PaperPlayer biorxiv neuroscience

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.22.393199v1?rss=1 Authors: Pistono, A., Senoussi, M., Guerrier, L., Rafiq, M., Gimeno, M., Peran, P., Jucla, M., Pariente, J. Abstract: Language production deficits occur early in the course of Alzheimer's disease (AD); however, only few studies have focused on language functional networks in prodromal AD. The current study aims to uncover the extent of language alteration at a prodromal stage, on a behavioral, structural and functional level, using univariate and multivariate analyses. Twenty-four AD participants and 24 matched healthy controls underwent a comprehensive language evaluation, a structural T1-3D MRI and resting-state fMRI. We performed seed-based analyses, using the left inferior frontal gyrus and left posterior temporal gyrus as seeds. Then, we analyzed connectivity between executive control networks and language network in each group. Finally, we used multivariate pattern analyses to test whether the two groups could be distinguished based on the pattern of atrophy within the language network; atrophy within the executive control networks, as well as the pattern of functional connectivity within the language network; and functional connectivity within executive control networks. AD participants had language impairment during standardized language tasks and connected-speech production. Univariate analyses were not able to discriminate participants at this stage, while multivariate pattern analyses could significantly predict the group membership of prodromal patients and healthy controls, both when classifying atrophy patterns or connectivity patterns of the language network. Language functional networks could discriminate AD participants better than executive control networks. Most notably, they revealed an increased connectivity at a prodromal stage. Multivariate analyses represent a useful tool for investigating the functional and structural (re-)organization of the neural bases of language. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.21.390229v1?rss=1 Authors: Hecht, E. E., Kukekova, A., Gutman, D. A., Acland, G. M., Preuss, T. M., Trut, L. Abstract: The Russian fox-farm experiment is an unusually long-running and well-controlled study designed to replicate wolf-to-dog domestication. As such, it offers an unprecedented window onto the neural mechanisms governing the evolution of behavior. Here we report adaptations to gray matter morphology resulting from selection for tameness vs. aggressive response toward humans. Contrasting with prior work in other domesticated species, tame foxes did not show reduced brain volume. Rather, gray matter volume in both the tame and aggressive strains was increased relative to foxes bred without selection on behavior. Furthermore, tame- and aggressive-enlarged regions overlapped substantially, including portions of motor, somatosensory, and prefrontal cortex, amygdala, hippocampus, and cerebellum. We also observed differential morphological covariation across distributed gray matter networks. In one prefrontal-hypothalamic network, this covariation differentiated the tame and aggressive foxes together from the conventional strain. These findings indicate that selection for opposite behaviors can influence brain morphology in a similar way. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.392258v1?rss=1 Authors: Huang, P., Correia, M. M., Rua, C., Rodgers, C. T., Henson, R. N., Carlin, J. D. Abstract: The arrival of submillimetre ultra high-field fMRI makes it possible to compare activation profiles across cortical layers. However, the Blood Oxygenation Level Dependent (BOLD) signal measured by Gradient-Echo fMRI is biased towards superficial layers of the cortex, which is a serious confound for laminar analysis. Several univariate and multivariate analysis methods have been proposed to correct this bias. We compare these methods using computational simulations and example human 7T fMRI data from Regions-of-Interest (ROIs) during a visual attention paradigm. The simulations show that two methods - the ratio of ROI means across conditions and a novel application of Deming regression - offer the most robust correction for superficial bias. Deming regression has the additional advantage that it does not require that the conditions differ in their mean activation over voxels within an ROI. When applied to the example dataset, these methods suggest that attentional modulation of activation is similar across cortical layers within the ventral visual stream, despite a naive activation-based analysis producing stronger modulation in superficial layers. Our study demonstrates that accurate correction of superficial bias is crucial to avoid drawing erroneous conclusions from laminar analyses of Gradient-Echo fMRI data. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.392274v1?rss=1 Authors: Fengler, A., Frank, M., Govindarajan, L., Chen, T. Abstract: In cognitive neuroscience, computational modeling can formally adjudicate between theories and affords quantitative fits to behavioral/brain data. Pragmatically, however, the space of plausible generative models considered is dramatically limited by the set of models with known likelihood functions. For many models, the lack of a closed-form likelihood typically impedes Bayesian inference methods. As a result, standard models are evaluated for convenience, even when other models might be superior. Likelihood-free methods exist but are limited by their computational cost or their restriction to particular inference scenarios. Here, we propose neural networks that learn approximate likelihoods for arbitrary generative models, allowing fast posterior sampling with only a one-off cost for model simulations that is amortized for future inference. We show that these methods can accurately recover posterior parameter distributions for a variety of neurocognitive process models. We provide code allowing users to deploy these methods for arbitrary hierarchical model instantiations without further training. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.391698v1?rss=1 Authors: Voldsbekk, I., Barth, C., Maximov, I. I., Kaufmann, T., Beck, D., Richard, G., Moberget, T., Westlye, L. T., de Lange, A.-M. G. Abstract: Maternal brain adaptations occur in response to pregnancy, but little is known about how parity impacts white matter (WM) microstructure and WM ageing trajectories later in life. Utilising global and regional brain-age prediction based on multi-shell diffusion MRI data, we investigated the association between previous childbirths and WM brain age in 8,895 women in the UK Biobank cohort (age range = 54 - 81 years). The results showed that a higher number of previous childbirths was associated with lower WM brain age, in line with previous studies showing less evident grey matter (GM) brain ageing in parous relative to nulliparous women. Both global WM and GM brain age estimates showed unique contributions to the association with previous childbirths, suggesting partly independent processes. Corpus callosum contributed uniquely to the global WM association with previous childbirths, and showed a stronger relationship relative to several other tracts. While our findings demonstrate a link between reproductive history and brain WM characteristics later in life, longitudinal studies are required to understand how parity influences women's WM trajectories across the lifespan. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.21.392910v1?rss=1 Authors: Zeng, Y., Qin, S., Cui, Z., Wu, L., Xu, J., Tao, F., Yang, Z. Abstract: The dynamical organization of brain networks is essential to support human cognition and emotion for rapid adaption to ever-changing environment. As the core nodes of emotion-related brain circuitry, the basolateral amygdala (BLA) and centromedial amygdala (CMA) are recognized as two major amygdalar nuclei that regulate distinct affective functions and internal autonomic responses via their unique connections with cortical and subcortical structures in rodents. However, little is known how the dynamical organization of emotion-related brain circuitry reflects internal autonomic responses in humans. Using resting-state functional magnetic resonance imaging (fMRI) with concurrent recording of skin conductance, we show robust dynamic integration and segregation states of amygdala subregion-related intrinsic functional networks linked to spontaneous autonomic arousal. To be specific, time-varying connectivity analysis of resting-state fMRI data with K-means clustering approach revealed two distinct states of BLA- and CMA-based connectivity patterns, with a segregation state showing generally stronger BLA- than CMA-based connectivity with cortical regions, and an integration state showing substantial overlapping, in a spatio-temporal manner, between BLA- and CMA-based connectivity networks. Further analysis of skin conductance revealed significantly higher physiological arousal during the integration state than the segregation state, and state-specific BLA- and CMA-based connectivity with distinct subcortical and neocortical targets were predictive of spontaneous fluctuations of skin conductance. Our findings characterize dynamic functional organization of emotion-related amygdala nuclei circuits and networks and its links to spontaneous autonomic arousal in humans. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.22.392985v1?rss=1 Authors: Noro, Y., Shimizu, H., Mineta, K., Gojobori, T. Abstract: The last common ancestor of Bilateria and Cnidaria is believed to be one of the first animals to develop a nervous system over 500 million years ago. Many of the genes involved in the neural function of the advanced nervous system in Bilateria are well conserved in Cnidaria. Thus, Cnidarian representative species, Hydra, is considered to be a living fossil and a good model organism for the study of the putative primitive nervous system in its last common ancestor. The diffuse nervous system of Hydra consists of several peptidergic neuron subsets. However, the specific functions of these subsets remain unclear. Using calcium imaging, here we show that the neuron subsets that express neuropeptide, Hym-176 function as motor neurons to evoke longitudinal contraction. We found that all neurons in a subset defined by the Hym-176 gene (Hym-176A) or its paralogs (Hym-176B) expression are excited simultaneously, which is then followed by longitudinal contraction. This indicates not only that these neuron subsets are motor neurons but also that a single molecularly defined neuron subset forms a single coactive motor circuit. This is in contrast with the Bilaterian nervous system, where a single molecularly defined neuron subset harbors multiple coactive circuits, showing a mixture of neurons firing with different timings. Furthermore, we found that the two motor circuits, one expressing Hym-176B in the body column and the other expressing Hym-176A in the foot, are coordinately regulated to exert region-specific contraction. Our results demonstrate that one neuron subset is likely to form a monofunctional circuit as a minimum functional unit to build a more complex behavior in Hydra. We propose that this simple feature (one subset, one circuit, one function) found in Hydra is a fundamental trait of the primitive nervous system. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.22.393355v1?rss=1 Authors: Tran, T. T., Tobin, K. E., Block, S. H., Puliyadi, V., Gallagher, M., Bakker, A. Abstract: There has been considerable focus on investigating age-related memory changes in cognitively healthy older adults, in the absence of neurodegenerative disorders. Previous studies have reported age-related domain-specific changes in older adults, showing increased difficulty encoding and processing object information but minimal to no impairment in processing spatial information compared to younger adults. However, few of these studies have examined age-related changes in the encoding of concurrently presented object and spatial stimuli, specifically the integration of both spatial and non-spatial (object) information. To more closely resemble real-life memory encoding and the integration of both spatial and non-spatial information, the current study developed a new experimental paradigm with novel environments that allowed for the placement of different objects in different positions within the environment. The current findings show that older adults have decreased performance in recognizing changes of the object position within the spatial context but no significant differences in recognizing changes in the identity of the object within the spatial context compared to younger adults. These findings suggest there may be potential age-related differences in the mechanisms underlying the representations of complex environments and furthermore, the integration of spatial and non-spatial information may be differentially processed relative to independent and isolated representations of object and spatial information. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.21.392563v1?rss=1 Authors: Cataldo, A., Dupin, L., Dempsey-Jones, H., Gomi, H., Haggard, P. Abstract: Classical accounts of spatial perception are based either on the topological layout of sensory receptors, or on implicit spatial information provided by motor commands. In everyday self-touch, as when stroking the left arm with the right hand, these elements are inextricably linked, meaning that tactile and motor contributions to spatial perception cannot readily be disentangled. Here, we developed a robot-mediated form of self-touch in order to decouple the spatial extent of active or passive movements from their tactile consequences. Participants judged the spatial extent of either the movement of the right hand, or of the resulting tactile stimulation to their left forearm. Across five experiments, we found bidirectional interference between motor and tactile information. Crucially, both directions of interference were stronger during active than passive movements. Thus, voluntary motor commands produced stronger integration of multiple signals relevant to spatial perception. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.21.392449v1?rss=1 Authors: Baik, S.-H., Selvaraji, S., Fann, D. Y., Jo, D.-G., Herr, D. R., Lai, M. K. P., Chen, C. L.-H., Drummond, G. R., Lim, K.-L., Sobey, C. G., Arumugam, T. Abstract: Vascular dementia (VaD) is a progressive cognitive impairment of vascular etiology. VaD is characterized by cerebral hypoperfusion, increased blood-brain barrier permeability and white matter lesions. An increased burden of VaD is expected due to rapidly aging populations. The hippocampus is particularly susceptible to hypoperfusion, and the resulting memory impairment may play a crucial role in VaD. Here we have investigated the hippocampal gene expression profile of young and old mice subjected to chronic cerebral hypoperfusion by bilateral common carotid artery stenosis (BCAS). Our data in sham-operated young and aged mice show the normal age-associated decline in cerebral blood flow and differential gene expression. BCAS and ageing caused broadly similar effects, however, BCAS-induced changes in hippocampal gene expression differed between young and aged mice. Specifically, transcriptomic analysis indicated that in comparison to young sham mice, many pathways altered by BCAS in young mice resembled those present in sham aged mice. Immunoblot analyses confirmed these findings. Finally, relative to young sham mice the cell type-specific profile of genes in both young BCAS and old sham animals further revealed common cell-specific genes. Our data provide a genetic-based molecular framework for chronic hypoperfusion-induced hippocampal damage and reveal common cellular signaling pathways likely to be important in the pathophysiology of VaD. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.21.391458v1?rss=1 Authors: Cataldo, A., Hagura, N., Hyder, Y., Haggard, P. Abstract: Human perception of touch is mediated by inputs from multiple channels. Classical theories postulate independent contributions of each channel to each tactile feature, with little or no interaction between channels. In contrast to this view, we show that inputs from two sub-modalities of mechanical input channels interact to determine tactile perception. The flutter-range vibration channel was activated anomalously using hydroxy--sanshool, a bioactive compound of Szechuan pepper, which chemically induces tingling sensations. We tested whether this tingling sensation on the lips was modulated by sustained mechanical pressure. Across four experiments, we show that sustained touch inhibits sanshool tingling sensations in a location-specific, pressure-level and time-dependent manner. Additional experiments ruled out mediation of nociceptive or affective (C-tactile) channels underlying this interaction. These results reveal novel inhibitory influence from steady-pressure onto flutter-range tactile perceptual channels, consistent with early-stage interactions between mechanoreceptor inputs within the somatosensory pathway. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.391482v1?rss=1 Authors: Lopez-Gonzalez, A., Panda, R., Ponce-Alvarez, A., Zamora, G., Escrichs, A., Martial, C., Thibaut, A., Gosseries, O., Kringelbach, M. L., Annen, J., Laureys, S., Deco, G. Abstract: Low-level states of consciousness are characterised by disruptions of brain dynamics that sustain arousal and awareness. Yet, how structural, dynamical, local and network brain properties interplay in the different levels of consciousness is unknown. Here, we studied the fMRI brain dynamics from patients that suffered brain injuries leading to a disorder of consciousness and from subjects undergoing propofol-induced anaesthesia. We showed that pathological and pharmacological low-level states of consciousness displayed less recurrent, less diverse, less connected, and more segregated synchronization patterns than conscious states. We interpreted these effects using whole-brain models built on healthy and injured connectomes. We showed that altered dynamics arise from a global reduction of network interactions, together with more homogeneous and more structurally constrained local dynamics. These effects were accentuated using injured connectomes. Notably, these changes lead the hub regions to lose their stability during low-level states of consciousness, thus attenuating the core-periphery structure of brain dynamics. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.22.393397v1?rss=1 Authors: Magri, C., Konkle, T., Caramazza, A. Abstract: In human occipitotemporal cortex, brain responses to depicted inanimate objects have a large-scale organization by real-world object size. Critically, the size of objects in the world is systematically related to behaviorally-relevant properties: small objects are often grasped and manipulated (e.g., forks), while large objects tend to be less motor-relevant (e.g., tables), though this relationship does not always have to be true (e.g., picture frames and wheelbarrows). To determine how these two dimensions interact, we measured brain activity with functional magnetic resonance imaging while participants viewed a stimulus set of small and large objects with either low or high motor-relevance. The results revealed that the size organization was evident for objects with both low and high motor-relevance; further, a motor-relevance map was also evident across both large and small objects. Targeted contrasts revealed that typical combinations (small motor-relevant vs. large non-motor-relevant) yielded more robust topographies than the atypical covariance contrast (small non-motor-relevant vs. large motor-relevant). In subsequent exploratory analyses, a factor analysis revealed that the construct of motor-relevance was better explained by two underlying factors: one more related to manipulability, and the other to whether an object moves or is stable. The factor related to manipulability better explained responses in lateral small-object preferring regions, while the factor related to object stability (lack of movement) better explained responses in ventromedial large-object preferring regions. Taken together, these results reveal that the structure of neural responses to objects of different sizes further reflect behavior-relevant properties of manipulability and stability, and contribute to a deeper understanding of some of the factors that help the large-scale organization of object representation in high-level visual cortex. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.392308v1?rss=1 Authors: Ohata, R., Asai, T., Imaizumi, S., Imamizu, H. Abstract: The subjective experience of causing an action is known as the sense of agency. Dysfunction in the sense of agency has been suggested as a cause of auditory hallucinations (AHs), an important diagnostic criterion for schizophrenia. However, agency over speech has not been extensively characterized in previous empirical studies. Here, we examine both implicit and explicit measures of the sense of agency and reveal bottom-up and top-down components that constitute self-agency during speech. The first is action-outcome causality, which is perceived based on a low-level sensorimotor process when hearing their own voice following their speech. The second component is self-voice identity, which is embedded in the acoustic quality of voice and dominantly influences agency over speech at the cognitive judgment level. Our findings provide profound insight into the sense of agency over speech and present an informative perspective for understanding aberrant experience in AHs. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.392001v1?rss=1 Authors: Györi, J., Kohn, A. B., Romanova, D., Moroz, L. L. Abstract: ATP and its ionotropic P2X receptors are components of the most ancient signaling systems. However, little is known about the distribution and function of purinergic transmission in invertebrates. Here, we cloned, expressed, and pharmacologically characterized P2X receptors in the sea slug Aplysia californica - the prominent model in cellular and system neuroscience. These P2X receptors were successfully expressed in Xenopus oocytes and displayed activation by ATP (EC50=306 M) with two-phased kinetics as well as Na+-dependence. The ATP analog, Bz-ATP, was a less effective agonist (~20%) than ATP, and PPADS was a more potent inhibitor of the P2X receptors than the suramin. We showed that P2X receptors are uniquely expressed within Aplysia's cerebral bioenergetic center (F-cluster). Using RNA-seq, we found that the F-cluster contains more than a dozen unique secretory peptides, including three insulins, interleukins, and potential toxins, as well as ecdysone-type receptors and a district subset of ion channels. This structure is one of the most prominent integrative centers in the entire CNS and remarkably different from the morphologically similar neurosecretory center (bag-cluster) involved in egg-laying behavior. Using RNA-seq, we also characterized the expression of P2X receptors across more than a dozen Aplysia peripheral tissues and developmental stages. We showed that P2X receptors are predominantly expressed in chemosensory structures and during early cleavage stages. The localization and pharmacology of P2X receptors in Aplysia highlight the evolutionary conservation of bioenergetic sensors and chemosensory purinergic transmission across animals. This study also provides a foundation to decipher homeostatic mechanisms in development and neuroendocrine systems. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.390955v1?rss=1 Authors: Minino, R., Troisi Lopez, E., Sorrentino, P., Rucco, R., Lardone, A., Pesoli, M., Tafuri, D., Mandolesi, L., Sorrentino, G., Liparoti, M. Abstract: The use of rhythmic acoustic stimulation (RAS) in improving gait and balance in healthy elderly subjects has been widely investigated. However, methodologies and results are often controversial. In this study, we hypothesize that both the kinematic features of gait and stability, depend on the frequency at which RAS is administered. Our aim was to observe, through 3D Gait Analysis, the effect of different types of RAS (at a fixed frequency or based on the average cadence of each subject) on both gait spatio-temporal parameters and stability. The latter was estimated through an innovative measure, the trunk displacement index (TDI) that we have recently implemented. We observed that the low frequencies RAS led to a general slowdown of gait, which did not provide any clear benefit and produced harmful effects on stability when the frequency became too low compared to the individual natural frequency. On the contrary, the high frequencies of RAS showed a slight acceleration of gait, accompanied by better stability (as documented by a lower TDI value), regardless of the type of RAS. Finally, the RAS equal to the individual natural cadence also produced an increase in stability. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.390120v1?rss=1 Authors: Cetin-Karayumak, S., Stegmayer, K., Walther, S., Szeszko, P. R., Crow, T., James, A., Keshavan, M., Kubicki, M., Rathi, Y. Abstract: The findings from diffusion-weighted magnetic resonance imaging (dMRI) studies often show inconsistent and sometimes contradictory results due to small sample sizes as well as differences in acquisition parameters and pre-/post-processing methods. To address these challenges, collaborative multi-site initiatives have provided an opportunity to collect larger and more diverse groups of subjects, including those with neuropsychiatric disorders, leading to increased power and findings that may be more representative at the group and individual level. With the availability of these datasets openly, the ability of joint analysis of multi-site dMRI data has become more important than ever. However, intrinsic- or acquisition-related variability in scanner models, acquisition protocols, and reconstruction settings hinder pooling multi-site dMRI directly. One powerful and fast statistical harmonization method called ComBat (https://github.com/Jfortin1/ComBatHarmonization) was developed to mitigate the "batch effect" in gene expression microarray data and was adapted for multi-site dMRI harmonization to reduce scanner/site effect. Our goal is to evaluate this commonly used harmonization approach using a large diffusion MRI dataset involving 542 individuals from 5 sites. We investigated two important aspects of using ComBat for harmonization of fractional anisotropy (FA) across sites: First, we assessed how well ComBat preserves the inter-subject biological variability (measured by the effect sizes of between-group FA differences) after harmonization. Second, we evaluated the effect of minor differences in pre-processing on ComBat's performance. While the majority of effect sizes are mostly preserved in some sites after harmonization, they are not well-preserved at other sites where non-linear scanner contributions exist. Further, even minor differences in pre-processing can yield unwanted effects during ComBat harmonization. Thus, our findings suggest paying careful attention to the data being harmonized as well as using the same processing pipeline while using ComBat for data harmonization. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.392175v1?rss=1 Authors: Tokarew, J. M., El Kodsi, D. N., Lengacher, N. A., Fehr, T. K., Nguyen, A. P., Shutinoski, B., O'Nuallain, B., Jin, M., Khan, J., Ng, A. C. H., Li, J., Jiang, Q., Zhang, M., Wang, L., Sengupta, R., Barber, K., Tran, A., Zandee, S., Dong, X., Scherzer, C. R., Prat, A., Tsai, E., Takanashi, M., Hattori, N., Chan, J. A., Zecca, L., West, A., Holmgren, A., Puente, L., Shaw, G. S., Toth, G., Woulfe, J., Taylor, P., Tomlinson, J. J., Schlossmacher, M. G. Abstract: The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions, which are reflected in its posttranslational modifications. We found that in human control brain, including the S. nigra, parkin is largely insoluble after age 40 years, which is linked to its oxidation, e.g., at Cys95 and Cys253. In mice, oxidative stress increases posttranslational modifications at parkin cysteines and reduces its solubility. Oxidation of recombinant parkin also promotes insolubility and aggregate formation, but in parallel, lowers hydrogen peroxide (H2O2). This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. Intriguingly, in parkin-deficient human brain H2O2 concentrations are elevated. In prkn-null mice, H2O2 levels are dysregulated under oxidative stress conditions, such as acutely by MPTP-toxin exposure or chronically due to a second genetic hit. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic M17 cells, in part through lowering H2O2. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at primate-specific Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation. In sections of normal, adult human midbrain, parkin specifically co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63+ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H2O2, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these redox effects may augment oxidative stress in dopamine producing neurons of mutant PRKN allele carriers, thereby contributing to neurodegeneration. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.391805v1?rss=1 Authors: Wall, M. B., Freeman, T. P., Hindocha, C., Demetriou, L., Ertl, N., Freeman, A. M., Jones, A. P. M., Lawn, W., Pope, R., Mokrysz, C., Solomons, D., Statton, B., Walker, H. R., Yamamori, Y., Yang, Z., Yim, J. L. L., Nutt, D. J., Howes, O. D., Curran, H. V., Bloomfield, M. Abstract: Cannabidiol (CBD) and {Delta}9-tetrahydrocannabinol (THC) are two major constituents of cannabis with contrasting mechanisms of action. THC is the major psychoactive, addiction-promoting, and psychotomimetic compound, while CBD may have somewhat opposite effects. The brain effects of these drugs alone and in combination are poorly understood. In particular the striatum is implicated in the pathophysiology of several psychiatric disorders, but it is unclear how THC and CBD influence striato-cortical connectivity. Across two placebo-controlled, double-blind studies, we examine the effects of THC, CBD, and THC+CBD on the functional connectivity of striatal sub-divisions (associative, limbic, and sensorimotor) using resting-state functional Magnetic Resonance Imaging (fMRI) and seed-based functional connectivity analyses. Study 1 (N=17; inhaled 8mg THC, 8mg THC+10mg CBD, placebo) showed strong disruptive effects of both THC and THC+CBD conditions on connectivity in the associative and sensorimotor networks, but a specific effect of THC in the limbic striatum, which was alleviated in the THC+CBD condition such that it did not differ from placebo. In Study 2 (N=23, oral 600mg CBD, placebo) CBD increased connectivity in the associative network, but relatively minor decreases/disruptions were found in the limbic and sensorimotor. In conclusion, THC strongly disrupts striato-cortical networks, and this effect is selectively mitigated in the limbic striatum when co-administered with CBD. When administered alone, 600mg oral CBD has a more complex effect profile of relative increases and decreases in connectivity. The insula emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with potential implications for understanding cannabis related disorders, and the development of cannabinoid therapeutics. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.17.387043v1?rss=1 Authors: Kalidindi, H. T., Cross, K. P., Lillicrap, T. P., Omrani, M., Falotico, E., Sabes, P. N., Scott, S. H. Abstract: Recent studies hypothesize that motor cortical (MC) dynamics are generated largely through its recurrent connections based on observations that MC activity exhibits rotational structure. However, behavioural and neurophysiological studies suggest that MC behaves like a feedback controller where continuous sensory feedback and interactions with other brain areas contribute substantially to MC processing. We investigated these apparently conflicting theories by building recurrent neural networks that controlled a model arm and received sensory feedback about the limb. Networks were trained to counteract perturbations to the limb and to reach towards spatial targets. Network activities and sensory feedback signals to the network exhibited rotational structure even when the recurrent connections were removed. Furthermore, neural recordings in monkeys performing similar tasks also exhibited rotational structure not only in MC but also in somatosensory cortex. Our results argue that rotational structure may reflect dynamics throughout voluntary motor circuits involved in online control of motor actions. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.17.385898v1?rss=1 Authors: Wang, X., Li, X.-H., Cho, J. W., Russ, B., Rajamani, N., Omelchenko, A., Ai, L., Korchmaros, A., Garcia-Saldivar, P., Wang, Z., Kalin, N. H., Schroeder, C. E., Craddock, R. C., Fox, A. S., Evans, A. C., Messinger, A., Milham, M. P., Xu, T. Abstract: Brain extraction (a.k.a. skull stripping) is a fundamental step in the neuroimaging pipeline as it can affect the accuracy of downstream preprocess such as image registration, tissue classification, etc. Most brain extraction tools have been mainly orientated for human data and are often challenging for non-human primates (NHP). In recent attempts to improve the performance in NHP, deep learning models appear to outperform the traditional tools. However, given the minimal sample size of most NHP studies and notable variations in data quality, the deep learning models are very rarely applied in multi-site samples in NHP imaging. To overcome this challenge, we propose to use transfer-learning framework that leverages a large human imaging dataset to pretrain a convolutional neural network (i.e. U-Net Model), and then transferred to NHP data using a small NHP training sample. The resulting transfer-learning model converged faster and achieved more accurate performance than a similar U-Net Model trained exclusively on NHP samples. We improved the generalizability of the model by upgrading the transfer-learned model using additional training datasets from multiple research sites in the Primate Data-Exchange (PRIME-DE) consortium. Our final model outperformed brain extraction routines from popular MRI packages (AFNI, FSL, and FreeSurfer) across multiple heterogeneous multiple sites from PRIME-DE with less computational cost (20s~10min). Our model, code, and the skull-stripped mask repository of 136 macaque monkeys are publicly available for unrestricted use by the neuroimaging community at https://github.com/HumanBrainED/NHP-BrainExtraction. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.17.385450v1?rss=1 Authors: Earley, E. J., Johnson, R. E., Sensinger, J. W., Hargrove, L. Abstract: Accurate control of human limbs involves both feedforward and feedback signals. For prosthetic arms, feedforward control is commonly accomplished by recording myoelectric signals from the residual limb to predict the user's intent, but augmented feedback signals are not explicitly provided in commercial devices. Previous studies have demonstrated inconsistent results when artificial feedback was provided in the presence of vision. We hypothesized that negligible benefits in past studies may have been due to artificial feedback with low precision compared to vision, which results in heavy reliance on vision during reaching tasks. Furthermore, we anticipated more reliable benefits from artificial feedback when providing information that vision estimates with high uncertainty - joint speed. In this study, we test an artificial sensory feedback system providing joint speed information and how it impacts performance and adaptation during a hybrid positional-and-myoelectric ballistic reaching task. We found modest improvement in overall reaching errors after perturbed control, and that high prosthesis control noise was compensated for by strategic overreaching with the positional control and underreaching with the myoelectric control. These results provide insights into the relevant factors influencing the improvements conferred by artificial sensory feedback. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.19.390286v1?rss=1 Authors: Chiuffa Tunes, G., de Oliveira, E. F., Vieira, E. U. P., Caetano, M. S., Cravo, A. M., Reyes, M. B. Abstract: Although time is a fundamental dimension of life, we do not know how the brain encodes the temporal information. Several brain areas underlie the temporal information, such as the hippocampus, prefrontal cortex, and striatum, but evidence of how they cooperate to process temporal information is scarce. Notably, the analysis of neural activity during learning are rare, mainly because timing tasks usually take a long time to train. Here we investigated how the time encoding evolves when animals learn to time a 1.5 s interval. We designed a novel training protocol where rats go from naive- to proficient-level timing performance within a single session, allowing us to investigate neuronal activity from very early learning stages. We used pharmacological experiments and machine-learning algorithms to evaluate the level of time encoding in the medial prefrontal cortex and the dorsal striatum. Our results show a double dissociation between the roles of the medial prefrontal cortex and the dorsal striatum during temporal learning, where the former commits to early learning stages while the latter become more engaged as animals become more proficient in the task. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.390435v1?rss=1 Authors: Karimi, H., Marefat, H., Khanbagi, M., Kalafatis, C., Modarres, M. H., Vahabi, Z., Khaligh-Razavi, S.-M. Abstract: Electroencephalography (EEG) has been commonly used to measure brain alterations in Alzheimer's Disease (AD). However, reported changes are limited to those obtained from using univariate measures, including activation level and frequency bands. To look beyond the activation level, we used multivariate pattern analysis (MVPA) to elicit the pattern of information processing from EEG responses to an animacy categorization task. Comparing healthy controls (HC) with patients with mild cognitive impairment (MCI), we found that the neural speed of animacy information processing is decreased in MCI patients. Moreover, we found critical time-points during which the representational pattern of animacy for MCI patients was significantly discriminable from that of HC, while the activation level remained unchanged. Together, these results suggest that the speed and pattern of animacy information processing provide clinically useful information as a potential biomarker for detecting early changes in MCI and AD patients. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.19.386193v1?rss=1 Authors: Tzvi, E., Bey, R., Nitschke, M., Brueggemann, N., Classen, J., Muente, T. F., Kraemer, U. M., Rumpf, J.