Executive Control and Associated Brain Activity in Children With Familial High-Risk of Schizophrenia or Bipolar Disorder: A Danish Register-based Study.

BACKGROUND AND HYPOTHESES: Impaired executive control is a potential prognostic and endophenotypic marker of schizophrenia (SZ) and bipolar disorder (BP). Assessing children with familial high-risk (FHR) of SZ or BP enables characterization of early risk markers and we hypothesize that they express impaired executive control as well as aberrant brain activation compared to population-based control (PBC) children. STUDY DESIGN: Using a flanker task, we examined executive control together with functional magnetic resonance imaging (fMRI) in 11- to 12-year-old children with FHR of SZ (FHR-SZ) or FHR of BP (FHR-BP) and PBC children as part of a register-based, prospective cohort-study; The Danish High Risk and Resilience study-VIA 11. STUDY RESULTS: We included 85 (44% female) FHR-SZ, 63 (52% female) FHR-BP and 98 (50% female) PBC in the analyses. Executive control effects, caused by the spatial visuomotor conflict, showed no differences between groups. Bayesian ANOVA of reaction time (RT) variability, quantified by the coefficient of variation (CVRT), revealed a group effect with similarly higher CVRT in FHR-BP and FHR-SZ compared to PBC (BF10 = 6.82). The fMRI analyses revealed no evidence for between-group differences in task-related brain activation. Post hoc analyses excluding children with psychiatric illness yielded same results. CONCLUSION: FHR-SZ and FHR-BP at age 11-12 show intact ability to resolve a spatial visuomotor conflict and neural efficacy. The increased variability in RT may reflect difficulties in maintaining sustained attention. Since variability in RT was independent of existing psychiatric illness, it may reflect a potential endophenotypic marker of risk.

Physiological response in E. coli to YdgR overexpression depends on whether the protein has an intact function.

Membrane transport proteins are essential for the transport of a wide variety of molecules across the cell membrane to maintain cellular homeostasis. Generally, these transport proteins can be overexpressed in a suitable host (bacteria, yeast, or mammalian cells), and it is well documented that overexpression of membrane proteins alters the global metabolomic and proteomic profiles of the host cells. In the present study, we investigated the physiological consequences of overexpression of a membrane transport protein YdgR that belongs to the POT/PTR family from E. coli by using the lab strain BL21 (DE3)pLysS in its functional and attenuated mutant YdgR-E33Q. We found significant differences between the omics (metabolomics and proteomics) profiles of the cells expressing functional YdgR as compared to cells expressing attenuated YdgR, e.g., upregulation of several uncharacterized y-proteins and enzymes involved in the metabolism of peptides and amino acids. Furthermore, molecular network analysis suggested a relatively higher presence of proline-containing tripeptides in cells expressing functional YdgR. We envisage that an in-depth investigation of physiological alterations due to protein over-expression may be used for the deorphanization of the y-gene transportome.

Essentiality of the Escherichia coli YgfZ Protein for the In Vivo Thiomethylation of Ribosomal Protein S12 by the RimO Enzyme.

Enzymes carrying Iron-Sulfur (Fe-S) clusters perform many important cellular functions and their biogenesis require complex protein machinery. In mitochondria, the IBA57 protein is essential and promotes assembly of [4Fe-4S] clusters and their insertion into acceptor proteins. YgfZ is the bacterial homologue of IBA57 but its precise role in Fe-S cluster metabolism is uncharacterized. YgfZ is needed for activity of the radical S-adenosyl methionine [4Fe-4S] cluster enzyme MiaB which thiomethylates some tRNAs. The growth of cells lacking YgfZ is compromised especially at low temperature. The RimO enzyme is homologous to MiaB and thiomethylates a conserved aspartic acid in ribosomal protein S12. To quantitate thiomethylation by RimO, we developed a bottom-up LC-MS2 analysis of total cell extracts. We show here that the in vivo activity of RimO is very low in the absence of YgfZ and independent of growth temperature. We discuss these results in relation to the hypotheses relating to the role of the auxiliary 4Fe-4S cluster in the Radical SAM enzymes that make Carbon-Sulfur bonds.

