Conserved cobalamin acquisition protein 1 is essential for vitamin B12 uptake in both Chlamydomonas and Phaeodactylum.

Microalgae play an essential role in global net primary productivity and global biogeochemical cycling. Despite their phototrophic lifestyle, over half of algal species depend for growth on acquiring an external supply of the corrinoid vitamin B12 (cobalamin), a micronutrient produced only by a subset of prokaryotic organisms. Previous studies have identified protein components involved in vitamin B12 uptake in bacterial species and humans. However, little is known about its uptake in algae. Here, we demonstrate the essential role of a protein, cobalamin acquisition protein 1 (CBA1), in B12 uptake in Phaeodactylum tricornutum using CRISPR-Cas9 to generate targeted knockouts and in Chlamydomonas reinhardtii by insertional mutagenesis. In both cases, CBA1 knockout lines could not take up exogenous vitamin B12. Complementation of the C. reinhardtii mutants with the wild-type CBA1 gene restored B12 uptake, and regulation of CBA1 expression via a riboswitch element enabled control of the phenotype. When visualized by confocal microscopy, a YFP-fusion with C. reinhardtii CBA1 showed association with membranes. Bioinformatics analysis found that CBA1-like sequences are present in all major eukaryotic phyla. In algal taxa, the majority that encoded CBA1 also had genes for B12-dependent enzymes, suggesting CBA1 plays a conserved role. Our results thus provide insight into the molecular basis of algal B12 acquisition, a process that likely underpins many interactions in aquatic microbial communities.

Scene-selectivity in CA1/subicular complex: Multivoxel pattern analysis at 7T.

Prior univariate functional magnetic resonance imaging (fMRI) studies in humans suggest that the anteromedial subicular complex of the hippocampus is a hub for scene-based cognition. However, it is possible that univariate approaches were not sufficiently sensitive to detect scene-related activity in other subfields that have been implicated in spatial processing (e.g., CA1). Further, as connectivity-based functional gradients in the hippocampus do not respect classical subfield boundary definitions, category selectivity may be distributed across anatomical subfields. Region-of-interest approaches, therefore, may limit our ability to observe category selectivity across discrete subfield boundaries. To address these issues, we applied searchlight multivariate pattern analysis to 7T fMRI data of healthy adults who undertook a simultaneous visual odd-one-out discrimination task for scene and non-scene (including face) visual stimuli, hypothesising that scene classification would be possible in multiple hippocampal regions within, but not constrained to, anteromedial subicular complex and CA1. Indeed, we found that the scene-selective searchlight map overlapped not only with anteromedial subicular complex (distal subiculum, pre/para subiculum), but also inferior CA1, alongside posteromedial (including retrosplenial) and parahippocampal cortices. Probabilistic overlap maps revealed gradients of scene category selectivity, with the strongest overlap located in the medial hippocampus, converging with searchlight findings. This was contrasted with gradients of face category selectivity, which had stronger overlap in more lateral hippocampus, supporting ideas of parallel processing streams for these two categories. Our work helps to map the scene, in contrast to, face processing networks within, and connected to, the human hippocampus.

A role for the fornix in temporal sequence memory.

Converging evidence from studies of human and nonhuman animals suggests that the hippocampus contributes to sequence learning by using temporal context to bind sequentially occurring items. The fornix is a white matter pathway containing the major input and output pathways of the hippocampus, including projections from medial septum and to diencephalon, striatum, lateral septum and prefrontal cortex. If the fornix meaningfully contributes to hippocampal function, then individual differences in fornix microstructure might predict sequence memory. Here, we tested this prediction by performing tractography in 51 healthy adults who had undertaken a sequence memory task. Microstructure properties of the fornix were compared with those of tracts connecting medial temporal lobe regions but not predominantly the hippocampus: the Parahippocampal Cingulum bundle (PHC) (conveying retrosplenial projections to parahippocampal cortex) and the Inferior Longitudinal Fasciculus (ILF) (conveying occipital projections to perirhinal cortex). Using principal components analysis, we combined Free-Water Elimination Diffusion Tensor Imaging and Neurite Orientation Dispersion and Density Imaging measures obtained from multi-shell diffusion MRI into two informative indices: the first (PC1) capturing axonal packing/myelin and the second (PC2) capturing microstructural complexity. We found a significant correlation between fornix PC2 and implicit reaction-time indices of sequence memory, indicating that greater fornix microstructural complexity is associated with better sequence memory. No such relationship was found with measures from the PHC and ILF. This study highlights the importance of the fornix in aiding memory for objects within a temporal context, potentially reflecting a role in mediating inter-regional communication within an extended hippocampal system.