-J. Abstract: Previous studies have shown that persons with Parkinsons disease (pwPD) share specific deficits in learning new sequential movements, but the neural substrates of this impairment remain unclear. In addition, the degree to which striatal dopaminergic denervation in PD affects the cortico-striato-cerebellar motor learning network remains unknown. We aimed to answer these questions using fMRI in 16 pwPD and 16 healthy age-matched control subjects while they performed an implicit motor sequence learning task. While learning was absent in both pwPD and controls assessed with reaction time differences between sequential and random trials, larger error-rates during the latter suggest that at least some of the complex sequence was encoded. Moreover, we found that while healthy controls could improve general task performance indexed by decreased reaction times across both sequence and random blocks, pwPD could not, suggesting disease-specific deficits in learning of stimulus-response associations. Using fMRI, we found that this effect in pwPD was correlated with decreased activity in the hippocampus over time. Importantly, activity in the substantia nigra (SN) and adjacent bilateral midbrain was specifically increased during sequence learning in pwPD compared to healthy controls, and significantly correlated with sequence-specific learning deficits. As increased SN activity was also associated (on trend) with higher doses of dopaminergic medication as well as disease duration, the results suggest that learning deficits in PD are associated with disease progression, indexing an increased drive to recruit dopaminergic neurons in the SN, however unsuccessfully. Finally, we found no differences between pwPD and controls in task modulation of the cortico-striato-cerebellar network. Notably, in both groups Bayesian model selection revealed cortico-cerebellar connections modulated by the task, suggesting that despite behavioral and activation differences, the same cortico-cerebellar circuitry is recruited for implementing the motor task. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.19.390419v1?rss=1 Authors: Carnazza, K. E., Komer, L., Pineda, A., Na, Y., Ramlall, T., Buchman, V. L., Eliezer, D., Sharma, M., Burre, J. Abstract: -Synuclein (Syn), {beta}-synuclein ({beta}Syn), and {gamma}-synuclein ({gamma}Syn) are abundantly expressed in the vertebrate nervous system. Syn functions in neurotransmitter release via binding to and clustering synaptic vesicles and chaperoning of SNARE-complex assembly. The functions of {beta}Syn and {gamma}Syn are unknown. Functional redundancy of the three synucleins and mutual compensation when one synuclein is deleted have been proposed, but with conflicting evidence. Here, we demonstrate that {beta}Syn and {gamma}Syn have a reduced affinity towards membranes compared to Syn, and that direct interaction of {beta}Syn or {gamma}Syn with Syn results in reduced membrane binding of Syn. Our data suggest that all three synucleins affect synapse function, but only Syn mediates the downstream function of vesicle clustering and SNARE-complex assembly, while {beta}Syn and {gamma}Syn modulate the activity of Syn through regulating its binding to synaptic vesicles. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.19.390013v1?rss=1 Authors: Tabatabaee, M. s., Kerkovius, J. K., Menard, F. Abstract: In the brain, astrocytes undergo rapid morphological changes when stimulated by the excitatory neurotransmitter glutamate. We developed a chemical probe to monitor how glutamate affects the density and distribution of astrocytic L-type voltage-gated calcium channels (LTCC). The imaging probe FluoBar1 was created from a barbiturate ligand modified with a fluorescent coumarin moiety. The probe selectivity was examined with colocalization analyses of confocal fluorescence imaging in U118-MG and transfected COS-7 cells. Living cells treated with 50 nM FluoBar1 were imaged in real time to reveal changes in density and distribution of astrocytic LTCCs upon exposure to glutamate. The selectivity of the probe was demonstrated with immunoblotting and confocal imaging of immunostained cells expressing the CaV1.2 isoform of LTCCs proteins. Applying FluoBar1 to astrocyte model cells U118-MG allowed us to measure a 5-fold increase in fluorescence density of LTCCs upon glutamate exposure. The imaging probe FluoBar1 allows the real-time monitoring of LTCCs in living cells, revealing for first time that glutamate causes a rapid increase of LTCC membranar density in astrocyte model cells. It may help tackle previously intractable questions about LTCC dynamics in cellular events. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.391508v1?rss=1 Authors: Dutkiewicz, A. P., Morielli, A. D. Abstract: The endogenous opioid system of the cerebral cortex is an important feature of antinociception and reward valuation through its modulation of inhibitory neocortical interneurons. Dysregulation of this system, through disease or drugs, disrupts the reward system and contributes to eating and mood disorders, impulsive actions, and addiction. Impulsive behaviors can be induced experimentally through infusion of the opioid receptor specific agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-Enkephalin (DAMGO) into the frontal cortex in animal models. The mechanism involves increased potassium channel function, which suppresses neocortical interneuron activity. However, much of the data on the effect of this receptor on ion channels have been derived from noncortical ORs, and the identity and effects of the ion channels that the OR targets in neocortical neurons have not been thoroughly investigated. Based on previous experiments by other labs, we hypothesized that the OR could activate -dendrotoxin (-DTX) sensitive channels (Kv1.1, Kv1.2, and Kv1.6 subunits) to exert its inhibitory effects in cortical interneurons. This, in turn, is expected to confer a variety of effects on passive and active electrical properties of the cell. We performed patch-clamp electrophysiology to examine the electrophysiological effects of ORs in cultured neocortical interneurons. We found that a range of features among the 54 membrane and action potential properties we analyzed were modulated by ORs, including action potential kinetics and frequency. The Kv1.1, Kv1.2, and Kv1.6 inhibitor -DTX reversed some effects on action potential frequency, but not effects on their kinetics. Therefore, ORs in neocortical interneurons influence -DTX-sensitive channels, as well as other channels, to modulate action potential kinetics and firing properties. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.19.390070v1?rss=1 Authors: Lemaire, T., Vicari, E., Neufeld, E., Kuster, N., Micera, S. Abstract: Low-Intensity Focused Ultrasound Stimulation (LIFUS) holds promise for the remote modulation of neuronal activity, but an incomplete mechanistic characterization hinders its clinical maturation. Here, we developed a computational framework to model intramembrane cavitation in multi-compartmental, morphologically-realistic neuronal representations, and used it to investigate ultrasound neuromodulation of peripheral nerves by spatially-varying pressure fields. Our findings show that LIFUS offers distinct parametric sub-spaces to selectively recruit myelinated or unmyelinated axons and modulate their spiking activity over physiologically relevant regimes and within safe exposure limits. This singular feature, explained by fiber-specific differences in membrane electromechanical coupling, consistently explains recent empirical findings and suggests that LIFUS can preferentially target nociceptive and sensory fibers to enable peripheral therapeutic applications not addressable by electric stimulation. These results open up new opportunities for the development of more selective and effective peripheral neuroprostheses. Our framework can be readily applied to other neural targets to establish application-specific LIFUS protocols. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.19.376202v1?rss=1 Authors: Maier, S. U., Grueschow, M. Abstract: Multiple theories have proposed that increasing central arousal through the brain's locus coeruleus - norepinephrine system may facilitate cognitive control and memory. However, for emotion research this hypothesis poses a puzzle, because conventionally, successful emotion regulation is associated with a decrease in arousal. Pupil diameter is a proxy to infer upon the central arousal state. We employed an emotion regulation paradigm with a combination of design features that allowed us to dissociate regulation- from stimulus-associated arousal in the pupil diameter time course of healthy adults. A pupil diameter increase during regulation predicted individual differences in emotion regulation success beyond task difficulty. Moreover, the extent of this individual arousal boost predicted performance in another self-control task, dietary health challenges. Participants who harnessed more regulation-associated arousal during emotion regulation were also more successful in choosing healthier foods. These results suggest that a common arousal-based facilitation mechanism may support an individual's self-control across domains. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.391623v1?rss=1 Authors: Gomez-Ramirez, J., Fernandez-Blazquez, M. A., Gonzalez-Rosa, J. Abstract: The goal of this work is to study how brain volume loss at old age is affected by factors such as age, APOE gene, sex, and school level. The study of brain volume loss at old age relative to young age requires at least in principle two MRI scans performed at both young and old age. There is, however, a way to address the problem by having only one MRI scan at old age. We compute the total brain loss of elderly subjects as the ratio between the estimated brain volume and the estimated total intracranial volume. Magnetic resonance imaging (MRI) scans of 890 healthy subjects aged 69 to 85 were assessed. The causal analysis of factors affecting brain atrophy was performed using Probabilistic Bayesian Modeling and the mathematics of Causal Inference. We find that healthy subjects get into their seventies with an average brain volume loss of 30% from their maximum brain volume at a young age. Both age and sex are causally related to brain atrophy, with women getting to elderly age with 1% larger brain volume relative to intracranial volume than men. How the brain ages and what are the reasons for sex differences in adult lifespan are causal questions that need to be addressed with causal inference and empirical data. The graphical causal modeling presented here can be instrumental in understanding a puzzling scientific inquiry -the biological age of the brain. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.391375v1?rss=1 Authors: Regev, M., Halpern, A. R., Owen, A. M., Patel, A. D., Zatorre, R. J. Abstract: Humans can internally represent auditory information without an external stimulus. When imagining music, how similar are unfolding neural representations to those during the original perceived experience? Participants memorized six one-minute-long musical pieces with high accuracy. Functional MRI data were collected during: 1) silent imagery of melodies to the beat of a visual metronome; 2) same but while tapping to the beat; and 3) passive listening. During imagery, inter-subject comparison showed that melody-specific temporal response patterns were reinstated in right associative auditory cortices. When tapping accompanied imagery, the melody-specific neural patterns were extended to associative cortices bilaterally. These results indicate that the specific contents of conscious experience are encoded similarly during imagery and perception in the dynamic activity of auditory cortices. Furthermore, rhythmic motion can enhance the reinstatement of neural patterns associated with the experience of complex sounds, in keeping with models of motor to sensory influences in auditory processing. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.18.387431v1?rss=1 Authors: Amalric, M., Cantlon, J. Abstract: A major goal of human neuroscience is to understand how the brain functions in the real world, and to measure neural processes under naturalistic conditions that are more ecologically valid than traditional laboratory tasks. A critical step toward this goal is understanding how neural activity during real world naturalistic tasks relates to neural activity in more traditional laboratory tasks. In the present study, we used intersubject correlations to locate reliable stimulus-driven neural processes among children and adults in naturalistic and laboratory versions of a mathematics task that shared the same content. We show that relative to a control condition with grammatical content, naturalistic and simplified mathematics tasks evoked overlapping activation within brain regions previously associated with math semantics. We further examined the temporal properties of children's neural responses during the naturalistic and laboratory tasks to determine whether temporal patterns of neural activity change over development, or dissociate based on semantic or task content. We introduce a rather novel measure, not yet used in fMRI studies of child learning: neural multiscale entropy. In addition to showing new evidence of naturalistic mathematics processing in the developing brain, we show that neural maturity and neural entropy are two independent but complementary markers of functional brain development. We discuss the implications of these results for the development of neural complexity in children. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.391391v1?rss=1 Authors: Kraus, F., Tune, S., Ruhe, A., Obleser, J., Woestmann, M. Abstract: Hearing loss is often asymmetric, such that hearing thresholds differ substantially between the two ears. The extreme case of such asymmetric hearing is single-sided deafness. A unilateral cochlear implant (CI) on the more severely impaired ear is an effective treatment to restore hearing. The neuro-cognitive cost of listening with a unilateral CI in multi-talker situations is at present unclear. Here, we simulated listening with a unilateral CI in young, normal-hearing listeners (N = 22) who were presented with 8-band noise-vocoded speech to one ear and intact speech to the other ear. Neural responses were recorded in the electroencephalogram (EEG) to obtain the spectro-temporal response function (sTRF) to speech. Listeners made more mistakes when answering questions about vocoded (versus intact) attended speech, indicating the behavioural cost of attending to spectrally degraded speech. At the neural level, we asked how unilateral acoustic degradation would impact the attention-induced amplification of tracking target versus distracting speech. Interestingly, unilateral degradation did not per se reduce the attention-induced amplification but instead delayed in time: Speech encoding accuracy, modelled on the basis of the sTRF, was significantly enhanced for attended versus ignored intact speech at earlier neural response latencies (

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.19.389023v1?rss=1 Authors: Preman, P., TCW, J., Calafate, S., Snellinx, A., Alfonso-Triguero, M., Corthout, N., Munck, S., Thal, D. R., Goate, A. M., De Strooper, B., Arranz, A. M. Abstract: Background: Increasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer's disease comes from molecular studies in rodent models. However, these models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression. Methods: To address these challenges, we established an approach to study human astroglia within the context of the mouse brain by transplanting human induced pluripotent stem cell (hiPSC)-derived glia progenitors into neonatal brains of immunodeficient mice. Results: Xenografted (hiPSC)-derived glia progenitors differentiate into astrocytes that integrate functionally within the mouse host brain and mature in a cell-autonomous way retaining human-specific morphologies, unique features and physiological properties. In Alzheimer's chimeric brains, transplanted hiPSC-derived astrocytes respond to the presence of amyloid plaques with various morphological changes that seem independent of the APOE allelic background. Conclusion: In sum, this chimeric model has great potential to analyze the role of patient-derived and genetically modified astroglia in Alzheimer's disease. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.392027v1?rss=1 Authors: Witchey, S., Caldwell, H. K. Abstract: Oxytocin (Oxt) signaling via its receptor, the Oxt receptor (Oxtr), is important to the onset of mammalian maternal care. Specifically, evidence suggests that Oxt signaling around the time of parturition underlies the critical shift in how pups are perceived, i.e. from aversive stimuli to rewarding stimuli. Previous work from our lab has found that both Oxtr knockout (-/-) mice and forebrain-specific Oxtr knockout (FB/FB) are more likely than controls to abandon their first litters. Based on these data, we hypothesized that this observed pup abandonment phenotype was due to a failure of the brain to switch to a more maternal state. In order to identify where in the brain Oxt signaling contributes to the onset of maternal care we performed three experiments. In Experiment 1, virgin Oxtr FB/FB females were assessed for genotypic differences in maternal behavior and c-Fos expression following maternal sensitization was quantified. In Experiment 2, c-Fos expression was quantified in Oxtr -/- and Oxtr FB/FB females following parturition. In Experiment 3, based on our findings from Experiment 2, the Oxtr in the nucleus accumbens shell (NAcc) was genetically deleted in female Oxtr floxed mice (Oxtr Flox/Flox) mice using a Cre recombinase expressing adeno-associated virus. In Experiment 1, sensitized virgin Oxtr FB/FB females had significantly lower retrieval latencies on the first day of testing and reduced c-Fos expression in the dorsal lateral septum compared to controls. In Experiment 2, increased c-Fos expression was observed in the NAcc shell of both Oxtr -/- and Oxtr FB/FB dams as compared to controls. In Experiment 3, virally mediated knockout of the Oxtr in the NAcc shell completely disrupted the onset of maternal care. Thus, by genetically deleting Oxtr expression in the NAcc the pup abandonment phenotype previously observed in Oxtr -/- mice and Oxtr FB/FB dams was recreated. Taken together, these data suggest that in post-parturient mice, Oxtr expression in the NAcc shell is critical to the onset of maternal behavior. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.391813v1?rss=1 Authors: Joos, B., Morris, C. E. Abstract: Skeletal muscle fibers (SMFs) and neurons are low and high duty-cycle excitable cells constituting exceptionally large and extraordinarily small fractions of vertebrate bodies. The immense ClC-1-based chloride-permeability (PCl) of SMFs has thwarted understanding of their Pump-Leak/Donnan (P-L/D) ion homeostasis. After formally defining P-L/D set-points and feedbacks, we therefore devise a simple yet demonstrably realistic model for SMFs. Hyper-stimulated, it approximates rodent fibers' ouabain-sensitive ATP-consumption. Size-matched neuron-model/SMF-model comparisons reveal steady-states occupying two ends of an energetics/resilience P-L/D continuum. Excitable neurons' costly vulnerable process is Pump-Leak dominated. Electrically-reluctant SMFs' robust low-cost process is Donnan dominated: collaboratively, Donnan effectors and [big PCl] stabilize Vrest, while SMFs' exquisitely small PNa minimizes ATP-consumption, thus maximizing resilience. "Classic" excitable cell homeostasis ([small PCl][big INaleak]), de rigueur for electrically-agile neurons, is untenable for vertebrates' (including humans') major tissue. Vertebrate bodies evolved thanks to syncytially-efficient SMFs using a Donnan dominated ([big PCl][small INaleak]) ion homeostatic strategy. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.19.390492v1?rss=1 Authors: Tang, R., Etzel, J. A., Kizhner, A., Braver, T. S. Abstract: The ability to flexibly adapt thoughts and actions in a goal-directed manner appears to rely on cognitive control mechanisms that are strongly impacted by individual differences. A powerful research strategy for investigating the nature of individual variation is to study monozygotic (identical) twins. Clear evidence of twin similarity effects have been observed in prior behavioral and neuroimaging studies, yet within the domain of cognitive control, the specificity and neural underpinnings of this similarity remains elusive. Here, we utilize a multi-task, within-subjects event-related neuroimaging design (with fMRI) to investigate twin effects through multivariate pattern similarity analyses. We focus on a set of fronto-parietal brain parcels exhibiting consistently increased activation associated with cognitive control demands across four task domains: selective attention, context processing, multi-tasking, and working memory. In these parcels, healthy young adult male and female monozygotic twin pairs had similar activation patterns, reliably in all tasks, a finding not observed in unrelated pairs. Twin activation pattern similarity effects were clearest under high control demands, were not present in a set of task-unrelated parcels, and were primarily observed during the within-trial timepoints in which the control demands peaked. Together, these results indicate that twin similarity in the neural representation of cognitive control may be domain-general but also functionally and temporally specific in relation to the level of control demand. The findings suggest a genetic and/or environmental basis for individual variation in cognitive control function, and highlight the potential of twin-based neuroimaging designs for exploring heritability questions within this domain. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.19.390336v1?rss=1 Authors: Jamieson, D., McLoughlin, L. T., Beaudequin, D. A., Shan, Z., Boyes, A., Schwenn, P., Lagopoulos, J., Hermens, D. F. Abstract: Background: Adolescence is an important period for developing ones sense of self. Social connectedness has been linked to a sense of self which in turn has links to resilience in mental disorders. Adolescence is also a period of increased risk of chronic sleep deprivation during a time of ongoing white matter (WM) maturation. The complex relationship between these variables and their relationship with the onset on mental disorders during adolescence remains largely unexplored. Methods: N = 64 participants aged 12 years (M = 12.6) completed the Pittsburgh Sleep Quality Index (PSQI), Social connectedness scale (SCS) and a diffusion weighted Magnetic Resonance Imaging (MRI) scan to investigate the relationship of these variables to predict psychological distress via the Kessler psychological distress scale (K10) in early adolescents. Multiple regression analysis was used with K10 entered as the dependent variable and SCS, PSQI, and values of white matter integrity as the predictor variables. Results: Results showed that while all four variables collectively accounted for a significant proportion of the variance in K10 (41.1%), SCS and PSQI were the only predictors that accounted for a significant proportion of variance uniquely. Conclusions: These findings suggest interventions aimed at increasing levels of social connectedness and sleep quality during adolescence may reduce psychological distress. Future longitudinal reporting of this combination of variables is suggested. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.19.390302v1?rss=1 Authors: Palidis, D. J., McGregor, H. R., Vo, A., MacDonald, P. A., Gribble, P. L. Abstract: Dopamine signaling is thought to mediate reward-based learning. We tested for a role of dopamine in motor adaptation by administering the dopamine precursor levodopa to healthy participants in two experiments involving reaching movements. Levodopa has been shown to impair reward-based learning in cognitive tasks. Thus, we hypothesized that levodopa would selectively impair aspects of motor adaptation that depend on reinforcement of rewarding actions. In the first experiment, participants performed two separate tasks in which adaptation was driven either by visual feedback of the hand position or binary reward feedback. We used EEG to measure event-related potentials evoked by task feedback. We hypothesized that levodopa would specifically diminish adaptation and the neural responses to feedback in the reward learning task. However, levodopa did not affect motor adaptation in either task nor did it diminish event-related potentials elicited by reward outcomes. In the second experiment, participants learned to compensate for mechanical force field perturbations applied to the hand during reaching. Previous exposure to a particular force field can result in savings during subsequent adaptation to the same force field and interference during adaptation to an opposite force field. We hypothesized that levodopa would diminish savings and anterograde interference, as previous work suggests that these phenomena result from a reinforcement learning process. However, we found no reliable effects of levodopa. These results suggest that reward-based motor adaptation, savings, and interference may not depend on the same dopaminergic mechanisms which have been shown to be disrupted by levodopa during various cognitive tasks. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.19.390393v1?rss=1 Authors: Ligneul, R., Mainen, Z., Ly, V., Cools, R. Abstract: Estimating environmental controllability enables agents to better predict upcoming events and decide when to engage controlled action selection. How does the human brain estimate environmental controllability? Trial-by-trial analysis of choices, decision times and neural activity in an explore-and-predict task demonstrate that humans solve this problem by comparing the predictions of an actor model with those of a reduced spectator model of their environment. Neural BOLD responses within striatal and medial prefrontal areas tracked the instantaneous difference in the prediction errors generated by these two statistical learning models. BOLD activity in the posterior cingulate, parietal and prefrontal cortices covaried with changes in estimated controllability. Exposure to inescapable stressors biased controllability estimates downward and increased reliance on the spectator model in an anxiety-dependent fashion. Taken together, these findings provide a mechanistic account of controllability estimation and its distortion in stress-related disorders. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.19.390427v1?rss=1 Authors: Cubillo, A., Hermes, H., Berger, E., Winkel, K., Schunk, D., Fehr, E., Hare, T. A. Abstract: The benefits and mechanistic effects of working memory training in children are the subject of much research and debate. The cumulative evidence indicates that training can alter brain structure and function in the short term and have lasting effects on behaviour. We show that five weeks of working memory training led to greater activity in prefrontal and striatal brain regions, better accuracy, and reduced intra-individual variability in response times. The reduction in intra-individual variability can be explained by changes to the evidence accumulation rates and thresholds in a sequential sampling decision model. Critically, intra-individual variability was more closely associated with academic skills and mental health 6-12 months after the end of training than task accuracy. These results indicate that intra-individual variability may be a useful way to quantify the immediate impact of cognitive training interventions and predict the future emergence of academic and socioemotional skills. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.391987v1?rss=1 Authors: Carullo, N. V. N., Revanna, J. S., Tuscher, J. J., Bauman, A. J., Day, J. J. Abstract: Site-specific genetic and epigenetic targeting of distinct cell populations is a central goal in molecular neuroscience and is crucial to understand the gene regulatory mechanisms that underlie complex phenotypes and behaviors. While recent technological advances have enabled unprecedented control over gene expression, many of these approaches are focused on selected model organisms and/or require labor-intensive customizations for different applications. The simplicity and modularity of CRISPR-based systems have transformed this aspect of genome editing, providing a variety of possible applications and targets. However, there are currently few available tools for cell-selective CRISPR regulation in neurons. Here, we optimized a CRISPR activation (CRISPRa) system for Cre recombinase-dependent, cell type-specific targeting. Unexpectedly, CRISPR systems based on a traditional double-floxed inverted open reading frame (DIO) strategy exhibited leaky target gene induction in the absence of Cre. Therefore, we developed an intron-containing Cre-dependent CRISPRa system (SVI-DIO-dCas9-VPR) that alleviated leaky gene induction and outperformed the traditional DIO system at endogenous genes in both HEK293T cells and rat primary neuron cultures. Using gene-specific CRISPR sgRNAs, we demonstrate that SVI-DIO-dCas9-VPR can activate highly inducible genes (GRM2 and Tent5b) as well as moderately inducible genes (Sstr2 and Gadd45b) in a Cre-specific manner. These results provide a robust framework for Cre-dependent CRISPR-dCas9 approaches across different model systems, and will enable cell-specific targeting when combined with common Cre driver lines or Cre delivery via viral vectors. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.391227v1?rss=1 Authors: Broderick, M. P., Lalor, E. C. Abstract: Prior knowledge facilitates perception and allows us to interpret our sensory environment. However, the neural mechanisms underlying this process remain unclear. Theories of predictive coding propose that feedback connections between cortical levels carry predictions about upcoming sensory events whereas feedforward connections carry the error between the prediction and the sensory input. Although predictive coding has gained much ground as a viable mechanism for perception, in the context spoken language comprehension it lacks empirical support using more naturalistic stimuli. In this study, we investigated theories of predictive coding using continuous, everyday speech. EEG recordings from human participants listening to an audiobook were analysed using a 2-stage regression framework. This tested the effect of top-down linguistic information, estimated using computational language models, on the bottom-up encoding of acoustic and phonetic speech features. Our results show enhanced encoding of both semantic predictions and surprising words, based on preceding context. This suggests that signals pertaining to prediction and error units can be observed in the same electrophysiological responses to natural speech. In addition, temporal analysis of these signals reveals support for theories of predictive coding that propose that perception is first biased towards what is expected followed by what is informative. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.391839v1?rss=1 Authors: Morris, C. E., Wheeler, J. J., Joos, B. Abstract: The inherited muscle-wasting disease, Duchenne muscular dystrophy (DMD), renders skeletal muscle fibers (SMFs) Na+-overloaded, ischemic, membrane-damaged, cation-leaky, depolarized, and prone to myogenic firing. DMD fibers nevertheless survive up to 3 decades before succumbing to Ca2+-necrosis. The Ca2+-necrosis is explicable, the longevity is not. Modeling here shows that SMFs' ion homeostasis strategy, a low-cost resilient Pump-Leak/Donnan feedback process we term "Donnan dominated", underpins that longevity. Together, SMFs' huge chloride-permeability and tiny sodium-permeability minimize excitability and pump costs, facilitating the outsized SMF pump-reserve that lets DMD fibers withstand deep ischemia and leaky channels. We illustrate how, as these impairments intensify, patients' chronic Na+-overload (now non-invasively evident via Na23-MRI) would change. In simulations, prolonged excitation ([->] physiological Na+-overloading) and/or intense ischemia ([->] too little Na+-pumping) and accumulated bleb-damage ([->] too much Na+-leaking) eventually trigger Ca2+-overloading conditions. Our analysis implies an urgent need to identify SMFs' pivotal small PNa, thereby opening new therapeutic remediation routes. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.19.390740v1?rss=1 Authors: Shiotani, K., Tanisumi, Y., Hirokawa, J., Sakurai, Y., Manabe, H. Abstract: Olfactory information directly reaches the amygdala through the olfactory cortex, without the involvement of thalamic areas, unlike other sensory systems. The anterior cortical amygdaloid nucleus (ACo) is one of the olfactory cortices that receives olfactory sensory input, and is part of the olfactory cortical amygdala, which relays olfactory information to the amygdala. To examine its electrophysiological features, we recorded individual ACo neurons during the odor-guided go/no-go task to obtain a water reward. Many ACo neurons exhibited odor-evoked go cue-preferred during the late phase of odor-sampling supporting the population dynamics that differentiate go/no-go responses before executing the odor-evoked behaviors. We observed two types of neurons with different anticipation signals: one neuron type exhibited gradual increases of activity toward reward delivery, while another type exhibited a phasic go cue-preferred activity during odor sampling as well as another phasic anticipatory activity for rewards. These results suggest that the ACo may be involved in reward-related behavioral learning by associating the olfactory information with reward anticipation. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.18.389197v1?rss=1 Authors: Zhang, W., Wu, S., Josic, K., Doiron, B. Abstract: A large part of the synaptic input received by cortical neurons comes from local cortico-cortical connectivity. Despite their abundance, the role of local recurrence in cortical function is unclear, and in simple coding schemes it is often the case that a circuit with no recurrent connections performs optimally. We consider a recurrent excitatory-inhibitory circuit model of a cortical hypercolumn which performs sampling-based Bayesian inference to infer latent hierarchical stimulus features. We show that local recurrent connections can store an internal model of the correlations between stimulus features that are present in the external world. When the resulting recurrent input is combined with feedforward input it produces a population code from which the posterior over the stimulus features can be linearly read out. Internal Poisson spiking variability provides the proper fluctuations for the population to sample stimulus features, yet the resultant population variability is aligned along the stimulus feature direction, producing what are termed differential correlations. Importantly, the amplitude of these internally generated differential correlations is determined by the associative prior in the model stored in the recurrent connections, thus providing experimentally testable predictions for how population connectivity and response variability are connected to the structure of latent external stimuli. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.19.390104v1?rss=1 Authors: Stankewitz, A., Keidel, L., Rehm, M., Irving, S., Kaczmarz, S., Preibisch, C., Witkovsky, V., Zimmer, C., Schulz, E., Toelle, T. R. Abstract: To assess the natural trajectory of brain activity over the migraine cycle, we assessed (1) the cerebral perfusion and (2) the hypothalamic connectivity during spontaneous headache attacks with follow-up recordings towards the next migraine attack. Using pseudo-continuous arterial spin labelling and resting-state functional magnetic resonance imaging, 12 migraine patients were examined in 82 sessions. We detected cyclic changes of brain perfusion in the limbic circuit (insula, hippocampus, and nucleus accumbens), with the highest perfusion during headache attacks. In addition, we found an increase of hypothalamic connectivity to the limbic system over the interictal interval, then collapsing during the headache. Our data provide strong evidence for the predominant role of the hypothalamus as a zeitgeber for generating migraine attacks. Our findings suggest that migraine attacks are the result of the hypothalamus losing control over the limbic system. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.19.390096v1?rss=1 Authors: Ioannucci, S., Borragan, G., Zenon, A. Abstract: Theories of mental fatigue disagree on whether performance decrement is caused by motivational or functional alterations. We tested the assumption that keeping neural networks active for an extensive period of time entrains consequences at the subjective, objective and neurophysiological level, the defining characteristics of fatigue, when confounds such as motivation, boredom and level of skill are controlled. We reveal that passive visual stimulation affects visual gamma activity and the performance of a subsequent task when carried out in the same portion of visual space. This outcome was influenced by the participants level of arousal, manipulated through variations in the difficulty of concurrent auditory tasks. Thus, repeated stimulation of neural networks leads to their altered functional performance and this mechanism seems to play a role in the development of mental fatigue. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.19.388231v1?rss=1 Authors: Goulding Mew, B., Custovic, D., Soreq, E., Lorenz, R., Violante, I. R., Sandrone, S., Hampshire, A. Abstract: Flexible behaviour requires cognitive-control mechanisms to efficiently resolve conflict between competing information and alternative actions. Whether a global neural resource mediates all forms of conflict or this is achieved within domain-specific systems remains debated. We use a novel fMRI paradigm to orthogonally manipulate rule, response and stimulus-based conflict within a full-factorial design. Whole-brain voxelwise analyses show that activation patterns associated with these conflict types are distinct but partially overlapping within Multiple Demand Cortex (MDC), the brain regions that are most commonly active during cognitive tasks. Region of interest analysis shows that most MDC sub-regions are activated for all conflict types, but to significantly varying levels. We propose that conflict resolution is an emergent property of distributed brain networks, the functional-anatomical components of which place on a continuous, not categorical, scale from domain-specialised to domain general. MDC brain regions place towards one end of that scale but display considerable functional heterogeneity. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.18.378265v1?rss=1 Authors: Meekings, S., Jasmin, K., Lima, C. F., Scott, S. K. Abstract: This study tested the idea that stuttering is caused by over-reliance on auditory feedback. The theory is motivated by the observation that many fluency-inducing situations, such as synchronised speech and masked speech, alter or obscure the talker's feedback. Typical speakers show 'speaking-induced suppression' of neural activation in superior temporal gyrus (STG) during self-produced vocalisation, compared to listening to recorded speech. If people who stutter over-attend to auditory feedback, they may lack this suppression response. In a 1.5T fMRI scanner, people who stutter spoke in synchrony with an experimenter, in synchrony with a recording, on their own, in noise, listened to the experimenter speaking and read silently. Behavioural testing outside the scanner demonstrated that synchronising with another talker resulted in a marked increase in fluency regardless of baseline stuttering severity. In the scanner, participants stuttered most when they spoke alone, and least when they synchronised with a live talker. There was no reduction in STG activity in the Speak Alone condition, when participants stuttered most. There was also strong activity in STG in response to the two synchronised speech conditions, when participants stuttered least, suggesting that either stuttering does not result from over-reliance on feedback, or that the STG activation seen here does not reflect speech feedback monitoring. We discuss this result with reference to neural responses seen in the typical population. Copy rights belong to original authors. Visit the link for more info