest reliability of PPI and potential correlation with working memory (WM). Here, we aimed to validate and extend the test-retest reliability of PPI in healthy humans and its correlation with WM performance.Methods:We applied an acoustic startle PPI paradigm with four different prepulse intensities (64, 68, 72 and 76 dB) and two different WM tasks [n-back, change detection task (CDT)] in a group of 26 healthy adults (final sample size n = 23). To assess test-retest reliability, we performed all tests on two separate days ~27 days (range: 21–32 days) apart.Results:We were able to confirm high test-retest reliability of the PPI with a mean intraclass correlation (ICC) of > 0.80 and significant positive correlation of PPI with n-back but not with CDT performance. Detailed analysis showed that PPI across all prepulse intensities significantly correlated with both the 2-back and 0-back conditions, suggesting regulation by cross-conditional processes (e.g. attention). However, when removing the 0-back component from the 2-back data, we found a specific and significant correlation with WM for the 76-dB PPI condition.Conclusion:With the present study, we were able to confirm the high test-retest reliability of the PPI in humans and could validate and expand on its correlation with WM performance.

Background Previous studies have linked disturbances in the kynurenine pathway, responsible for the main catabolism of tryptophan and a key regulator of the immune system, to mental disorders such as major depressive disorder (MDD), bipolar disorder (BD) or schizophrenia (SCZ). However, the relationship between tryptophan catabolism and the presentation of psychiatric disorders seems to be rather complex, as up to now results have mostly been inconsistent or even contradictory. In this study, we measured plasma levels of tryptophan catabolites (TRYCATs: tryptophan, kynurenine, kynurenic acid and quinolinic acid) in a sample of in total 175 participants consisting of individuals suffering from an acute disease episode seeking inpatient treatment as well as healthy controls (HC) to investigate whether individual metabolites could serve as a biomarker for differential diagnosis. Results Significantly decreased levels of tryptophan, kynurenine, kynurenic acid and quinolinic acid were found in the patient group as a whole. This was mainly driven by the difference between BD patients and HC. Specifically, the manic symptom domain in manic and mixed phase BD patients displayed significantly lower kynurenine and kynurenic acid levels. We could not find significant differences between the psychiatric disorders disqualifying TRYCATs as biomarkers for differential diagnosis. None of the assessed potential demographic or pharmaceutical confounding factors revealed a significant correlation to TRYCAT concentrations. Upon reaching (partial) remission, the changes in TRYCAT levels partially normalized in the patient group. Conclusions Our data suggests an involvement of the kynurenine pathway in mental disorders, especially BD. Although we cannot prove a causal relationship, underlying mechanisms might include pro-inflammatory states in the central nervous system and/or increased neurotoxicity contributing to the immune assault. Also considering the manifold, but inconsistent previous analyses regarding TRYCAT concentrations in psychiatric disease, larger, cross-sectional and longitudinal studies will be needed for detangling the mystery about the role the tryptophan catabolism plays in the pathophysiology of mental disorders and for answering the burning question if it might constitute a possible therapeutic target in the future.

Zusammenfassung Zielsetzung In besonders auf Kommunikation basierenden Fächern wie Psychiatrie, Psychotherapie und Psychosomatik stellt die Lehre in Zeiten der COVID-19-Pandemie eine besondere Herausforderung dar. In dieser Übersicht berichten Dozierende und Lehrbeauftragte von ihren Erfahrungen im E-Teaching und teilen innovative Lösungsansätze. Methodik Wir präsentieren eine erfahrungsbasierte Sammlung von Vorgehensweisen, die sich auf Lehre und Prüfungsformate sowie auch aktivierende Methoden beziehen. Ergebnisse Es konnte eine Reihe von nützlichen Tools für die Lehre erstellt werden. Dazu gehören Lehrvideos mit Schauspielpatienten, strukturierte Hausaufgaben zur Verfassung von psychopathologischen Befunden, strukturierte Übergaben und praktische Prüfungen im Videochatformat. Es wurden Podcasts mit ÄrztInnen- und PatientInnen-Interviews und der Unterricht anhand von cineastischem Material genutzt, um das Interesse und die Motivation der Studierenden an dem Fachgebiet zu fördern. Schlussfolgerungen Die Umstellung auf Online-Formate ermöglicht Chancen und Vorteile für die Weiterentwicklung von zeit- und ortsunabhängigem Lernen. Eine schnelle Veränderung in diese Richtung birgt jedoch auch Nachteile. Insbesondere in der Lehre in den psychosozialen Fächern ist die direkte PatientInnen- und Studierendeninteraktion wichtig, um Übertragungs- und Gegenübertragungsphänomene sowie atmosphärische Aspekte aufzugreifen. Studien zur Effektivität der neu entwickelten Formate und didaktische sowie technische Schulungen von Dozierenden zur digitalen Lehre sind notwendig.

Introduction Illuminating neurobiological mechanisms underlying the protective effect of recently discovered common genetic resilience variants for schizophrenia is crucial for more effective prevention efforts. Current models implicate adaptive neuroplastic changes in the visual system and their pro-cognitive effects as a schizophrenia resilience mechanism. We investigated whether common genetic resilience variants might affect brain structure in similar neural circuits. Method Using structural magnetic resonance imaging, we measured the impact of an established schizophrenia polygenic resilience score (PRSResilience) on cortical volume, thickness, and surface area in 101 healthy subjects and in a replication sample of 33 224 healthy subjects (UK Biobank). Finding We observed a significant positive whole-brain correlation between PRSResilience and cortical volume in the right fusiform gyrus (FFG) (r = 0.35; P = .0004). Post-hoc analyses in this cluster revealed an impact of PRSResilience on cortical surface area. The replication sample showed a positive correlation between PRSResilience and global cortical volume and surface area in the left FFG. Conclusion Our findings represent the first evidence of a neurobiological correlate of a genetic resilience factor for schizophrenia. They support the view that schizophrenia resilience emerges from strengthening neural circuits in the ventral visual pathway and an increased capacity for the disambiguation of social and nonsocial visual information. This may aid psychosocial functioning, ameliorate the detrimental effects of subtle perceptual and cognitive disturbances in at-risk individuals, and facilitate coping with the cognitive and psychosocial consequences of stressors. Our results thus provide a novel link between visual cognition, the vulnerability-stress concept, and schizophrenia resilience models.