Improved sensitivity and microvascular weighting of 3T laminar fMRI with GE-BOLD using NORDIC and phase regression.

INTRODUCTION: Functional MRI with spatial resolution in the submillimeter domain enables measurements of activation across cortical layers in humans. This is valuable as different types of cortical computations, e.g., feedforward versus feedback related activity, take place in different cortical layers. Laminar fMRI studies have almost exclusively employed 7T scanners to overcome the reduced signal stability associated with small voxels. However, such systems are relatively rare and only a subset of those are clinically approved. In the present study, we examined if the feasibility of laminar fMRI at 3T could be improved by use of NORDIC denoising and phase regression. METHODS: 5 healthy subjects were scanned on a Siemens MAGNETOM Prisma 3T scanner. To assess across-session reliability, each subject was scanned in 3-8 sessions on 3-4 consecutive days. A 3D gradient echo EPI (GE-EPI) sequence was used for BOLD acquisitions (voxel size 0.82 mm isotopic, TR = 2.2 s) using a block design finger tapping paradigm. NORDIC denoising was applied to the magnitude and phase time series to overcome limitations in temporal signal-to-noise ratio (tSNR) and the denoised phase time series were subsequently used to correct for large vein contamination through phase regression. RESULTS AND CONCLUSION: NORDIC denoising resulted in tSNR values comparable to or higher than commonly observed at 7T. Layer-dependent activation profiles could thus be extracted robustly, within and across sessions, from regions of interest located in the hand knob of the primary motor cortex (M1). Phase regression led to substantially reduced superficial bias in obtained layer profiles, although residual macrovascular contribution remained. We believe the present results support an improved feasibility of laminar fMRI at 3T.

Clipped DeepControl: Deep neural network two-dimensional pulse design with an amplitude constraint layer.

Advanced radio-frequency pulse design used in magnetic resonance imaging has recently been demonstrated with deep learning of (convolutional) neural networks and reinforcement learning. For two-dimensionally selective radio-frequency pulses, the (convolutional) neural network pulse prediction time (a few milliseconds) was in comparison more than three orders of magnitude faster than the conventional optimal control computation. The network pulses were from the supervised training capable of compensating scan-subject dependent inhomogeneities of B0 and B1+ fields. Unfortunately, the network presented with a small percentage of pulse amplitude overshoots in the test subset, despite the optimal control pulses used in training were fully constrained. Here, we have extended the convolutional neural network with a custom-made clipping layer that completely eliminates the risk of pulse amplitude overshoots, while preserving the ability to compensate for the inhomogeneous field conditions.

The Danish High-Risk and Resilience Study-VIA 15 - A Study Protocol for the Third Clinical Assessment of a Cohort of 522 Children Born to Parents Diagnosed With Schizophrenia or Bipolar Disorder and Population-Based Controls.

Background: Children born to parents with severe mental illness have gained more attention during the last decades because of increasing evidence documenting that these children constitute a population with an increased risk of developing mental illness and other negative life outcomes. Because of high-quality research with cohorts of offspring with familial risk and increased knowledge about gene-environment interactions, early interventions and preventive strategies are now being developed all over the world. Adolescence is a period characterized by massive changes, both in terms of physical, neurologic, psychological, social, and behavioral aspects. It is also the period of life with the highest risk of experiencing onset of a mental disorder. Therefore, investigating the impact of various risk and resilience factors in adolescence is important. Methods: The Danish High-Risk and Resilience Study started data collection in 2012, where 522 7-year-old children were enrolled in the first wave of the study, the VIA 7 study. The cohort was identified through Danish registers based on diagnoses of the parents. A total of 202 children had a parent diagnosed with schizophrenia, 120 children had a parent diagnosed with bipolar disorder, and 200 children had parents without these diagnoses. At age 11 years, all children were assessed for the second time in the VIA 11 study, with a follow-up retention rate of 89%. A comprehensive assessment battery covering domains of psychopathology, neurocognition, social cognition and behavior, motor development and physical health, genetic analyses, attachment, stress, parental functioning, and home environment was carried out at each wave. Magnetic resonance imaging scans of the brain and electroencephalograms were included from age 11 years. This study protocol describes the third wave of assessment, the VIA 15 study, participants being 15 years of age and the full, 3-day-long assessment battery this time including also risk behavior, magnetoencephalography, sleep, and a white noise paradigm. Data collection started on May 1, 2021. Discussion: We will discuss the importance of longitudinal studies and cross-sectional data collection and how studies like this may inform us about unmet needs and windows of opportunity for future preventive interventions, early illness identification, and treatment in the future.

