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Nitrones (e.g. α-phenyl-N-tert-butyl nitrone; PBN) are cerebroprotective in experimental stroke. Free radical trapping is their proposed mechanism. As PBN has low radical trapping potency, we tested Sgk1 induction as another possible mechanism. PBN was injected (100 mg/kg, i.p.) into adult male rats and mice. Sgk1 was quantified in cerebral tissue by microarray, quantitative RT-PCR and western analyses. Sgk1+/+ and Sgk1−/− mice were randomized to receive PBN or saline immediately following transient (60 min) occlusion of the middle cerebral artery. Neurological deficit was measured at 24 h and 48 h and infarct volume at 48 h post-occlusion. Following systemic PBN administration, rapid induction of Sgk1 was detected by microarray (at 4 h) and confirmed by RT-PCR and phosphorylation of the Sgk1-specific substrate NDRG1 (at 6 h). PBN-treated Sgk1+/+ mice had lower neurological deficit ( p < 0.01) and infarct volume ( p < 0.01) than saline-treated Sgk1+/+ mice. PBN-treated Sgk1−/− mice did not differ from saline-treated Sgk1−/− mice. Saline-treated Sgk1−/− and Sgk1+/+ mice did not differ. Brain Sgk3:Sgk1 mRNA ratio was 1.0:10.6 in Sgk1+/+ mice. Sgk3 was not augmented in Sgk1−/− mice. We conclude that acute systemic treatment with PBN induces Sgk1 in brain tissue. Sgk1 may play a part in PBN-dependent actions in acute brain ischemia.

The hippocampus is located within the medial temporal lobe and plays a key role in learning and episodic, semantic, and spatial memory. Dysfunction has been reported in neurologic and psychiatric disorders including epilepsy (Wu et al., 2005), Alzheimer's disease (Apostolova et al., 2006), schizophrenia (Tanskanen et al., 2005), and depression (Bremner et al., 2000). Temporal lobe epilepsy (TLE) is the most common drug-resistant focal epilepsy, with seizures frequently arising from the hippocampus. In surgical series of TLE, the pathology is often hippocampal sclerosis (HS) comprising neuronal loss and gliosis and marked by atrophy and signal change on magnetic resonance imaging (Van Paesschen, 2004). Atrophy of the hippocampus through HS provides a good biomarker for the laterality of the seizure focus (Bernasconi et al., 2003), and combined with concordant neurophysiology and neuropsychological data can be sufficient to recommend surgery. Hippocampal atrophy is associated with a favorable surgical outcome (Schramm & Clusmann, 2008). Visual assessment of hippocampal volumes is unreliable, as it may be compromised by head position and primarily detects hippocampal asymmetry rather than volume loss, making bilateral atrophy difficult to identify. Hippocampal segmentation and volumetry are thus important for diagnosis and surgical planning (Watson et al., 1997). The gold standard for hippocampal segmentation is manual delineation by trained raters. This is accurate, reproducible, and sensitive but is time-consuming, requires anatomic knowledge, and is subject to interrater and intrarater variability. The hippocampus is challenging to delineate as it is small and highly variable with ill-defined margins. Many protocols exist for manual segmentation depending on which structures are included and the boundary definition (Konrad et al., 2009). Automated segmentation techniques aim to ensure operator independence, high reproducibility, and reduced demand for human time and expertise. The strongest drive for automation has come from researchers working with large cohorts of patients with Alzheimer's disease patients. Hippocampal volumes are an early marker for the disease, are related to cognitive status, and may reflect disease progression in clinical trials (Frisoni & Jack, 2011). In atlas-based segmentation approaches, a template and associated manual labels are registered (matched) to the new image (Carmichael et al., 2005). Commonly used methods, including FreeSurfer (Fischl et al., 2002), rely on a single template so that subjects that differ significantly from the template, for example HS, are poorly segmented. Segmentation of hippocampi that are sclerotic is more challenging than segmenting hippocampi in Alzheimer's disease, as the latter is associated with more prominent cerebrospinal fluid (CSF)–hippocampal boundaries, whereas the former is associated with signal change. The use of an atlas with multiple template images is more effective than a single template (Heckemann et al., 2006) and depends on the quality of registration and template selection strategy. Most previous atlas-based segmentation studies used small template databases of healthy subjects. Results obtained in TLE are significantly worse than in healthy subjects or Alzheimer's disease (Kim et al., 2012), as aside from atrophy, approximately 40% of patients with TLE demonstrate an atypical shape or position of the hippocampus (Bernasconi et al., 2005). In this study, we adapted our published method developed for use in Alzheimer's disease (Cardoso et al., 2013) to a large cohort of adult patients with epilepsy by employing accurate nonlinear registration (Modat et al., 2010) and a large template database that encompasses the range of pathology observed in epilepsy at a tertiary referral center. Manual segmentations of the most similar images from the template database are combined using a label fusion strategy based on local similarity to ensure accurate segmentation regardless of pathology. We demonstrate that this technique achieves reliable segmentation with no more variability than that seen between different expert raters. The algorithm is made freely available via an online Web-based service (https://hipposeg.cs.ucl.ac.uk). In addition, the software, scripts, and an anonymized version of the template database are available from this website.