IntroductionIlluminating neurobiological mechanisms underlying the protective effect of recently discovered common genetic resilience variants for schizophrenia is crucial for more effective prevention efforts. Current models implicate adaptive neuroplastic changes in the visual system and their pro-cognitive effects as a schizophrenia resilience mechanism. We investigated whether common genetic resilience variants might affect brain structure in similar neural circuits.MethodUsing structural magnetic resonance imaging, we measured the impact of an established schizophrenia polygenic resilience score (PRSResilience) on cortical volume, thickness, and surface area in 101 healthy subjects and in a replication sample of 33,224 healthy subjects (UK Biobank).FindingWe observed a significant positive whole-brain correlation between PRSResilience and cortical volume in the right fusiform gyrus (FFG) (r=0.35; p=.0004). Post-hoc analyses in this cluster revealed an impact of PRSResilience on cortical surface area. The replication sample showed a positive correlation between PRSResilience and global cortical volume and surface area in the left FFG.ConclusionOur findings represent the first evidence of a neurobiological correlate of a genetic resilience factor for schizophrenia. They support the view that schizophrenia resilience emerges from strengthening neural circuits in the ventral visual pathway and an increased capacity for the disambiguation of social and non-social visual information. This may aid psychosocial functioning, ameliorate the detrimental effects of subtle perceptual and cognitive disturbances in at-risk individuals, and facilitate coping with the cognitive and psychosocial consequences of stressors. Our results thus provide a novel link between visual cognition, the vulnerability-stress concept and schizophrenia resilience models.

Studying the visual system with fMRI often requires using localizer paradigms to define regions of interest (ROIs). However, the considerable interindividual variability of the cerebral cortex represents a crucial confound for group-level analyses. Cortex-based alignment (CBA) techniques reliably reduce interindividual macroanatomical variability. Yet, their utility has not been assessed for visual field localizer paradigms, which map specific parts of the visual field within retinotopically organized visual areas. We evaluated CBA for an attention-enhanced visual field localizer, mapping homologous parts of each visual quadrant in 50 participants. We compared CBA with volume-based alignment and a surface-based analysis, which did not include macroanatomical alignment. CBA led to the strongest increase in the probability of activation overlap (up to 86%). At the group level, CBA led to the most consistent increase in ROI size while preserving vertical ROI symmetry. Overall, our results indicate that in addition to the increased signal-to-noise ratio of a surface-based analysis, macroanatomical alignment considerably improves statistical power. These findings confirm and extend the utility of CBA for the study of the visual system in the context of group analyses. CBA should be particularly relevant when studying neuropsychiatric disorders with abnormally increased interindividual macroanatomical variability.

BackgroundPeople with schizophrenia (PSZ) are impaired in attentional prioritization of non-salient but relevant stimuli over salient distractors during visual working memory (VWM) encoding. Conversely, guidance of top-down attention by exogenous predictive cues is intact. Yet, it is unknown whether this preserved ability can help PSZ overcome impaired attentional prioritization in the presence of salient distractors.MethodsWe employed a visuospatial change-detection task using four Gabor Patches with differing orientations in 66 PSZ and 74 healthy controls (HCS). Two patches flickered which were either the targets or non-targets and either a predictive or a non-predictive cue was displayed to manipulate top-down attention, resulting in four conditions.ResultsAcross all conditions, PSZ stored significantly less information in VWM than HCS (all p < 0.001). PSZ stored significantly more flickering and non-flickering information in the predictive cue conditions compared to the non-predictive cue conditions (p = 0.049, d = 0.5; p < 0.001, d = 1.0). Additionally, PSZ stored significantly more flickering than non-flickering information in the non-predictive cue conditions (p < 0.001, d = 0.9). These effects were not observed in HCS.ConclusionsOur findings indicate that attentional prioritization is disrupted in schizophrenia, but the top-down utilization of cues is intact. We conclude that additional top-down information significantly improves the amount of information encoded in PSZ. We report a specific deficit in attentional control, which is possibly mediated by GABAergic inhibition in early visual areas. This finding proposes a mechanism that enhances attentional prioritization and could be utilized in future therapies.

Pervasive and wide-ranging cognitive deficits are a core feature of schizophrenia and an important determinant of long-term functional outcome. The lack of sufficiently effective treatments for cognitive impairment associated with schizophrenia (CIAS) represents a major unmet need and a central roadblock towards recovery. This is partly due to the current therapeutic focus on clinical symptoms, and the relative neglect of cognitive impairments despite their functionally disabling effects. Furthermore, effective treatment is impeded by our limited knowledge of the complex pathophysiology, which gives rise to perturbed information processing. Here, we review mechanisms and effectiveness of available pharmacological and non-pharmacological treatments for CIAS. Current evidence indicates, that while techniques which broadly enhance neural plasticity show the greatest therapeutic potential, effect sizes are at best moderate. Among other reasons, this is due to a considerable heterogeneity of responses to individual interventions. Furthermore, we discuss how recent conceptual advances in operationalizing cognitive impairments based on cognitive neuroscience have the potential to address these issues and facilitate the development of novel treatment strategies for CIAS. This includes more clearly elucidating pathophysiological mechanisms in both humans and animal models, identifying new treatment targets as well as establishing biomarkers for a better prediction of treatment responses.

The study of the visual system and its role for human cognition in health and disease with fMRI often requires the use of localizer paradigms to define anatomical regions of interest (ROIs). However, the considerable degree of interindividual variability of the cerebral cortex represents an important confound, especially when analyzing visual localizer data on the group level. Cortex-based alignment (CBA) techniques lead to a reliable reduction of interindividual anatomical variability. Yet, the potential benefits of CBA has not been investigated for visual field localizer paradigms used to map specific parts of the visual field within retinotopically organized early visual areas. We evaluated CBA for an attention-enhanced visual field localizer mapping a homologous part of each visual quadrant in a cohort of 50 participants. After CBA, group ROIs showed markedly increased spatial consistency. CBA also led to an increase in the probability of activation overlap of up to forty percent. Furthermore, the size of group ROIs for the lower visual hemifield was larger than for the upper visual hemifield after CBA. This asymmetry, which mirrors previous findings from electrophysiological and fMRI studies, was not detectable before CBA. Our results confirm and extend the utility of CBA for the study of the visual system particularly in the context of group analyses. This method should be particularly important for the study of neuropsychiatric disorders with abnormally increased interindividual anatomical variability.

Background Impaired working memory is a core cognitive deficit in both bipolar disorder and schizophrenia. Its study might yield crucial insights into the underpinnings of both disorders on the cognitive and neurophysiological level. Visual working memory capacity is a particularly promising construct for such translational studies. However, it has not yet been investigated across the full spectrum of both disorders. The aim of our study was to compare the degree of reductions of visual working memory capacity in patients with bipolar disorder (PBD) and patients with schizophrenia (PSZ) using a paradigm well established in cognitive neuroscience. Methods 62 PBD, 64 PSZ, and 70 healthy controls (HC) completed a canonical visual change detection task. Participants had to encode the color of four circles and indicate after a short delay whether the color of one of the circles had changed or not. We estimated working memory capacity using Pashler’s K. Results Working memory capacity was significantly reduced in both PBD and PSZ compared to HC. We observed a small effect size (r = .202) for the difference between HC and PBD and a medium effect size (r = .370) for the difference between HC and PSZ. Working memory capacity in PSZ was also significantly reduced compared to PBD with a small effect size (r = .201). Thus, PBD showed an intermediate level of impairment. Conclusions These findings provide evidence for a gradient of reduced working memory capacity in bipolar disorder and schizophrenia, with PSZ showing the strongest degree of impairment. This underscores the importance of disturbed information processing for both bipolar disorder and schizophrenia. Our results are compatible with the cognitive manifestation of a neurodevelopmental gradient affecting bipolar disorder to a lesser degree than schizophrenia. They also highlight the relevance of visual working memory capacity for the development of both behavior- and brain-based transdiagnostic biomarkers.