Case Study: Implementation and evaluation of a team-based authentic research project module for large cohorts.

Acquiring skills needed to plan and conduct research and communicate research outcomes are key learning aims in biochemical and biomedical disciplines. Final-year projects/dissertations are high-impact educational activities that commonly feature in undergraduate curricula. When cohort sizes exceed infrastructure and staff capacity, traditional models of supervised projects may not be feasible. This case study aims to share one model of practice with colleagues similarly engaged in design and delivery of final-year projects and research. Here, we outline the implementation and evaluation of a team-based, final-year research module on a transnational joint programme. Investigative Skills module was piloted in 2016-2017 and continues to run annually for >100 students. The research component is conducted over a timetabled, two-week block. In student questionnaires, the majority of respondents agreed that the projects were authentic, interesting and appropriate. The favourite aspect for most of the respondents was performing experimental work/doing research. Over 80% agreed that working in teams was conducive to accomplishing their goals, and their ideal team size is three to five students per team. The majority agreed that there was sufficient experimental work to do, but that more than two weeks practical time would be beneficial. The feedback has given insight into the whole of the student research experience of Investigative Skills, which is a sustainable model for authentic dissertation research for large cohorts.

Diffusional kurtosis imaging as a possible prognostic marker of cervical incomplete spinal cord injury outcome: a prospective pilot study.

BACKGROUND: Spinal cord injury (SCI) is associated with substantial chronic morbidity and mortality. Routine imaging techniques such as T1- and T2-weighted magnetic resonance imaging (MRI) are not effective in predicting neurological deficiency grade or outcome. Diffusional kurtosis imaging (DKI) is an MR imaging technique that provides microstructural information about biological tissue. There are no longitudinal prospective studies assessing DKI metrics in acute traumatic SCI. Therefore, the purpose of this study was to establish a DKI protocol for acute SCI and correlate the DKI metrics to the functional neurological outcome of the patients. METHODS: Eight consecutive SCI patients referred to our institution with cervical SCI were included in the study. An acute diagnostic MRI scan was supplemented with a novel fast, mean kurtosis DKI protocol, which describes the average deviation from Gaussian diffusional along nine different directions. Mean kurtosis values were measured at the injury site and normalized to the mean kurtosis values of a non-injured site. At discharge form specialized rehabilitation, patients were evaluated using the Spinal Cord Independence Measure-III (SCIM-III). The DKI metrics and SCIM-III were analysed using Spearman's rank correlation. RESULTS: This pilot study found a significant correlation between decreasing mean kurtosis values at the injury site of the spinal cord and higher grade of disability measured by the SCIM-III (p = 0.002). CONCLUSION: This pilot study found that DKI may be a valuable tool as a prognostic marker in the acute phase of SCI.

Optimal control gradient precision trade-offs: Application to fast generation of DeepControl libraries for MRI.

We have recently demonstrated supervised deep learning methods for rapid generation of radiofrequency pulses in magnetic resonance imaging (https://doi.org/10.1002/mrm.27740, https://doi.org/10.1002/mrm.28667). Unlike the previous iterative optimization approaches, deep learning methods generate a pulse using a fixed number of floating-point operations - this is important in MRI, where patient-specific pulses preferably must be produced in real time. However, deep learning requires vast training libraries, which must be generated using the traditional methods, e.g., iterative quantum optimal control methods. Those methods are usually variations of gradient descent, and the calculation of the gradient of the performance metric with respect to the pulse waveform can be the most numerically intensive step. In this communication, we explore various ways in which the calculation of gradients in quantum optimal control theory may be accelerated. Four optimization avenues are explored: truncated commutator series expansions at zeroth and first order, a novel midpoint truncation scheme at first order, and the exact complex-step method. For the spin systems relevant to MRI, the first-order midpoint truncation is found to be sufficiently accurate, but also significantly faster than the machine precision gradient. This makes the generation of training databases for the machine learning methods considerably more realistic.