The APOE e4 allele, which confers an increased risk of developing dementia in older adulthood, has been associated with enhanced cognitive performance in younger adults. An objective of the current study was to compare task-related behavioural and neural signatures for e4 carriers (e4+) and non-e4 carriers (e4-) to help elucidate potential mechanisms behind such cognitive differences. On two measures of attention, we recorded clear behavioural advantages in young adult e4+ relative to e4-, suggesting that e4+ performed these tasks with a wider field of attention. Behavioural advantages were associated with increased task-related brain activations detected by fMRI (BOLD). In addition, behavioural measures correlated with structural measures derived from a former DTI analysis of white matter integrity in our cohort. These data provide clear support for an antagonistic pleiotropy hypothesis - that the e4 allele confers some cognitive advantage in early life despite adverse consequences in old age. The data implicate differences in both structural and functional signatures as complementary mediators of the behavioural advantage.

Purpose Inhomogeneous magnetization transfer (ihMT) is an emerging form of MRI contrast that may offer high specificity for myelinated tissue. Existing ihMT and pulsed MT sequences often use separate radiofrequency pulses for saturation and signal excitation. This study investigates the use of nonselective multiband radiofrequency pulses for simultaneous off‐resonance saturation and on‐resonance excitation specifically for generation of ihMT contrast within rapid steady‐state pulse sequences. Theory and Methods A matrix‐based signal modeling approach was developed and applied for both balanced steady state free precession and spoiled gradient echo sequences, accounting specifically for multiband pulses. Phantom experiments were performed using a combination of balanced steady state free precession and spoiled gradient echo sequences, and compared with model fits. A human brain imaging exam was performed using balanced steady state free precession sequences to demonstrate the achieved contrast. Results A simple signal model derived assuming instantaneous radiofrequency pulses was shown to agree well with full integration of the governing equations and provided fits to phantom data for materials with strong ihMT contrast (PL161 root mean square error = 0.9%, and hair conditioner root mean square error = 2.4%). In vivo ihMT ratio images showed the expected white matter contrast that has been seen by other ihMT investigations, and the observed ihMT ratios corresponded well with predictions. Conclusions ihMT contrast can be generated by integrating multiband radiofrequency pulses directly into both spoiled gradient echo and balanced steady state free precession sequences, and the presented signal modeling approach can be used to understand the acquired signals.

How organisms learn the value of single stimuli through experience is well described. In many decisions, however, value estimates are computed “on the fly” by combining multiple stimulus attributes. The neural basis of this computation is poorly understood. Here we explore a common scenario in which decision-makers must combine information about quality and quantity to determine the best option. Using fMRI, we examined the neural representation of quality, quantity, and their integration into an integrated subjective value signal in humans of both genders. We found that activity within inferior frontal gyrus (IFG) correlated with offer quality, while activity in the intraparietal sulcus (IPS) specifically correlated with offer quantity. Several brain regions, including the anterior cingulate cortex (ACC), were sensitive to an interaction of quality and quantity. However, the ACC was uniquely activated by quality, quantity, and their interaction, suggesting that this region provides a substrate for flexible computation of value from both quality and quantity. Furthermore, ACC signals across subjects correlated with the strength of quality and quantity signals in IFG and IPS, respectively. ACC tracking of subjective value also correlated with choice predictability. Finally, activity in the ACC was elevated for choice trials, suggesting that ACC provides a nexus for the computation of subjective value in multiattribute decision-making. SIGNIFICANCE STATEMENT Would you prefer three apples or two oranges? Many choices we make each day require us to weigh up the quality and quantity of different outcomes. Using fMRI, we show that option quality is selectively represented in the inferior frontal gyrus, while option quantity correlates with areas of the intraparietal sulcus that have previously been associated with numerical processing. We show that information about the two is integrated into a value signal in the anterior cingulate cortex, and the fidelity of this integration predicts choice predictability. Our results demonstrate how on-the-fly value estimates are computed from multiple attributes in human value-based decision-making.