Objective Working memory (WM) impairments are a prominent neurocognitive symptom in schizophrenia (SZ) and include deficits in memory for serial order and abnormalities in serial position effects (i.e., primacy and recency effects). Former studies predominantly focused on investigating these deficits applying verbal or static visual stimuli, but little is known about WM processes that involve dynamic visual movements. We examined WM for visual motion directions, its susceptibility to distraction and the effect of serial positioning. Method Twenty-three patients with paranoid SZ and 23 healthy control subjects (HC) took part in the study. We conducted an adapted Sternberg-type recognition paradigm: three random dot kinematograms (RDKs) that depicted coherent visual motion were used as stimuli and a distractor stimulus was incorporated into the task. Results SZ patients performed significantly worse in the WM visual motion task, when a distractor stimulus was presented. While HC showed a recency effect for later RDKs, the effect was absent in SZ patients. WM deficits were associated with more severe psychopathological symptoms, poor visual and verbal learning, and a longer duration of illness. Furthermore, SZ patients showed impairments in several other neurocognitive domains. Conclusions Findings suggest that early WM processing of visual motion is susceptible to interruption and that WM impairments are associated with clinical symptoms in SZ. The absence of a recency effect is discussed in respect of 3 theoretical approaches-impaired WM for serial order information, abnormalities in early visual representations (i.e., masking effects), and deficits in later visual processing (i.e., attentional blink effect). (PsycINFO Database Record

Background N-methyl-D-aspartate receptor (NMDAR) hypofunction is an important pathophysiological mechanism in schizophrenia. At the postsynapse the NMDAR interacts with the post-synaptic density (PSD). Neuronal nitric oxide synthase 1 (NOS1) binds to the PSD scaffolding proteins PSD-93 and PSD-95, enabling NMDAR-mediated release of nitric oxide via NOS1. NOS1AP (adaptor of NOS1) is capable of disrupting the interactions between NOS1, PSD-93, and PSD95. Therefore, NOS1AP is closely involved in both glutamatergic and nitrinergic neurotransmission. NOS1AP has been implicated as a risk gene for schizophrenia and cognitive dysfunction. Its increased expression has been observed in dorsolateral prefrontal post-mortem brain tissue of patients with schizophrenia, and NOS1AP SNPs have been associated with established schizophrenia endophenotypes. These findings suggest that the influence of NOS1AP variants should be observable in neural systems implicated in schizophrenia. In the present study, we investigate the impact of NOS1AP and its interaction partners at the glutamatergic synapse on the cortical working memory (WM) networks using fMRI and a gene set analysis approach. Methods 97 right-handed individuals with no personal or family history of psychiatric disorders underwent fMRI in a 3T Siemens Trio scanner during the performance of a visuospatial change detection WM task. Data analysis in Brain Voyager QX 2.8 included standard data preprocessing. Additionally, a multiscale curvature driven cortex based alignment procedure was used to minimize macro-anatomical variability between subjects. Subsequently, data were analyzed using a random-effects multi-subject general linear model. We investigated 19 regions of interest (ROIs) within the core fronto-parietal WM network. We studied all phases of our WM paradigm (encoding, maintenance, retrieval), which were modeled by a total of 5 regressors (encoding, delays 1–3, retrieval). Genetic data was quality controlled and imputed using the RICOPILI pipeline. Gene-set analyses of the 19 ROIs were performed using MAGMA. Two gene sets were selected: 1) NOS1AP/NOS1; 2) NOS1AP/glutamatergic synapse. We applied a Bonferroni correction for the total of 19 ROIs and 5 regressors (95 tests) to both analyses. Results Both gene set analyses revealed multiple associations between brain activation in core fronto-parietal WM areas. For the NOS1/NOS1AP set, most associations were observed during the late maintenance phase (Delay 3) of our WM paradigm. One association was significant Bonferroni correction: a cluster in the left intraparietal sulcus during the late maintenance phase (Delay 3; β=2.2459, SD=0.0239, SE=0.6451, p=0,00025). For NOS1AP / glutamatergic synapse interaction partners, two associations were significant after Bonferroni correction: a cluster in the right IPS during the early maintenance phase (Delay 1; β=0.8525, SD=0.0257, SE=0.2127, p=0.0000308) and a cluster in a different part of the right IPS during the late maintenance phase (Delay 3; β=0.7186, SD=0.0216, SE=0.2119, p=0,000348). Discussion In our gene set analyses we observed multiple associations between brain activation during WM and NOS1AP and its interaction partners, which were most pronounced during the late maintenance phase of our WM task in bilateral areas within the IPS. Both the more constrained NOS1AP / NOS1 gene set and the NOS1AP / glutamatergic synapse gene set showed similar association patterns. Our results implicate the NOS1AP interactome and the glutamatergic system in information processing and brain function in a cognitive domain strongly impaired in schizophrenia. They also indicate that altered activation of parietal WM areas during the maintenance phase is most strongly affected.

Memory impairments are a major characteristic of schizophrenia (SZ). In the current study, we used an associative memory task to test the hypothesis that SZ patients and first-degree relatives have altered functional patterns in comparison to healthy controls. We analyzed the fMRI activation pattern during the presentation of a face-name task in 27 SZ patients, 23 first-degree relatives, and 27 healthy controls. In addition, we performed correlation analyses between individual psychopathology, accuracy and reaction time of the task and the beta scores of the functional brain activations. We observed a lower response accuracy and increased reaction time during the retrieval of face-name pairs in SZ patients compared with controls. Deficient performance was accompanied by abnormal functional activation patterns predominantly in DMN regions during encoding and retrieval. No significant correlation between individual psychopathology and neuronal activation during encoding or retrieval of face-name pairs was observed. Findings of first-degree relatives indicated slightly different functional pattern within brain networks in contrast to controls without significant differences in the behavioral task. Both the accuracy of memory performance as well as the functional activation pattern during retrieval revealed alterations in SZ patients, and, to a lesser degree, in relatives. The results are of potential relevance for integration within a comprehensive model of memory function in SZ. The development of a neurophysiological model of cognition in psychosis may help to clarify and improve therapeutic options to improve memory and functioning in the illness.