Rapid microstructural plasticity in the cortical semantic network following a short language learning session.

Despite the clear importance of language in our life, our vital ability to quickly and effectively learn new words and meanings is neurobiologically poorly understood. Conventional knowledge maintains that language learning-especially in adulthood-is slow and laborious. Furthermore, its structural basis remains unclear. Even though behavioural manifestations of learning are evident near instantly, previous neuroimaging work across a range of semantic categories has largely studied neural changes associated with months or years of practice. Here, we address rapid neuroanatomical plasticity accompanying new lexicon acquisition, specifically focussing on the learning of action-related language, which has been linked to the brain's motor systems. Our results show that it is possible to measure and to externally modulate (using transcranial magnetic stimulation (TMS) of motor cortex) cortical microanatomic reorganisation after mere minutes of new word learning. Learning-induced microstructural changes, as measured by diffusion kurtosis imaging (DKI) and machine learning-based analysis, were evident in prefrontal, temporal, and parietal neocortical sites, likely reflecting integrative lexico-semantic processing and formation of new memory circuits immediately during the learning tasks. These results suggest a structural basis for the rapid neocortical word encoding mechanism and reveal the causally interactive relationship of modal and associative brain regions in supporting learning and word acquisition.

Magnetic Resonance Imaging for the Planning, Execution, and Follow-up of Implant-Based Oral Rehabilitation: Systematic Review.

PURPOSE: To undertake a systematic literature review of magnetic resonance imaging (MRI) employed in the three phases of implant-based oral rehabilitation: planning, execution, and follow-up. MATERIALS AND METHODS: MEDLINE (PubMed) and EMBASE bibliographic databases were searched up to January 2020 for studies assessing the use of MRI alone or in connection with CT and/or CBCT in the planning, execution, or follow-up of dental implant placement and/or bone grafting procedures in the maxilla or the mandible. Included studies were also assessed according to the diagnostic imaging efficacy scale presented by Fryback and Thornbury (F&T). RESULTS: The search strategy yielded 10 studies, which were included in the systematic review. Six studies focused on the implant planning phase, one on the immediate follow-up phase, and three on both planning and follow-up. No studies acquired signal from the bone. There was no consensus on the gold standard, MRI sequence, or field strength (T). One study reached F&T level 1, eight reached level 2, and one reached level 3. CONCLUSION: The possible transition from radiography to ionizing-radiation-free imaging through MRI is still a novelty in dentistry and has yet to establish itself as a viable imaging modality suitable for replacing CT and CBCT. More studies are needed on the accuracy of the diverse MRI possibilities when applied for implant planning, execution, and follow-up before this diagnostic method can be considered as a reality for the clinician.

A bias towards natural rewards away from gambling cues in gamblers undergoing active treatment.

BACKGROUND: Disorders of substance and behavioral addiction are believed to be associated with a myopic bias towards the incentive salience of addiction-related cues away from general rewards in the environment. In non-treatment seeking gambling disorder patients, neural activity to anticipation of monetary rewards is enhanced relative to erotic rewards. Here we focus on the balance between anticipation of reward types in active treatment gamblers relative to healthy volunteers. METHODS: Fifty-three (25 gambling disorder males, 28 age-matched male healthy volunteers) were scanned with fMRI performing a Monetary Incentive Delay task with monetary and erotic outcomes. RESULTS: During reward anticipation, gambling disorder was associated with greater left orbitofrontal cortex and ventral striatal activity to erotic relative to monetary reward anticipation compared to healthy volunteers. Lower impulsivity correlated with greater activity in the dorsal striatum and dorsal anterior cingulate cortex to erotic anticipation in gambling disorder subjects. In the outcome phase, gambling disorder subjects showed greater activity in the ventral striatum, ventromedial and dorsolateral prefrontal cortex and anterior cingulate cortex to both reward types relative to healthy volunteers. CONCLUSIONS: These findings contrast directly with previous findings in non-treatment seeking gambling disorder. Our observations highlight the role of treatment state in active treatment gambling disorder, emphasizing a potential influence of treatment status, gambling abstinence or cognitive behavioral therapy on increasing the salience of general rewards beyond that of gambling-related cues. These findings support a potential therapeutic role for targeting the salience of non-gambling related rewards and potential biomarkers for treatment efficacy.