Tract-specific differences in white matter microstructure between young adult APOE ε4 carriers and non-carriers: A replication and extension study.

The parahippocampal cingulum bundle (PHCB) interconnects regions known to be vulnerable to early Alzheimer's disease (AD) pathology, including posteromedial cortex and medial temporal lobe. While AD-related pathology has been robustly associated with alterations in PHCB microstructure, specifically lower fractional anisotropy (FA) and higher mean diffusivity (MD), emerging evidence indicates that the reverse pattern is evident in younger adults at increased risk of AD. In one such study, Hodgetts et al. (2019) reported that healthy young adult carriers of the apolipoprotein-E (APOE) ε4 allele - the strongest common genetic risk factor for AD - showed higher FA and lower MD in the PHCB but not the inferior longitudinal fasciculus (ILF). These results are consistent with proposals claiming that heightened neural activity and intrinsic connectivity play a significant role in increasing posteromedial cortex vulnerability to amyloid-ß and tau spread beyond the medial temporal lobe. Given the implications for understanding AD risk, here we sought to replicate Hodgetts et al.'s finding in a larger sample (N = 128; 40 APOE ε4 carriers, 88 APOE ε4 non-carriers) of young adults (age range = 19-33). Extending this work, we also conducted an exploratory analysis using a more advanced measure of white matter microstructure: hindrance modulated orientational anisotropy (HMOA). Contrary to the original study, we did not observe higher FA or lower MD in the PHCB of APOE ε4 carriers relative to non-carriers. Bayes factors (BFs) further revealed moderate-to-strong evidence in support of these null findings. In addition, we observed no APOE ε4-related differences in PHCB HMOA. Our findings indicate that young adult APOE ε4 carriers and non-carriers do not differ in PHCB microstructure, casting some doubt on the notion that early-life variation in PHCB tract microstructure might enhance vulnerability to amyloid-ß accumulation and/or tau spread.

The interindividual variability of multimodal brain connectivity maintains spatial heterogeneity and relates to tissue microstructure.

Humans differ from each other in a wide range of biometrics, but to what extent brain connectivity varies between individuals remains largely unknown. By combining diffusion-weighted imaging (DWI) and magnetoencephalography (MEG), this study characterizes the inter-subject variability (ISV) of multimodal brain connectivity. Structural connectivity is characterized by higher ISV in association cortices including the core multiple-demand network and lower ISV in the sensorimotor cortex. MEG ISV exhibits frequency-dependent signatures, and the extent of MEG ISV is consistent with that of structural connectivity ISV in selective macroscopic cortical clusters. Across the cortex, the ISVs of structural connectivity and beta-band MEG functional connectivity are negatively associated with cortical myelin content indexed by the quantitative T1 relaxation rate measured by high-resolution 7 T MRI. Furthermore, MEG ISV from alpha to gamma bands relates to the hindrance and restriction of the white-matter tissue estimated by DWI microstructural models. Our findings depict the inter-relationship between the ISV of brain connectivity from multiple modalities, and highlight the role of tissue microstructure underpinning the ISV.

Study development and protocol for a cohort study examining the impact of baseline social cognition on response to treatment for people living with post-traumatic stress disorder.