BackgroundWorking memory (WM) deficits in schizophrenia (SCZ) have been linked to impairments in the encoding phase that are associated with aberrant neuronal functioning. Similar abnormalities have been observed in unaffected first-degree relatives (REL) and are thus discussed as candidate endophenotypes. The process of WM consolidation – i.e. the formation of durable WM representations – is assumed to be impaired in SCZ, but no study has investigated WM consolidation and neuronal correlates of visual WM encoding in REL before.MethodWe examined whole-brain activation during the encoding phase with an event-related functional magnetic resonance imaging study design in 25 SCZ subjects, 22 REL subjects, and 25 healthy controls. Subjects performed a visual masked change detection task that assessed WM performance and consolidation.ResultsSCZ showed deficient WM performance indicating an impairment consolidation process, accompanied by broad neuronal hypoactivation, most prominently in frontal brain regions, as well as increased activity of the anterior cingulate during the encoding phase. REL showed decreased neuronal activity in the middle and medial frontal gyrus and increased activity in the precentral gyrus and insula during encoding, but no significant behavioral deficits were observed. In respect of given consolidation times, REL showed a shift from decreased frontal activity at short time intervals to increased frontal activity at longer time intervals.ConclusionsFindings suggest WM consolidation may be slowed in REL so that the deployment of compensatory neuronal resources during encoding is needed to assure proper WM performance. This supports the view of WM-related neuronal dysfunctions as a potential endophenotypic marker.

Early exposure to negative environmental impact shapes individual behavior and potentially contributes to any mental disease. We reported previously that accumulated environmental risk markedly decreases age at schizophrenia onset. Follow-up of matched extreme group individuals (≤1 vs. ≥3 risks) unexpectedly revealed that high-risk subjects had >5 times greater probability of forensic hospitalization. In line with longstanding sociological theories, we hypothesized that risk accumulation before adulthood induces violent aggression and criminal conduct, independent of mental illness. We determined in 6 independent cohorts (4 schizophrenia and 2 general population samples) pre-adult risk exposure, comprising urbanicity, migration, physical and sexual abuse as primary, and cannabis or alcohol as secondary hits. All single hits by themselves were marginally associated with higher violent aggression. Most strikingly, however, their accumulation strongly predicted violent aggression (odds ratio 10.5). An epigenome-wide association scan to detect differential methylation of blood-derived DNA of selected extreme group individuals yielded overall negative results. Conversely, determination in peripheral blood mononuclear cells of histone-deacetylase1 mRNA as 'umbrella mediator' of epigenetic processes revealed an increase in the high-risk group, suggesting lasting epigenetic alterations. Together, we provide sound evidence of a disease-independent unfortunate relationship between well-defined pre-adult environmental hits and violent aggression, calling for more efficient prevention. This work was supported by the Max Planck Society, the Max Planck Förderstiftung, the DFG (CNMPB), EXTRABRAIN EU-FP7, the Niedersachsen-Research Network on Neuroinfectiology (N-RENNT), and EU-AIMS. The research of EUAIMS receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115300, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013), from the EFPIA companies, and from Autism Speaks. Moreover, support from Centro de Investigación en Red de Salud Mental (CIBERSAM); Instituto de Salud Carlos III (PI16/00998), Comissionat per a Universitats i Recerca del DIUE (2014SGR1636) and Spanish Ministry of Economy and Competitiveness (ES-EUEpiBrain, SAF2015-71526-REDT) is gratefully acknowledged. We thank all subjects for participating in the study, and all the many colleagues who have contributed over the past decade to the GRAS data collection.

Behavioral evidence indicates that working memory (WM) in schizophrenia is already impaired at the encoding stage. However, the neurophysiological basis of this primary deficit remains poorly understood. Using event-related fMRI, we assessed differences in brain activation and functional connectivity during the encoding, maintenance and retrieval stages of a visual WM task with 3 levels of memory load in 17 adolescents with early-onset schizophrenia (EOS) and 17 matched controls. The amount of information patients could store in WM was reduced at all memory load levels. During encoding, activation in left ventrolateral prefrontal cortex (VLPFC) and extrastriate visual cortex, which in controls positively correlated with the amount of stored information, was reduced in patients. Additionally, patients showed disturbed functional connectivity between prefrontal and visual areas. During retrieval, right inferior VLPFC hyperactivation was correlated with hypoactivation of left VLPFC in patients during encoding. Visual WM encoding is disturbed by a failure to adequately engage a visual-prefrontal network critical for the transfer of perceptual information into WM. Prefrontal hyperactivation appears to be a secondary consequence of this primary deficit. Isolating the component processes of WM can lead to more specific neurophysiological markers for translational efforts seeking to improve the treatment of cognitive dysfunction in schizophrenia.

This paper examines the potential of value engineering (VE) as a problem-solving tool for addressing various challenges in the marine construction industry. Through a review of large numbers of challenging engineering problems in the marine environment, the authors identified various complications caused by dynamic and uncertain marine environments in both the prebid and postbid stages of construction projects. These unexpected challenges required the project team to identify optimal solutions in a comprehensive and efficient manner. In past construction projects, a 10-step approach was designed and used by the authors to identify solutions for unexpected engineering problems. The approach has three limitations: (1) it is an informal and time-consuming process involving possibly redundant communications and coordination; (2) it is not specific and detailed enough to ensure that the optimal solution is in fact considered and selected in a comprehensive and efficient manner; and (3) it does not integrate standard metrics other than the estimated cost that can be used to quantitatively evaluate the performance of a solution in terms of productivity, quality, safety, and environmental impact. This paper first presents the current 10-step process for solving marine construction problems and limitations of this process. The paper then describes the VE seven-step process and highlights how the VE process and the 10-step approach share the same structure. All steps in the VE process can find correspondences in the 10-step process, whereas VE methodology formalizes the value of a solution and quantitative performance metrics to harvest and evaluate ideas from groups of engineers in a more systematic manner. Based on this shared structure, the paper discusses how to augment the 10-step approach with the VE methodology to achieve more comprehensive and efficient problem solving. Using a case study, the authors explain how such augmentation can effectively integrate the knowledge and experience of groups of engineers with diverse backgrounds in marine construction. Finally, the paper suggests future directions for using VE for marine construction projects.

Overall Abstract: Converging behavioural and neuroimaging evidence indicates that an inability to regulate behaviour by working memory (WM) is a core feature of people with schizophrenia (PSZ) which significantly influences their level of recovery. WM dysfunction has also gained interest as a target of cognitive enhancement interventions and as an intermediate phenotype in the study of the genetic architecture of schizophrenia. These translational strategies critically depend upon a clear understanding of the underlying cognitive and neurophysiological disturbances. The aim of the symposium is to highlight current approaches to identify the pathophysiological mechanisms underlying WM deficits on both the microcircuit and the systems level. M. Ichinose will report cognitive modelling data showing that PSZ have elevated internal noise during perceptual processing, which was inversely correlated with WM precision. This indicates that ‘noisy’ perception contribute to impairments in WM and other cognitive domains. R. Bittner will present behavioural data from PSZ and imaging genetics fMRI data from a large cohort of healthy participants. The results of these studies indicate, that specific impairments in bottom-up attentional processes associated with genetic risk contribute to the dysfunction of working memory encoding in schizophrenia. A. Anticevic will present computational microcircuit models, resting state fMRI data and fMRI data using ketamine which provide evidence for a disturbed excitation-inhibition (E-I) balance and resulting in large scale dysconnectivity in schizophrenia in the context of working memory and other cognitive processes. The research presented in this symposium integrates computational, neuroanatomical, electrophysiological, pharmacological, genetic, behavioural and neuroimaging methods to connect pathophysiological mechanisms at the microcircuit level such as increased neuronal noise and an abnormal E-I balance to disturbances in large scale brain networks at the systems level and to behavioral impairment. Such an integrative approach promises to yield new insights into the pathophysiology of cognitive dysfunction in schizophrenia.