Background Functional neurological disorder (FND) is an elusive disorder characterized by unexplained neurological symptoms alongside aberrant cognitive processing and negative affect, often associated with amygdala reactivity. Methods We examined the effect of negative conditioning on cognitive function and amygdala reactivity in 25 FND patients and 20 healthy volunteers (HV). Participants were first conditioned to stimuli paired with negative affective or neutral (CS +/CS −) information. During functional MRI, subjects then performed an instrumental associative learning task to avoid monetary losses in the context of the previously conditioned stimuli. We expected that FND patients would be better at learning to avoid losses when faced with negatively conditioned stimuli (increased harm avoidance). Multi-echo resting state fMRI was also collected from the same subjects and a robust denoising method was employed, important for removing motion and physiological artifacts. Results FND subjects were more sensitive to the negative CS + compared to HV, demonstrated by a reinforcement learning model. Contrary to expectation, FND patients were generally more impaired at learning to avoid losses under both contexts (CS +/CS −), persisting to choose the option that resulted in a negative outcome demonstrated by both behavioural and computational analyses. FND patients showed enhanced amygdala but reduced dorsolateral prefrontal cortex responses when they received negative feedback. Patients also had increased resting state functional connectivity between these two regions. Conclusions FND patients had impaired instrumental avoidance learning, findings that parallel previous observations of impaired action-outcome binding. FND patients further show enhanced behavioural and neural sensitivity to negative information. However, this did not translate to improved avoidance learning. Put together, our findings do not support the theory of harm avoidance in FND. We highlight a potential mechanism by which negative contexts interfere with adaptive behaviours in this under-explored disorder. Highlights • Functional neurological disorder (FND) is a relatively common but elusive disorder characterized by unexplained neurological symptoms and negative affect. • One theory of FND symptomology is related to unconscious harm avoidance, in which symptom expression occurs to avoid a stressful situation. • We show that FND patients were more sensitive to negative information. However, this did not translate to increased harm avoidance as patients were impaired at goal-directed avoidance learning. • This study suggests that excessive negative conditioning in this group may engender deficient, rather than increased, goal-directed cognitive ability and loss avoidance.

We describe a laser-plasma platform for photon-photon collision experiments to measure fundamental quantum electrodynamic processes such as the linear Breit-Wheeler process with real photons. The platform has been developed using the Gemini laser facility at the Rutherford Appleton Laboratory. A laser wakefield accelerator and a bremsstrahlung convertor are used to generate a collimated beam of photons with energies of hundreds of MeV, that collide with keV x-ray photons generated by a laser heated plasma target. To detect the pairs generated by the photon-photon collisions, a magnetic transport system has been developed which directs the pairs onto scintillation-based and hybrid silicon pixel single particle detectors. We present commissioning results from an experimental campaign using this laser-plasma platform for photon-photon physics, demonstrating successful generation of both photon sources, characterisation of the magnetic transport system and calibration of the single particle detectors, and discuss the feasibility of this platform for the observation of the Breit-Wheeler process. The design of the platform will also serve as the basis for the investigation of strong-field quantum electrodynamic processes such as the nonlinear Breit-Wheeler and the Trident process, or eventually, photon-photon scattering. Comment: 28 pages, 14 figures

RNA analysis at the cellular resolution in the human brain is challenging. Here, we describe an optimised approach for detecting single RNA transcripts in a cell-type specific manner in frozen human brain tissue using multiplexed fluorescent RNAscope probes. We developed a new robust analytical approach for RNAscope quantification. Our method shows that low RNA integrity does not significantly affect RNAscope signal, recapitulates bulk RNA analysis and provides spatial context to transcriptomic analysis of human post-mortem brain at single-cell resolution. In summary, our optimised method allows the usage of frozen human samples from brain banks to perform quantitative RNAscope analysis. ispartof: SCIENTIFIC REPORTS vol:9 issue:1 ispartof: location:England status: published