Background: Social cognitive impairments, specifically in facial emotion processing and mental state attribution, are common in post-traumatic stress disorder. However few studies so far have examined whether social cognitive ability impacts on PTSD recovery. Objective: To examine whether baseline social cognitive abilities are associated with treatment outcomes following trauma-focused therapy for PTSD. Method: This is a cohort study that will relate treatment outcomes post-discharge to baseline measures of social cognition (five tasks: Emotion Odd-One-Out Task (Oddity), Reading the Mind in the Eyes Task (RMET), Social Shapes Test (SST), Spontaneous Theory of Mind Protocol (STOMP), and Reflective Functioning Questionnaire (RFQ-8)) in people starting a course of psychological therapy for PTSD (target N = 60). The primary outcome will be pre- to post-treatment change in PTSD symptom severity (assessed using the PTSD Checklist for DSM-5). Secondary outcomes include functional impairment (assessed using the Work and Social Adjustment Scale), drop-out rate, and analyses differentiating participants with DSM-5 PTSD and ICD-11 PTSD and CPTSD. Regression models will be used to examine associations between baseline social cognitive performance and outcome measures while adjusting for potential confounders. Two pilot studies informed the development of our study protocol. The first involved qualitative analysis of interviews with nine participants with lived experience of mental health problems to inform our research questions and study protocol. The second involved trialling social cognitive tasks on 20 non-clinical participants to refine our test battery. Discussion: This study will address a gap in the literature about whether abilities in social cognition in people living with PTSD are associated with treatment-related recovery. HIGHLIGHTS: Impairments in social cognition are recognised in people with PTSD.Few studies have examined whether social cognitive ability is associated with recovery from PTSD.We present a study protocol, developed after pilot testing, to address this question.

Antecedentes: Las deficiencias en la cognición social, específicamente en el procesamiento de las emociones faciales y de la atribución de estados mentales, son comunes en el trastorno de estrés postraumático (TEPT). Sin embargo, hasta el momento pocos estudios han evaluado si la habilidad cognitiva social tiene un impacto en la recuperación del TEPT.Objetivo: Evaluar si las habilidades de cognición social de base están asociadas con los resultados del tratamiento después de la terapia centrada en el trauma para el TEPT.Métodos: Este es un estudio de cohortes que relacionará los resultados posteriores al alta del tratamiento con las medidas de referencia de la cognición social mediante cinco pruebas: la tarea de la emoción no correspondiente ('Emotion Odd-One-Out Task (Oddity)'), la tarea de lectura de la mente a través de la mirada ('Reading the Mind in the Eyes Task (RMET)'), la prueba de las figuras sociales ('Social Shapes Test (SST)'), el protocolo para la teoría de la mente espontánea ('Spontaneous Theory of Mind Protocol (STOMP)'), y el cuestionario de funcionamiento reflexivo ('Reflective Functioning Questionnaire (RFQ-8)'. Estas pruebas fueron realizadas en personas al iniciar el transcurso de la terapia psicológica para el TEPT (N objetivo = 60). El resultado principal será el cambio en la severidad de los síntomas del TEPT antes y después del tratamiento (evaluado utilizando la lista de verificación de síntomas de TEPT del DSM-5). Los resultados secundarios incluyen al deterioro funcional (evaluado mediante el cuestionario de trabajo y ajuste social, 'Work and Social Adjustment Scale' en inglés), la tasa de abandono, así como los análisis que diferencien a los participantes con TEPT según el DSM-5, y diferencien el TEPT y el TEPT complejo (TEPT-C) según la CIE-11. Se utilizarán modelos de regresión para examinar las asociaciones entre el rendimiento cognitivo social de referencia y las medidas de resultado mientras se ajustan por posibles variables de confusión. Dos estudios piloto sustentaron el desarrollo del protocolo del estudio. El primero involucró un análisis cualitativo de las entrevistas realizadas a nueve participantes con experiencias de problemas de salud mental para sustentar nuestras preguntas de investigación y el protocolo de estudio. El segundo involucró evaluar las pruebas de cognición social en veinte participantes sin condiciones clínicas para refinar la batería de pruebas.Discusión: Este estudio busca estrechar la brecha en la literatura sobre si las habilidades en la cognición social en personas que viven con TEPT están asociadas con la recuperación vinculada al tratamiento.