Background Patients with schizophrenia suffer from profound impairments of working memory and selective attention. These cognitive domains show a considerable overlap on both the behavioral and neurophysiological level. Importantly, selective attention appears to be crucial for the selection of information to be encoded into working memory. A number of studies have demonstrated that the efficiency of this “gatekeeper” function influences working memory performance. Furthermore, behavioural evidence indicates, that patients with schizophrenia have a specific deficit when required to suppress irrelevant but highly salient visual information during working memory encoding. Therefore, elucidating the neurophysiological mechanisms underlying the “gatekeeper” function of selective attention for working memory is highly relevant for understanding this deficit in schizophrenia. The aim of the current study was to investigate the neurophysiological correlates of encoding either salient or non-salient information in the presence of distractors of opposite saliency using functional magnetic resonance imaging (fMRI). Furthermore, we wanted to study the impact of additional top-down information guiding the selection of task relevant information. Methods 35 healthy volunteers underwent fMRI in a 3 T Siemens Trio scanner. During a change detection task four Gabor patches (two flickering and two non-flickering) with varying orientations were shown and participants had to memorise the orientations of the Gabor patches. A colored fixation cross was displayed before the stimuli either cueing two (predictive cue) or four (non-predictive cue) Gabor patch locations resulting in a 2 x 2 design of four conditions with the factors salience (flickering vs. non-flickering) and cue (predictive cue vs. non-predictive cue). During retrieval a single Gabor patch was displayed, and participants reported if the orientation was the same or had changed in that location. At the beginning of each block participants were instructed to either encode the flickering or non-flickering patches (targets) whose location could either be cued or uncued. In 80 % of trials, a target was probed during retrieval. Data analysis in Brain Voyager included standard data preprocessing. Additionally, a multiscale curvature driven cortex based alignment procedure was used to minimise macro-anatomical variability between subjects. Subsequently, functional data were analysed using a random-effects multi-subject general linear model (p

The Schizophrenia International Research Society held its first scientific conference in Venice, Italy, June 21 to 25th, 2008. A wide range of controversial topics were presented in overlapping and plenary oral sessions. These included new genetic studies, controversies about early detection of schizophrenia and the prodrome, treatment issues, clinical characteristics, cognition, neuropathology and neurophysiology, other etiological considerations, substance abuse co-morbidity, and animal models for investigating disease etiology and for use as targets in drug studies. Young investigators in the field were awarded travel grants to participate in the congress and one of their roles was to summarize the oral sessions and subsequent discussions. The reports that follow are the culmination of this work produced by 30 young investigators who attended the congress. It is hoped that these summaries will be useful synopses of what actually occurred at the congress for those who did not attend each session or were unable to be present. The abstracts of all presentations, as submitted by the authors a few months prior, were previously published as supplement 2 to volume 102/1-3, June 2008.

Construction engineering for major infrastructure projects covers a wide range of activities to evaluate and select the techniques for assembling materials and components. Construction engineering inherently presents a very challenging opportunity for creative design, particularly on infrastructure projects. This construction engineering activity can be described as one of creating and developing workable, cost-effective, low-risk technical solutions for an array of infrastructure construction problems that must be solved from the plans and specifications stage through facility completion. The purpose of this paper is to illustrate a 10-step construction engineering process and define important knowledge requirements to foster creative design solutions using four case studies, including (1) positioning and holding a concrete bridge caisson in a 7-knot tidal current for a 4-month period; (2) skidding a 55,000-t immersed tube tunnel element 200 m on dry land from casting site to launch site; (3) building a ...

The successful Mach 7 and 10 flights of the first fully integrated scramjet propulsion systems by the Hyper-X (X-43A) program have provided the means with which to verify the original design methodologies and assumptions. As part of Hyper-X s propulsion-airframe integration, the forebody was designed to include a spanwise array of vortex generators to promote boundary layer transition ahead of the engine. Turbulence at the inlet is thought to provide the most reliable engine design and allows direct scaling of flight results to groundbased data. Pre-flight estimations of boundary layer transition, for both Mach 7 and 10 flight conditions, suggested that forebody boundary layer trips were required to ensure fully turbulent conditions upstream of the inlet. This paper presents the results of an analysis of the thermocouple measurements used to infer the dynamics of the transition process during the trajectories for both flights, on both the lower surface (to assess trip performance) and the upper surface (to assess natural transition). The approach used in the analysis of the thermocouple data is outlined, along with a discussion of the calculated local flow properties that correspond to the transition events as identified in the flight data. The present analysis has confirmed that the boundary layer trips performed as expected for both flights, providing turbulent flow ahead of the inlet during critical portions of the trajectory, while the upper surface was laminar as predicted by the pre-flight analysis.

Background Cognitive impairments including deficits in working memory are commonly observed in schizophrenia. A bottom-up attentional bias has been suggested for encoding visually salient yet irrelevant information. To date it is not known if this bias persists when additional top-down information in the form of a predictive cue is provided. We were motivated to clarify this issue. Methods 40 patients with schizophrenia were measured and matched with 40 healthy control participants. During a change detection task four Gabor patches (two flickering and two non-flickering) with varying orientations were shown and participants had to memorize the orientations of the Gabor patches. A colored fixation cross was displayed before the stimuli either cueing two (predictive cue) or all four (non-predictive cue) Gabor patch locations resulting in a 2 x 2 design of four conditions with the factors salience (flickering vs. non-flickering) and cue (predictive cue vs. non-predictive cue). During retrieval a single Gabor patch was displayed, and participants reported if the orientation was the same or had changed in that location. At the beginning of each block participants were instructed to either encode the flickering or non-flickering patches (targets) whose location could either be cued or uncued. In 80 % of trials, a target was probed during retrieval. Results Patients encoded less information than healthy controls in all four conditions. Both healthy controls and patients encoded more visually salient information than non-salient information, and performance was near chance level during non-target trials. Patients encoded significantly more information when a predictive cue was provided before encoding visually non-salient information. Discussion Patients were able to overcome their bottom-up attentional bias of encoding visually salient irrelevant information when provided with top-down information. These findings are in line with previous reports of a bottom-up attentional bias during working memory encoding in schizophrenia. We propose that this bias can be overcome by providing additional top-down information.