DeepControl: 2DRF pulses facilitating B1+ inhomogeneity and B0 off-resonance compensation in vivo at 7 T.

PURPOSE: Rapid 2DRF pulse design with subject-specific B1+ inhomogeneity and B0 off-resonance compensation at 7 T predicted from convolutional neural networks is presented. METHODS: The convolution neural network was trained on half a million single-channel transmit 2DRF pulses optimized with an optimal control method using artificial 2D targets, B1+ and B0 maps. Predicted pulses were tested in a phantom and in vivo at 7 T with measured B1+ and B0 maps from a high-resolution gradient echo sequence. RESULTS: Pulse prediction by the trained convolutional neural network was done on the fly during the MR session in approximately 9 ms for multiple hand-drawn regions of interest and the measured B1+ and B0 maps. Compensation of B1+ inhomogeneity and B0 off-resonances has been confirmed in the phantom and in vivo experiments. The reconstructed image data agree well with the simulations using the acquired B1+ and B0 maps, and the 2DRF pulse predicted by the convolutional neural networks is as good as the conventional RF pulse obtained by optimal control. CONCLUSION: The proposed convolutional neural network-based 2DRF pulse design method predicts 2DRF pulses with an excellent excitation pattern and compensated B1+ and B0 variations at 7 T. The rapid 2DRF pulse prediction (9 ms) enables subject-specific high-quality 2DRF pulses without the need to run lengthy optimizations.

Microstructural changes in the brain after long-term post-concussion symptoms: A randomized trial.

A recent randomized controlled trial in young patients with long-term post-concussion symptoms showed that a novel behavioral intervention "Get going After concussIoN" is superior to enhanced usual care in terms of symptom reduction. It is unknown whether these interventional effects are associated with microstructural brain changes. The aim of this study was to examine whether diffusion-weighted MRI indices, which are sensitive to the interactions between cellular structures and water molecules' Brownian motion, respond differently to the interventions of the above-mentioned trial and whether such differences correlate with the improvement of post-concussion symptoms. Twenty-three patients from the intervention group (mean age 22.8, 18 females) and 19 patients from the control group (enhanced usual care) (mean age 23.9, 14 females) were enrolled. The primary outcome measure was the mean kurtosis tensor, which is sensitive to the microscopic complexity of brain tissue. The mean kurtosis tensor was significantly increased in the intervention group (p = 0.003) in the corpus callosum but not in the thalamus (p = 0.78) and the hippocampus (p = 0.34). An increase in mean kurtosis tensor in the corpus callosum tended to be associated with a reduction in symptoms, but this association did not reach significance (p = 0.059). Changes in diffusion tensor imaging metrics did not differ between intervention groups and were not associated with symptoms. The current study found different diffusion-weighted MRI responses from the microscopic cellular structures of the corpus callosum between patients receiving a novel behavioral intervention and patients receiving enhanced usual care. Correlations with improvement of post-concussion symptoms were not evident.

Isolation, Purification, and Antimicrobial Characterization of Cannabidiolic Acid and Cannabidiol from Cannabis sativa L.