Biosynthesis of cobamides: Methods for the detection, analysis and production of cobamides and biosynthetic intermediates.

Vitamin B12, cobalamin, belongs to the broader cobamide family whose members are characterized by the presence of a cobalt-containing corrinoid ring. The ability to detect, isolate and characterize cobamides and their biosynthetic intermediates is an important prerequisite when attempting to study the synthesis of this remarkable group of compounds that play diverse roles across the three kingdoms of life. The synthesis of cobamides is restricted to only certain prokaryotes and their structural complexity entails an equally complex synthesis orchestrated through a multi-step biochemical pathway. In this chapter, we have outlined methods that we have found extremely helpful in the characterization of the biochemical pathway, including a plate microbiological assay, a corrinoid affinity extraction method, LCMS characterization and a multigene cloning strategy.

Subiculum-BNST structural connectivity in humans and macaques.

Invasive tract-tracing studies in rodents implicate a direct connection between the subiculum and bed nucleus of the stria terminalis (BNST) as a key component of neural pathways mediating hippocampal regulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis. A clear characterisation of the connections linking the subiculum and BNST in humans and non-human primates is lacking. To address this, we first delineated the projections from the subiculum to the BNST using anterograde tracers injected into macaque monkeys, revealing evidence for a monosynaptic subiculum-BNST projection involving the fornix. Second, we used in vivo diffusion MRI tractography in macaques and humans to demonstrate substantial subiculum complex connectivity to the BNST in both species. This connection was primarily carried by the fornix, with additional connectivity via the amygdala, consistent with rodent anatomy. Third, utilising the twin-based nature of our human sample, we found that microstructural properties of these tracts were moderately heritable (h2 ∼ 0.5). In a final analysis, we found no evidence of any significant association between subiculum complex-BNST tract microstructure and indices of perceived stress/dispositional negativity and alcohol use, derived from principal component analysis decomposition of self-report data. Our findings address a key translational gap in our knowledge of the neurocircuitry regulating stress.

Pubertal timing and functional neurodevelopmental alterations independently mediate the effect of family conflict on adolescent psychopathology.

This study tested the hypothesis that early life adversity (ELA) heightens psychopathology risk by concurrently altering pubertal and neurodevelopmental timing, and associated gene transcription signatures. Analyses focused on threat- (family conflict/neighbourhood crime) and deprivation-related ELAs (parental inattentiveness/unmet material needs), using longitudinal data from 1514 biologically unrelated youths in the Adolescent Brain and Cognitive Development (ABCD) study. Typical developmental changes in white matter microstructure corresponded to widespread BOLD signal variability (BOLDsv) increases (linked to cell communication and biosynthesis genes) and region-specific task-related BOLDsv increases/decreases (linked to signal transduction, immune and external environmental response genes). Increasing resting-state (RS), but decreasing task-related BOLDsv predicted normative functional network segregation. Family conflict was the strongest concurrent and prospective contributor to psychopathology, while material deprivation constituted an additive risk factor. ELA-linked psychopathology was predicted by higher Time 1 threat-evoked BOLDSV (associated with axonal development, myelination, cell differentiation and signal transduction genes), reduced Time 2 RS BOLDsv (associated with cell metabolism and attention genes) and greater Time 1 to Time 2 control/attention network segregation. Earlier pubertal timing and neurodevelopmental alterations independently mediated ELA effects on psychopathology. Our results underscore the differential roles of the immediate and wider external environment(s) in concurrent and longer-term ELA consequences.

Plasmodium falciparum hydroxymethylbilane synthase does not house any cosynthase activity within the haem biosynthetic pathway.