Background Working memory and attention are fundamental and closely linked cognitive domains. This close link is exemplified by the crucial role of selective attention for the selection of information to be encoded into working memory. Patients with schizophrenia are markedly impaired in many aspects of both domains. However, the interplay between these cognitive deficits on both the cognitive and neurophysiological level remains poorly understood. Based on our previous findings regarding the central role of impaired working memory encoding to working memory dysfunction in schizophrenia, we hypothesize, that impaired attentional processes contribute to working memory dysfunction specifically during the encoding stage. This hypothesis was tested in both a behavioral experiment and in an fMRI imaging genetics study. Methods For the behavioral study, we investigated 35 patients with schizophrenia and 35 matched healthy controls. In a change detection task, participants were simultaneously presented with both highly salient and non-salient spatial information. They were instructed to encode either the highly salient or the non-salient information. In half of the conditions, they were aided by a cue pointing them towards the relevant information. Our goal was to test, whether patients with schizophrenia were biased toward a particular type of information and whether a top-down cue would influence such a bias. In the imaging genetics study, we investigated 100 right-handed individuals without personal or family history of psychiatric disorders, who performed a visuospatial change detection task. The fMRI data were preprocessed and analyzed using Brain Voyager QX 20. For genotyping we used a custom Illumina HumanCoreExome-24 BeadChip array. We calculated polygenic scores (PGS) for schizophrenia based on 108 loci associated with schizophrenia in a recent mega-analysis of the Psychiatric Genetic Consortium (PGC2). We computed whole brain correlations between BOLD activation and PGS to elucidate the relationship between genetic risk for schizophrenia and abnormal brain function. Results In the behavioral study, patients were significantly more impaired when required to encode non-salient compared to salient information. However, this impairment was specific to conditions without a top-down cue. This demonstrates, that patients could use top-down attention to overcome a bottom-up bias towards highly salient information during working memory encoding. In the fMRI data, we observed a significant negative correlation between BOLD activation in the right temporo-parietal junction (TPJ) during working memory encoding and PGS for schizophrenia. Across all subjects, this area showed robust deactivation during encoding. The TPJ is a crucial region of the ventral attention network and is closely involved in bottom-up attentional processes. Previous fMRI studies observed stronger deactivation of the TPJ during working memory encoding with increasing cognitive demand. Therefore, our results indicate that participants with a higher genetic risk for schizophrenia had to commit more cognitive resources by downregulating their ventral attention network. Discussion Taken together, the results of both studies point toward specific disturbance of bottom-up attention during working memory encoding, which might be linked to genetic risk for schizophrenia. Conversely, top-down attention appears to be relatively spared. These findings provide new constraints for cognitive and neurophysiological models of impaired working memory encoding in schizophrenia.

The Sutong Bridge across the lower Yangtze River in China will have, when completed, the longest span (1,088 m) and the highest towers (306 m) of any cable stayed span in the world. The foundations for this record setting span will also be record setting. They are located in water depths exceeding 30 m with maximum flows exceeding 3 m/sec. The soil at the site of the main pylons consists of layers of silty sands and silty clays extending to bed rock at 270 m below river elevation.This paper describes the innovative methods used by the team of foundation designers and constructors to support this record setting bridge at this very challenging site. This paper covers three specific topics related to the foundations of the Sutong Bridge: • Design and construction of the 131 drilled shafts (2.8/2.5 m diameter and 114/117 m long) under each of the two main pylons, including the post-grouting of all drilled shaft tips.• Design and construction of the scour protection for the two main pylons.• Constructi...

Humans are severely limited in their ability to memorize visual information over short periods of time. Selective attention has been implicated as a limiting factor. Here we used functional magnetic resonance imaging to test the hypothesis that this limitation is due to common neural resources shared by visual working memory (WM) and selective attention. We combined visual search and delayed discrimination of complex objects and independently modulated the demands on selective attention and WM encoding. Participants were presented with a search array and performed easy or difficult visual search in order to encode one or three complex objects into visual WM. Overlapping activation for attention-demanding visual search and WM encoding was observed in distributed posterior and frontal regions. In the right prefrontal cortex and bilateral insula blood oxygen-level-dependent activation additively increased with increased WM load and attentional demand. Conversely, several visual, parietal and premotor areas showed overlapping activation for the two task components and were severely reduced in their WM load response under the condition with high attentional demand. Regions in the left prefrontal cortex were selectively responsive to WM load. Areas selectively responsive to high attentional demand were found within the right prefrontal and bilateral occipital cortex. These results indicate that encoding into visual WM and visual selective attention require to a high degree access to common neural resources. We propose that competition for resources shared by visual attention and WM encoding can limit processing capabilities in distributed posterior brain regions.

Visual selective attention and visual working memory (WM) share the same capacity-limited resources. We investigated whether and how participants can cope with a task in which these 2 mechanisms interfere. The task required participants to scan an array of 9 objects in order to select the target locations and to encode the items presented at these locations into WM (1 to 5 shapes). Determination of the target locations required either few attentional resources (“popout condition”) or an attention-demanding serial search (“non pop-out condition”). Participants were able to achieve high memory performance in all stimulation conditions but, in the non popout conditions, this came at the cost of additional processing time. Both empirical evidence and subjective reports suggest that participants invested the additional time in memorizing the locations of all target objects prior to the encoding of their shapes into WM. Thus, they seemed to be unable to interleave the steps of search with those of encoding. We propose that the memory for target locations substitutes for perceptual pop-out and thus may be the key component that allows for flexible coping with the common processing limitations of visual WM and attention. The findings have implications for understanding how we cope with real-life situations in which the demands on visual attention and WM occur simultaneously.

Working memory (WM) capacity limitations and their neurophysiological correlates are of special relevance for the understanding of higher cognitive functions. Evidence from behavioral studies suggests that restricted attentional resources contribute to these capacity limitations. In an event-related functional magnetic resonance imaging (fMRI) study, we probed the capacity of the human visual WM system for up to four complex nonnatural objects using a delayed discrimination task. A number of prefrontal and parietal areas bilaterally showed increased blood oxygen level-dependent activity, relative to baseline, throughout the task when more than one object had to be held in memory. Monotonic increases in response to memory load were observed bilaterally in the dorsolateral prefrontal cortex (DLPFC) and the presupplementary motor area (pre-SMA). Conversely, activity in the frontal eye fields (FEFs) and in areas along the intraparietal sulcus (IPS) peaked when subjects had to maintain only two or three objects and decreased in the highest load condition. This dissociation of memory load effects on cortical activity suggests that the cognitive operations subserved by the IPS and FEF, which are most likely related to attention, fail to support visual WM when the capacity limit is approached. The correlation of brain activity with performance implies that only the operations performed by the DLPFC and pre-SMA, which support an integrated representation of visual information, helped subjects to maintain a reasonable level of performance in the highest load condition. These results indicate that at least two distinct cortical subsystems are recruited for visual WM, and that their interplay changes when the capacity limit is reached.