The emergence of multi-drug resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) causes a major threat to public health due to its limited therapeutic options. There is an urgent need for the development of new effective antimicrobial agents and alternative strategies that are effective against resistant bacteria. The parallel legalization of cannabis and its products has fueled research into its many therapeutic avenues in many countries around the world. This study aimed at the development of a reliable method for the extraction, purification, characterization, and quantification of cannabidiolic acid (CBDA) and its decarboxylated form cannabidiol (CBD) present in the fiber type Cannabis sativa L. The two compounds were extracted by ethanol, purified on a C18 sep-pack column, and the extracts were analyzed by high performance liquid chromatography coupled with ultraviolet (UV)-vis and ESI-MS (electrospray ionization mass spectrometry) detection. The antimicrobial effect of CBDA and CBD was also evaluated. CBD displayed a substantial inhibitory effect on Gram-positive bacteria with minimal inhibitory concentrations ranging from 1 to 2 µg/mL. Time kill analysis and minimal bactericidal concentration revealed potential bactericidal activity of CBDA and CBD. While cannabinoids showed a significant antimicrobial effect on the Gram-positive S. aureus and Staphylococcus epidermidis, no activity was noticed on Gram-negative Escherichia coli and Pseudomonas aeruginosa. CBDA presented a two-fold lower antimicrobial activity than its decarboxylated form, suggesting that the antimicrobial pharmacophore of the analyzed cannabinoids falls in the ability for permeabilizing the bacterial cell membrane and acting as a detergent-like agent. A synergy test performed on MRSA with CBD and a range of antibiotics did not indicate a synergetic effect, but noteworthy no antagonist influence either. CBD and CBDA manifested low hemolytic activity on human red blood cells. Likewise, the safety of CBD toward human keratinocyte cells presents no toxicity at a concentration of up to seven-fold higher than the antibacterial minimal inhibitory concentration. Similarly, both CBD and CBDA are well tolerated by mammals, including humans, and conserve a safe value limits for blood-contacting drug development. Overall, CBD exhibited a strong antimicrobial effect against Gram-positive strains and could serve as an alternative drug for tackling MRSA.

Doxorubicin selectively induces apoptosis through the inhibition of a novel isoform of Bcl­2 in acute myeloid leukaemia MOLM­13 cells with reduced Beclin 1 expression.

The overexpression of anti­apoptotic Bcl­2 in acute myeloid leukaemia (AML) may contribute to difficulties in eradicating these cells during chemotherapy. In the present study, doxorubicin (Dox) was evaluated for its potential to induce selective apoptotic cell death in AML MOLM­13 cells and to modulate autophagy through Bcl­2 and Beclin 1 protein expression. Annexin V/propidium iodide and 5(6)­carboxyfluorescein diacetate succinimidyl ester (CFSE) flow cytometric analyses were conducted to determine the effects of Dox on cell death and cell proliferation, respectively, following 48 h of co­incubation with AML MOLM­13 or U­937 monocytic cells. The protein expression levels of Bcl­2 and Beclin 1 in untreated and treated cells were quantified by western blot analysis. Dox reduced the viability of MOLM­13 cells partly by inhibiting cell division and inducing cell apoptosis. Dox demonstrated a level of selectivity in its cytotoxicity against MOLM­13 compared to U­937 cells (P<0.05). Dox induced a significant decrease in Beclin 1 protein levels in MOLM­13 cells without significantly affecting the protein levels in U­937 monocytes. A novel Bcl­2 15­20 kDa (p15­20­Bcl­2) isoform was found to be selectively expressed in AML MOLM­13 cells (but absent in the leukaemic cell lines tested, OCI­AML2, CML K562 and U­937). Dox induced a highly significant inhibition of p15­20­Bcl­2 at concentrations of 0.5, 0.75 and 1 µM (P<0.01). However, the usual 26 kDa Bcl­2 (p26­Bcl­2­α) isoform protein expression was not affected by the drug in either the MOLM­13 or U­937 cells. It was thus postulated that Dox exhibited some selectivity by targeting the p15­20­Bcl­2 isoform in MOLM­13 cells and activating Beclin 1 to induce cell death.

The sensation of groove engages motor and reward networks.