Uroporphyrinogen III, the universal progenitor of macrocyclic, modified tetrapyrroles, is produced from aminolaevulinic acid (ALA) by a conserved pathway involving three enzymes: porphobilinogen synthase (PBGS), hydroxymethylbilane synthase (HmbS) and uroporphyrinogen III synthase (UroS). The gene encoding uroporphyrinogen III synthase has not yet been identified in Plasmodium falciparum, but it has been suggested that this activity is housed inside a bifunctional hybroxymethylbilane synthase (HmbS). Additionally, an unknown protein encoded by PF3D7_1247600 has also been predicted to possess UroS activity. In this study it is demonstrated that neither of these proteins possess UroS activity and the real UroS remains to be identified. This was demonstrated by the failure of codon-optimized genes to complement a defined Escherichia coli hemD- mutant (SASZ31) deficient in UroS activity. Furthermore, HPLC analysis of the oxidized reaction product from recombinant, purified P. falciparum HmbS showed that only uroporphyrin I could be detected (corresponding to hydroxymethylbilane production). No uroporphyrin III was detected, showing that P. falciparum HmbS does not have UroS activity and can only catalyze the formation of hydroxymethylbilane from porphobilinogen.

Brain-environment alignment during movie watching predicts fluid intelligence and affective function in adulthood.

BOLD fMRI studies have provided compelling evidence that the human brain demonstrates substantial moment-to-moment fluctuations in both activity and functional connectivity (FC) patterns. While the role of brain signal variability in fostering cognitive adaptation to ongoing environmental demands is well-documented, the relevance of moment-to-moment changes in FC patterns is still debated. Here, we adopt a graph theoretical approach in order to shed light on the cognitive-affective implications of FC variability and associated profiles of functional network communication in adulthood. Our goal is to identify brain communication pathways underlying FC reconfiguration at multiple timescales, thereby improving understanding of how faster perceptually bound versus slower conceptual processes shape neural tuning to the dynamics of the external world and, thus, indirectly, mold affective and cognitive responding to the environment. To this end, we used neuroimaging and behavioural data collected during movie watching by the Cambridge Center for Ageing and Neuroscience (N = 642, 326 women) and the Human Connectome Project (N = 176, 106 women). FC variability evoked by changes to both the concrete perceptual and the more abstract conceptual representation of an ongoing situation increased from young to older adulthood. However, coupling between variability in FC patterns and concrete environmental features was stronger at younger ages. FC variability (both moment-to-moment/concrete featural and abstract conceptual boundary-evoked) was associated with age-distinct profiles of network communication, specifically, greater functional integration of the default mode network in older adulthood, but greater informational flow across neural networks implicated in environmentally driven attention and control (cingulo-opercular, salience, ventral attention) in younger adulthood. Whole-brain communication pathways anchored in default mode regions relevant to episodic and semantic context creation (i.e., angular and middle temporal gyri) supported FC reconfiguration in response to changes in the conceptual representation of an ongoing situation (i.e., narrative event boundaries), as well as stronger coupling between moment-to-moment fluctuations in FC and concrete environmental features. Fluid intelligence/abstract reasoning was directly linked to levels of brain-environment alignment, but only indirectly associated with levels of FC variability. Specifically, stronger coupling between moment-to-moment FC variability and concrete environmental features predicted poorer fluid intelligence and greater affectively driven environmental vigilance. Complementarily, across the adult lifespan, higher fluid (but not crystallised) intelligence was related to stronger expression of the network communication profile underlying momentary and event boundary-based FC variability during youth. Our results indicate that the adaptiveness of dynamic FC reconfiguration during naturalistic information processing changes across the lifespan due to the associated network communication profiles. Moreover, our findings on brain-environment alignment complement the existing literature on the beneficial consequences of modulating brain signal variability in response to environmental complexity. Specifically, they imply that coupling between moment-to-moment FC variability and concrete environmental features may index a bias towards perceptually-bound, rather than conceptual processing, which hinders affective functioning and strategic cognitive engagement with the external environment.

Extended-amygdala intrinsic functional connectivity networks: A population study.