Introduction Schizophrenia is a complex genetic disorder, whose highly polygenic architecture has only partly been elucidated. Recent genome-wide association studies (GWAS) have provided evidence for a growing number of common genetic risk variants. However, the impact of these risk genes on brain function remain poorly understood. In the current imaging genetics study, we investigated the correlation between brain activation during a visuospatial working memory task and genetic risk for schizophrenia. Methods 98 right-handed individuals without personal or family history of psychiatric disorders underwent fMRI during the performance of a visuospatial change detection task. During encoding, an array of three red rectangular bars, which varied in orientation, was presented for 33 ms. After a delay period, a second array was presented for 3000 ms (retrieval). This array was identical to the first array in 50% of trials. Data analysis in Brain Voyager QX 2.8 included standard data preprocessing and a multiscale curvature driven cortex based alignment procedure to minimize macro-anatomical variability between subjects. Subsequently, functional data were analyzed using a random-effects multi-subject general linear model. Participants were genotyped using a custom Illumina HumanCoreExome-24 BeadChip array. Polygenic scores (PGS) for schizophrenia were calculated based on Psychiatric Genetic Consortium data (PGC2). Results We observed a significant negative correlation between BOLD activation in the right temporo-parietal junction (TPJ) and PGS for schizophrenia during the encoding phase. Closer inspection indicated that the right TPJ – part of the ventral attention network – was reliably deactivated across all particpants during the encoding phase. However, participants with higher PGS showed stronger deactivation. Conclusions Previous studies reported stronger deactivation of the right TPJ during working memory encoding with increasing cognitive demand. Therefore, our results indicate that participants with a higher genetic risk for schizophrenia had to commit more cognitive resources to encode information into working memory. This finding is also well in line with converging evidence for a primary disturbance of working memory encoding in schizophrenia.

Background: Schizophrenia is a complex genetic disorder, whose genetic architecture remains poorly understood. Recent genome-wide association studies (GWAS) have provided evidence for a growing number of common genetic risk variants. In the current imaging genetics study we aimed to investigate the correlation between brain activation during a visual working memory task and genetic risk for schizophrenia.

We tested the effects of variation of stimulus onset asynchrony (SOA) on visual working memory (WM) performance across different load levels and the underlying brain activation patterns using functional magnetic resonance imaging (fMRI) in 48 healthy participants. Participants were instructed to memorise arrays of coloured squares and had to perform a match/non-match judgement on a probe stimulus after a jittered delay. We presented visual pattern masks at four SOAs after the offset of the memory array (100 ms, 200 ms, 400 ms, and 800 ms). Memory performance decreased with increased load and shortened SOA. Brain activation data showed significant effects of load (during encoding and retrieval), SOA (retrieval) and an interaction of load by SOA (encoding), mainly in frontal and parietal areas. There was also a direct relationship between successfully stored items and activation in the right inferior parietal lobule and the left middle frontal gyrus. The neurobehavioral results suggest that the frontal regions, together with the inferior parietal lobe, are associated with successful WM performance, especially under the most challenging conditions of high load and short SOAs.

Computational e uid dynamics tools have been used extensively in the analysis and development of the X-43A Hyper-X Research Vehicle. A signiecant element of this analysis is the prediction of integrated vehicle aeropropulsive performance,which includes an integration of aerodynamic and propulsion eoweelds. Thedevelopment of the Mach7X-43Arequiredapree ightassessmentoflongitudinalandlateral-directionalaeropropulsivecharacteristics nearthetargeteight-testcondition.Thedevelopmentofthispree ightdatabasewasaccomplishedthroughextensive aerodynamic wind-tunnel testing and a combination of three-dimensional inviscid airframe calculations and cowlto-tail scramjet cycle analyses togenerate longitudinal performance increments between mission sequences. These increments were measured directly and validated through tests of the Hyper-X e ight engine and vehicle e owpath simulator in the NASA Langley Research Center 8-Foot High Temperature Tunnel. Predictions were reened with tip-to-tailNavier‐Stokescalculations,which alsoprovidedinformation onscramjetexhaustplumeexpansion inthe aftbody region. A qualitative assessment of lateral-directional stability characteristics was made through a series of tip-to-tail inviscid calculations, including a simulation of the powered scramjet eight-test condition. Additional comparisons with wind-tunnel forceand momentdataas well as surfacepressuremeasurements from theHyper-X e ight engine and vehicle eowpath simulator model and wind-tunnel testing were made to assess solution accuracy.

A method for estimating the axial distribution of thrust performance potential in a supersonic combustor is described. A complementary technique for illustrating the spatial evolution and distribution of thrust potential and loss mechanisms in reacting flows is developed. A wall jet case and swept ramp injector case for Mach 17 and Mach 13.5 flight enthalpy inflow conditions, respectively, are numerically modeled and analyzed using these techniques.

Schizophrenia is one of the most disabling forms of mental illness. One of the most important challenges is to establish biological markers which can accurately identify at-risk individuals in preclinical stages and thus improve the effects of early intervention strategies. Here, we review recent findings in the field of molecular genetics, CSF (cerebrospinal fluid) based markers as well as structural and functional neuroimaging in the light of their relevance for schizophrenia biomarker research. We also examine evidence supporting the hypothesis that schizophrenia and neurodegenerative disorders such as Alzheimer's disease may share certain pathophysiological features, e.g. chronic inflammation and oxidative stress, and discuss their possible role in schizophrenia. The heterogeneous, multifaceted and multifactorial nature of the traditionally clinically operationalized entity “schizophrenia” presents an enormous challenge towards the identification of single diagnostic or surrogate markers. We propose that abnormal neural coordination is a major point of convergence of a number of crucial pathophysiological pathways. Therefore, functional markers reflecting disturbed neural coordination might be particularly attractive biomarker candidates, because of their ability to integrate the influence of diverse pathophysiological mechanisms. Similarly, combinatorial and multimodal approaches may be a promising way to more accurately capture the complex biological underpinnings schizophrenia. We consider the development of such integrative biomarkers to be essential in order to facilitate a timely diagnosis of schizophrenia. They should also advance our understanding of the subtle and intricate biological nature of schizophrenia.

Background:Working memory (WM) deficits are a core feature of schizophrenia. Recent electrophysiological evidence indicates that the brain systems for visual encoding are especially impaired. However, patients still achieve performance levels clearly above chance, which indicates the existence of residual mechanisms supporting WM encoding. The present study presents evidence that alpha phase locking of the electroencephalogram is a marker for such residual cognitive mechanisms.Methods:Alpha phase locking during encoding into WM was compared between 17 patients with early-onset schizophrenia (EOS) and 17 healthy control subjects. Results of phase locking were correlated with accuracy. A median split based on alpha phase locking in patients was used to compare accuracy between control subjects and patients with high and low alpha phase locking.Results:Alpha phase locking increased with WM memory load in both EOS and control subjects, although alpha phase locking was generally reduced in EOS. Furthermore, for EOS, a positive correlation between alpha phase locking and performance was obtained. Additionally, patients exhibiting high phase locking did not differ in performance from control subjects.Conclusions:These results provide the first evidence for a relationship between alpha phase locking and visual WM encoding. This neural mechanism seems to be preserved in some patients with schizophrenia and then allows them to attain normal performance levels.