The sensation of groove has been defined as the pleasurable desire to move to music, suggesting that both motor timing and reward processes are involved in this experience. Although many studies have investigated rhythmic timing and musical reward separately, none have examined whether the associated cortical and subcortical networks are engaged while participants listen to groove-based music. In the current study, musicians and non-musicians listened to and rated experimentally controlled groove-based stimuli while undergoing functional magnetic resonance imaging. Medium complexity rhythms elicited higher ratings of pleasure and wanting to move and were associated with activity in regions linked to beat perception and reward, as well as prefrontal and parietal regions implicated in generating and updating stimuli-based expectations. Activity in basal ganglia regions of interest, including the nucleus accumbens, caudate and putamen, was associated with ratings of pleasure and wanting to move, supporting their important role in the sensation of groove. We propose a model in which different cortico-striatal circuits interact to support the mechanisms underlying groove, including internal generation of the beat, beat-based expectations, and expectation-based affect. These results show that the sensation of groove is supported by motor and reward networks in the brain and, along with our proposed model, suggest that the basal ganglia are crucial nodes in networks that interact to generate this powerful response to music.

Language beyond the language system: Dorsal visuospatial pathways support processing of demonstratives and spatial language during naturalistic fast fMRI.

Spatial demonstratives are powerful linguistic tools used to establish joint attention. Identifying the meaning of semantically underspecified expressions like "this one" hinges on the integration of linguistic and visual cues, attentional orienting and pragmatic inference. This synergy between language and extralinguistic cognition is pivotal to language comprehension in general, but especially prominent in demonstratives. In this study, we aimed to elucidate which neural architectures enable this intertwining between language and extralinguistic cognition using a naturalistic fMRI paradigm. In our experiment, 28 participants listened to a specially crafted dialogical narrative with a controlled number of spatial demonstratives. A fast multiband-EPI acquisition sequence (TR = 388 m s) combined with finite impulse response (FIR) modelling of the hemodynamic response was used to capture signal changes at word-level resolution. We found that spatial demonstratives bilaterally engage a network of parietal areas, including the supramarginal gyrus, the angular gyrus, and precuneus, implicated in information integration and visuospatial processing. Moreover, demonstratives recruit frontal regions, including the right FEF, implicated in attentional orienting and reference frames shifts. Finally, using multivariate similarity analyses, we provide evidence for a general involvement of the dorsal ("where") stream in the processing of spatial expressions, as opposed to ventral pathways encoding object semantics. Overall, our results suggest that language processing relies on a distributed architecture, recruiting neural resources for perception, attention, and extra-linguistic aspects of cognition in a dynamic and context-dependent fashion.

APOE gene-dependent BOLD responses to a breath-hold across the adult lifespan.

Age and apolipoprotein E (APOE) e4 genotype are two of the strongest known risk factors for sporadic Alzheimer's disease (AD). Neuroimaging has shown hemodynamic response changes with age, in asymptomatic carriers of the APOE e4 allele, and in AD. In this study, we aimed to characterize and differentiate age- and APOE gene-specific hemodynamic changes to breath-hold and visual stimulation. A further aim was to study whether these responses were modulated by 3-day intake of nitrate, a nitric oxide (NO) source. The study was designed as a randomized, double-blinded, placebo-controlled crossover study, and the study cohort comprised 41 APOE e4 carriers (e3/e4 or e4/e4 genotype) and 40 non-carriers (e3/e3 genotype) aged 30-70 years at enrollment. The participants underwent two scanning sessions, each preceded by ingestion of sodium nitrate or sodium chloride (control). During functional magnetic resonance imaging (fMRI) sessions, participants performed two concurrent tasks; a breath-hold task to probe cerebrovascular reactivity and a visual stimulation task to evoke functional hyperemia, respectively. We found that the blood oxygenation level dependent (BOLD) hemodynamic response to breath-hold was altered in APOE e4 carriers relative to non-carriers. Mid-aged (50-60 years of age) e4 carriers exhibited a significantly increased peak time relative to mid-aged e3 carriers, and peak time for younger (30-40 years of age) e4 carriers was significantly shorter than that of mid-aged e4 carriers. The response width was significantly increased for e4 carriers. The response peak magnitude significantly decreased with age. For the visual stimulation task, we found age-related changes, with reduced response magnitude with age but no significant effect of APOE allele type. We found no effect of nitrate ingestion on BOLD responses evoked by the breath-hold and visual stimulation tasks. The APOE gene-dependent response to breath-hold may reflect NO-independent differences in vascular function.