Pre-clinical and human neuroimaging research implicates the extended-amygdala (ExtA) (including the bed nucleus of the stria terminalis [BST] and central nucleus of the amygdala [CeA]) in networks mediating negative emotional states associated with stress and substance-use behaviours. The extent to which individual ExtA structures form a functionally integrated unit is controversial. We utilised a large sample (n > 1,000 healthy young adult humans) to compare the intrinsic functional connectivity networks (ICNs) of the BST and CeA using task-free functional magnetic resonance imaging (fMRI) data from the Human Connectome Project. We assessed whether inter-individual differences within these ICNs were related to two principal components representing negative disposition and alcohol use. Building on recent primate evidence, we tested whether within BST-CeA intrinsic functional connectivity (iFC) was heritable and further examined co-heritability with our principal components. We demonstrate the BST and CeA to have discrete, but largely overlapping ICNs similar to previous findings. We found no evidence that within BST-CeA iFC was heritable; however, post hoc analyses found significant BST iFC heritability with the broader superficial and centromedial amygdala regions. There were no significant correlations or co-heritability associations with our principal components either across the ICNs or for specific BST-Amygdala iFC. Possible differences in phenotype associations across task-free, task-based, and clinical fMRI are discussed, along with suggestions for more causal investigative paradigms that make use of the now well-established ExtA ICNs.

Brain structure correlates of expected social threat and reward.

Prospection (mentally simulating future events) generates emotionally-charged mental images that guide social decision-making. Positive and negative social expectancies-imagining new social interactions to be rewarding versus threatening-are core components of social approach and avoidance motivation, respectively. Interindividual differences in such positive and negative future-related cognitions may be underpinned by distinct neuroanatomical substrates. Here, we asked 100 healthy adults to vividly imagine themselves in a novel self-relevant event that was ambiguous with regards to possible social acceptance or rejection. During this task we measured participants' expectancies for social reward (anticipated feelings of social connection) or threat (anticipated feelings of rejection). On a separate day they underwent structural MRI; voxel-based morphometry was used to explore the relation between social reward and threat expectancies and regional grey matter volumes (rGMV). Increased rGMV in key default-network regions involved in prospection, socio-emotional cognition, and subjective valuation, including ventromedial prefrontal cortex, correlated with both higher social reward and lower social threat expectancies. In contrast, social threat expectancies uniquely correlated with rGMV of regions involved in social attention (posterior superior temporal sulcus, pSTS) and interoception (somatosensory cortex). These findings provide novel insight into the neurobiology of future-oriented cognitive-affective processes critical to adaptive social functioning.

Replacement of the Cobalt Center of Vitamin B12 by Nickel: Nibalamin and Nibyric Acid Prepared from Metal-Free B12 †Ligands Hydrogenobalamin and Hydrogenobyric Acid.

The (formal) replacement of Co in cobalamin (Cbl) by NiII generates nibalamin (Nibl), a new transition-metal analogue of vitamin B12 . Described here is Nibl, synthesized by incorporation of a NiII ion into the metal-free B12  ligand hydrogenobalamin (Hbl), itself prepared from hydrogenobyric acid (Hby). The related NiII  corrin nibyric acid (Niby) was similarly synthesized from Hby, the metal-free cobyric acid ligand. The solution structures of Hbl, and Niby and Nibl, were characterized by spectroscopic studies. Hbl features two inner protons bound at N2 and N4 of the corrin ligand, as discovered in Hby. X-ray analysis of Niby shows the structural adaptation of the corrin ligand to NiII ions and the coordination behavior of NiII . The diamagnetic Niby and Nibl, and corresponding isoelectronic CoI corrins, were deduced to be isostructural. Nibl is a structural mimic of four-coordinate base-off Cbls, as verified by its ability to act as a strong inhibitor of bacterial adenosyltransferase.

The affective priming paradigm as an indirect measure of food attitudes and related choice behaviour.