The establishment of a quasi-steady flow in a generic scramjet combustor was studied for the case of a time varying inflow to the combustor. Such transient flow is characteristic of the reflected shock tunnel and expansion tube test facilities. Several numerical simulations of hypervelocity flow through a straight duct combustor with either a side wall step fuel injector or a centrally located strut injector are presented. Comparisons were made between impulsively started but otherwise constant flow conditions (typical of the expansion tube or tailored operations of the reflected shock tunnel) and the relaxing flow produced by the 'undertailored' operations of the reflected shock tunnel. Generally the inviscid flow features, such as the shock pattern and pressure distribution, were unaffected by the time varying inlet conditions and approached steady state in approx. the times indicated by experimental correlations. However, viscous features, such as heat transfer and skin friction, were altered by the relaxing inlet flow conditions.

Impairments in working memory (WM) are a core cognitive deficit in schizophrenia. Neurophysiological models suggest that deficits during WM maintenance in schizophrenia may be explained by abnormalities in the GABAergic system, which will lead to deficits in high-frequency oscillations. However, it is not yet clear which of the three WM phases (encoding, maintenance, retrieval) are affected by dysfunctional oscillatory activity. We investigated the relationship between impairments in oscillatory activity in a broad frequency range (3–100 Hz) and WM load in the different phases of WM in 14 patients with early-onset schizophrenia and 14 matched control participants using a delayed matching to sample paradigm.During encoding, successful memorization was predicted by evoked theta, alpha, and beta oscillatory activity in controls. Patients showed severe reductions in the evoked activity in these frequency bands. During early WM maintenance, patients showed a comparable WM load-dependent increase in induced alpha and gamma activity to controls. In contrast, during the later maintenance phase, patients showed a shift in the peak of induced gamma activity to the lower WM load conditions. Finally, induced theta and gamma activity were reduced in patients during retrieval.Our findings suggest that the WM deficit in schizophrenia is associated with impaired oscillatory activity during all phases of the task and that the cortical storage system reaches its capacity limit at lower loads. Inability to maintain oscillatory activity in specific frequency bands could thus result in the information overload that may underlie both cognitive deficits and psychopathological symptoms of schizophrenia.

The successful Mach 7 and 10 flights of the first fully integrated scramjet propulsion systems by the Hyper-X (X-43A) program have provided the means with which to verify the original design methodologies and assumptions. As part of Hyper-X s propulsion-airframe integration, the forebody was designed to include a spanwise array of vortex generators to promote boundary layer transition ahead of the engine. Turbulence at the inlet is thought to provide the most reliable engine design and allows direct scaling of flight results to groundbased data. Pre-flight estimations of boundary layer transition, for both Mach 7 and 10 flight conditions, suggested that forebody boundary layer trips were required to ensure fully turbulent conditions upstream of the inlet. This paper presents the results of an analysis of the thermocouple measurements used to infer the dynamics of the transition process during the trajectories for both flights, on both the lower surface (to assess trip performance) and the upper surface (to assess natural transition). The approach used in the analysis of the thermocouple data is outlined, along with a discussion of the calculated local flow properties that correspond to the transition events as identified in the flight data. The present analysis has confirmed that the boundary layer trips performed as expected for both flights, providing turbulent flow ahead of the inlet during critical portions of the trajectory, while the upper surface was laminar as predicted by the pre-flight analysis.

Context Working memory (WM) deficits in patients with schizophrenia have mainly been associated with prefrontal dysfunction. However, the contribution of perceptual deficits and abnormalities in sensory areas has not been explored. The present study closes this important gap in our understanding of WM dysfunction in schizophrenia by monitoring neural activity during WM encoding and retrieval with event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI). Objective To investigate the neurophysiological changes that contribute to WM impairment in early-onset schizophrenia at perceptual and cognitive stages using the ERP components P1, P3a, P370, and P570 and fMRI data from extrastriate visual areas. Design We conducted the study between June 1, 2003, and December 20, 2006. Electroencephalographic and fMRI data were acquired separately during a visual delayed discrimination task. Participants encoded up to 3 abstract shapes that were presented sequentially for 600 milliseconds each and decided after a 12-second delay whether a probe matched 1 of the sample stimuli. Setting Between-group study at an inpatient psychiatric hospital and outpatient psychiatric facilities. Participants Seventeen adolescents with early-onset schizophrenia according to DSM-IV criteria and 17 matched controls participated in the study. Main Outcome Measures Amplitude of the ERP components P1, P3a, P370, and P570 and the fMRI signal from extrastriate visual areas. Results The P1 amplitude was reduced in patients during encoding and retrieval. The P1 amplitude increased with WM load during encoding only in controls. In this group, a stronger P1 amplitude increase predicted better WM performance. The P1 reduction was mirrored by reduced activation of visual areas in patients in fMRI. The P370 amplitude during encoding and retrieval was also reduced in patients. Conclusions The P1 amplitude reduction indicates an early visual deficit in adolescents with schizophrenia. Our findings suggest that P1 is of particular relevance for successful WM encoding. Early visual deficits contribute to impaired WM in schizophrenia in addition to deficits in later memory-related processes.

The Sutong Bridge across the lower Yangtze River in China will have, when completed, the longest span (1,088 m) and the highest towers (306 m) of any cable stayed bridge in the world. The foundations for this record-setting span are drilled shafts under each of the main pylons. The North Pylon is supported on 131 drilled shafts, 2.5 m diameter and 114 m long. The South Pylon is supported on 131 drilled shafts 2.5 m in diameter and 117 m long. The tips of all drilled shafts were post-grouted after an extensive test program confirmed significant increase in capacity with post-grouting. This paper presents a description of the post-grouting test program, the results obtained, and the construction methods used for post grouting of the production drilled shafts.

In construction of drilled shafts under water, placing concrete in the shafts is technically demanding and involves complex construction logistics. Past construction experience has demonstrated that high quality concrete can be placed in drilled shafts under water with a proper concrete mix and proper placement techniques. However, a significant number of failures have occurred which have resulted in excessive cost overruns and delays. These problems may have occurred because proper underwater concrete construction techniques have not been widely disseminated within the industry. This is a technical area where competent design and sound construction planning can achieve a significant reduction in both risk and cost. This paper will discuss some key technical issues in the concrete mix design, concrete production and placement for the drilled shaft construction. The paper also describes two lesson-learned case histories from drilled shaft construction projects.