In this Registered Report, we assessed the utility of the affective priming paradigm (APP) as an indirect measure of food attitudes and related choice behaviour in two separate cohorts. Participants undertook a speeded evaluative categorization task in which target words were preceded by food primes that differed in terms of affective congruence with the target, explicit liking (most liked or least liked), and healthiness (healthy or unhealthy). Non-food priming effects were tested as a manipulation check, and the relationship between food priming effects and impulsive choice behaviour was also investigated using a binary food choice task. As predicted, priming effects were observed for both healthy and unhealthy foods, but there was no difference in the magnitude of these effects. This may suggest that the paradigm is most sensitive to affective, but not cognitive, components of attitudes (i.e., healthiness), but alternative theoretical explanations and implications of this finding are discussed. Food and non-food priming effects were observed in both reaction time (RT) and error rate (ER) data, but contrary to expectations, we found no association between food RT priming effects and choice behaviour. All findings from confirmatory analyses regarding RT and ER priming effects, and the absence of the expected correlations between priming effects and impulsive food choices, were successfully replicated in the online cohort of participants. Overall, this study confirms the robustness of the APP as an indirect measure of food liking and raises questions about its applied value for research of eating behaviours.

The role of the pre-commissural fornix in episodic autobiographical memory and simulation.

Neuropsychological and functional magnetic resonance imaging evidence suggests that the ability to vividly remember our personal past, and imagine future scenarios, involves two closely connected regions: the hippocampus and ventromedial prefrontal cortex (vmPFC). Despite evidence of a direct anatomical connection from hippocampus to vmPFC, it is unknown whether hippocampal-vmPFC structural connectivity supports both past- and future-oriented episodic thinking. To address this, we applied a novel deterministic tractography protocol to diffusion-weighted magnetic resonance imaging (dMRI) data from a group of healthy young adult humans who undertook an adapted past-future autobiographical interview (portions of this data were published in Hodgetts et al., 2017a). This tractography protocol enabled distinct subdivisions of the fornix, detected previously in axonal tracer studies, to be reconstructed in vivo, namely the pre-commissural (connecting the hippocampus to vmPFC) and post-commissural (linking the hippocampus and medial diencephalon) fornix. As predicted, we found that inter-individual differences in pre-commissural - but not post-commissural - fornix microstructure (fractional anisotropy) were significantly correlated with the episodic richness of both past and future autobiographical narratives. Notably, these results held when controlling for non-episodic narrative content, verbal fluency, and grey matter volumes of the hippocampus and vmPFC. This study provides novel evidence that reconstructing events from one's personal past, and constructing possible future events, involves a distinct, structurally-instantiated hippocampal-vmPFC pathway.

Freezing of Gait in People with Parkinson's Disease: Nature, Occurrence, and Risk Factors.

BACKGROUND: Freezing of gait (FOG) is a common symptom of Parkinson's disease (PD) which can result in falls and fall related injuries, poor quality of life and reduced functional independence. It is a heterogeneous phenomenon that is difficult to quantify and eludes a unified pathophysiological framework. OBJECTIVE: Our aim was to document the occurrence and nature of freezing, cognitive stops and stumbles in people with PD during walks with varying cognitive loads and conditions designed to elicit FOG. METHODS: 130 people with PD walked under four conditions (normal walking, walking plus easy and hard dual-tasks, and a FOG elicitation condition. Video and accelerometry recordings were examined to document freezes and other gait disruptions. RESULTS: Participants experienced 391 freezes, 97 cognitive stops and 73 stumbles in the trial walks; with total gait disruptions increasing with task complexity. Most freezes in the FOG elicitation condition occurred during turning and approach destination. People who experienced freezing during the walks were more likely to have Postural Instability and Gait Difficulty (PIGD) subtype, longer disease duration and more severe UPDRS part II and part III sub-scores than people who did not freeze. They also took higher doses of levodopa, reported freezing in the past month, more prior falls, had poorer executive function, poorer proprioception, slower reaction time, poorer standing and leaning balance, more depressive symptoms, lower quality of life and greater fear of falling. PD disease duration, reduced controlled leaning balance and poor proprioception were identified as independent and significant determinants of freezing in logistic regression analysis. CONCLUSION: The multiple motor and cognitive factors identified as being associated with freezing, including poor proprioception and impaired controlled leaning balance provide new insights into this debilitating PD symptom and may contribute to potential new targets for rehabilitation.

Structural connections support emotional connections: Uncinate Fasciculus microstructure is related to the ability to decode facial emotion expressions.

The Uncinate Fasciculus (UF) is an association fibre tract connecting regions in the frontal and anterior temporal lobes. UF disruption is seen in several disorders associated with impaired social behaviour, but its functional role is unclear. Here we set out to test the hypothesis that the UF is important for facial expression processing, an ability fundamental to adaptive social behaviour. In two separate experiments in healthy adults, we used high-angular resolution diffusion-weighted imaging (HARDI) and constrained spherical deconvolution (CSD) tractography to virtually dissect the UF, plus a control tract (the corticospinal tract (CST)), and quantify, via fractional anisotropy (FA), individual differences in tract microstructure. In Experiment 1, participants completed the Reading the Mind in the Eyes Task (RMET), a well-validated assay of facial expression decoding. In Experiment 2, a different set of participants completed the RMET, plus an odd-emotion-out task of facial emotion discrimination. In both experiments, participants also completed a control odd-identity-out facial identity discrimination task. In Experiment 1, FA of the right-, but not the left-hemisphere, UF was significantly correlated with performance on the RMET task, specifically for emotional, but not neutral expressions. UF FA was not significantly correlated with facial identity discrimination performance. In Experiment 2, FA of the right-, but not left-hemisphere, UF was again significantly correlated with performance on emotional items from the RMET, together with performance on the facial emotion discrimination task. Again, no significant association was found between UF FA and facial identity discrimination performance. Our findings highlight the contribution of right-hemisphere UF microstructure to inter-individual variability in the ability to decode facial emotion expressions, and may explain why disruption of this pathway affects social behaviour.

The role of the fornix in human navigational learning.

Experiments on rodents have demonstrated that transecting the white matter fibre pathway linking the hippocampus with an array of cortical and subcortical structures - the fornix - impairs flexible navigational learning in the Morris Water Maze (MWM), as well as similar spatial learning tasks. While diffusion magnetic resonance imaging (dMRI) studies in humans have linked inter-individual differences in fornix microstructure to episodic memory abilities, its role in human spatial learning is currently unknown. We used high-angular resolution diffusion MRI combined with constrained spherical deconvolution-based tractography, to ask whether inter-individual differences in fornix microstructure in healthy young adults would be associated with spatial learning in a virtual reality navigation task. To efficiently capture individual learning across trials, we adopted a novel curve fitting approach to estimate a single index of learning rate. We found a statistically significant correlation between learning rate and the microstructure (mean diffusivity) of the fornix, but not that of a comparison tract linking occipital and anterior temporal cortices (the inferior longitudinal fasciculus, ILF). Further, this correlation remained significant when controlling for both hippocampal volume and participant gender. These findings extend previous animal studies by demonstrating the functional relevance of the fornix for human spatial learning in a virtual reality environment, and highlight the importance of a distributed neuroanatomical network, underpinned by key white matter pathways, such as the fornix, in complex spatial behaviour.

Zinc Substitution of Cobalt in Vitamin†B12 : Zincobyric acid and Zincobalamin as Luminescent Structural B12 -Mimics.

Replacing the central cobalt ion of vitamin B12 by other metals has been a long-held aspiration within the B12 -field. Herein, we describe the synthesis from hydrogenobyric acid of zincobyric acid (Znby) and zincobalamin (Znbl), the Zn-analogues of the natural cobalt-corrins cobyric acid and vitamin B12 , respectively. The solution structures of Znby and Znbl were studied by NMR-spectroscopy. Single crystals of Znby were produced, providing the first X-ray crystallographic structure of a zinc corrin. The structures of Znby and of computationally generated Znbl were found to resemble the corresponding CoII -corrins, making such Zn-corrins potentially useful for investigations of B12 -dependent processes. The singlet excited state of Znby had a short life-time, limited by rapid intersystem crossing to the triplet state. Znby allowed the unprecedented observation of a corrin triplet (ET =190 kJ mol-1 ) and was found to be an excellent photo-sensitizer for 1 O2 (ΦΔ =0.70).