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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2016

Commentary: BRAIN NETWORKS. Correlated gene expression supports synchronous activity in brain networks. Science 348, 1241-4.

A recent report claims that functional brain networks defined with resting-state functional magnetic resonance imaging (fMRI) can be recapitulated with correlated gene expression (i.e. high within-network tissue-tissue \"strength fraction\", SF) (Richiardi et al., 2015). However, the authors do not adequately control for spatial proximity. We replicated their main analysis, performed a more effective adjustment for spatial proximity, and tested whether \"null networks\" (i.e. clusters with center coordinates randomly placed throughout cortex) also exhibit high SF. Removing proximal tissue-tissue correlations by Euclidean distance, as opposed to removing correlations within arbitrary tissue labels as in (Richiardi et al., 2015), reduces within-network SF to no greater than null. Moreover, randomly placed clusters also have significantly high SF, indicating that high within-network SF is entirely attributable to proximity and is unrelated to functional brain networks defined by resting-state fMRI. We discuss why additional validations in the original article are invalid and/or misleading and suggest future directions.

Neuroscience↗

bioRxiv2016

A transcallosal fiber network between left and right homotopic inferior frontal regions for supporting complex linguistic processing

Inferior frontal regions in the left and right hemisphere support different aspects of language processing. In the canonical model, left inferior frontal regions are mostly involved in processing based on phonological, syntactic and semantic features of language, whereas the right inferior frontal regions process paralinguistic aspects like affective prosody.\n\nUsing diffusion tensor imaging (DTI) based probabilistic fiber tracking in 20 healthy volunteers, we identify a callosal fiber system connecting left and right inferior frontal regions that are involved in linguistic processing of varying complexity. Anatomically, we show that the interhemispheric fibers are highly aligned and distributed along a rostral to caudal gradient in the body and genu of the corpus callosum to connect homotopic inferior frontal regions.\n\nIn light of converging data, taking previous DTI-based tracking studies and clinical case studies into account, our findings suggest that the right inferior frontal cortex not only processes paralinguistic aspects of language (such as affective prosody), as purported by the canonical model, but also supports the computation of linguistic aspects of varying complexity in the human brain. Our model may explain patterns of right hemispheric contribution to stroke recovery as well as disorders of prosodic processing. Beyond language-related brain function, we discuss how interspecies differences in interhemispheric connectivity and fiber density, including the system we described here, may also explain differences in transcallosal information transfer and cognitive abilities across different mammalian species.

Neuroscience↗

bioRxiv2016

Recovery of hand function after stroke: separable systems for finger strength and control

Loss of hand function after stroke is a major cause of long-term disability. Hand function can be partitioned into strength and independent control of fingers (individuation). Here we developed a novel paradigm, which independently quantifies these two aspects of hand function, to track hand recovery in 54 patients with hemiparesis over the first year after their stroke. Most recovery of both strength and individuation occurred in the first three months after stroke. Improvement in strength and individuation were tightly correlated up to a strength level of approximately 60% of the unaffected side. Beyond this threshold, further gains in strength were not accompanied by improvements in individuation. Any observed improvements in individuation beyond the 60% threshold were attributable instead to a second independent stable factor. Lesion analysis revealed that damage to the hand area in motor cortex and the corticospinal tract (CST) correlated more with individuation than with strength. CST involvement correlated with individuation even after factoring out the strength-individuation correlation. The most parsimonious explanation for these behavioral and lesion-based findings is that most strength recovery, along with some individuation, can be attributed to descending systems other than the CST, whereas further recovery of individuation is CST dependent.

Neuroscience↗

bioRxiv2016

A dual-strategy expression screen for candidate connectivity labels in the developing thalamus

The thalamus or \"inner chamber\" of the brain is divided into ~30 discrete nuclei, with highly specific patterns of afferent and efferent connectivity. To identify genes that may direct these patterns of connectivity, we used two strategies. First, we used a bioinformatics pipeline to survey the predicted proteomes of nematode, fruitfly, mouse and human for extracellular proteins containing any of a list of motifs found in known guidance or connectivity molecules. Second, we performed clustering analyses on the Allen Developing Mouse Brain Atlas data to identify genes encoding surface proteins expressed with temporal profiles similar to known guidance or connectivity molecules. In both cases, we then screened the resultant genes for selective expression patterns in the developing thalamus. These approaches identified 82 candidate connectivity labels in the developing thalamus. These molecules include many members of the Ephrin, Eph-receptor, cadherin, protocadherin, semaphorin, plexin, Odz/teneurin, Neto, cerebellin, calsyntenin and Netrin-G families, as well as diverse members of the immunoglobulin (Ig) and leucine-rich receptor (LRR) superfamilies, receptor tyrosine kinases and phosphatases, a variety of growth factors and receptors, and a large number of miscellaneous membrane-associated or secreted proteins not previously implicated in axonal guidance or neuronal connectivity. The diversity of their expression patterns indicates that thalamic nuclei are highly differentiated from each other, with each one displaying a unique repertoire of these molecules, consistent with a combinatorial logic to the specification of thalamic connectivity.

Neuroscience↗

bioRxiv2016

A Neural Locus for Perceptually-Relevant Saccadic Suppression in Visual-Motor Neurons of the Primate Superior Colliculus

Saccadic eye movements cause rapid retinal-image shifts that go perceptually unnoticed several times per second. The mechanisms for perceptual saccadic suppression have been controversial, in part due to sparse understanding of neural substrates. Here we uncovered an unexpectedly specific neural locus for saccadic suppression in the primate superior colliculus (SC). We first developed a sensitive behavioral measure of perceptual suppression in two male macaque monkeys (Macaca mulatta), demonstrating known selectivity to low spatial frequencies. We then investigated visual responses in either purely visual SC neurons or anatomically-deeper visual-motor neurons, which are also involved in saccade generation commands. Surprisingly, visual-motor neurons showed the strongest visual suppression, and the suppression was dependent on spatial frequency like in perception. Most importantly, visual-motor neuron suppression selectivity was highly predictive of behavioral suppression effects in each individual animal, with our recorded population explaining up to ~74% of behavioral variance even on completely different experimental sessions. In contrast, purely visual SC neurons only had mild and unselective suppression (only explaining up to ~48% of behavioral variance). These results run contrary to a hypothesized SC mechanism for saccadic suppression, in which a motor command in the visual-motor and motor neurons is relayed to the more superficial purely visual neurons to suppress them, and to then potentially be fed back to cortex. Instead, our results indicate that an extra-retinal modulatory signal mediating perceptual suppression is already established in visual-motor neurons.\n\nNew & NoteworthySaccades, which repeatedly re-align the line of sight, introduce spurious signals in retinal images that normally go unnoticed. In part, this happens because of peri-saccadic suppression of visual sensitivity. Here we discovered that a specific sub-type of superior colliculus (SC) neurons may play a critical role in saccadic suppression. Curiously, it is the neurons that help mediate the saccadic command itself that exhibit perceptually-relevant changes in visual sensitivity, not the previously hypothesized purely visual neurons.

Neuroscience↗

bioRxiv2016

Representations of Subjective Effort Cost

The perceived effort level of an action shapes everyday decisions. Despite the importance of these perceptions for decision-making, the behavioral and neural representations of the subjective cost of effort are not well understood. While a number of studies have implicated anterior cingulate cortex (ACC) in decisions about effort/reward trade-offs, none have experimentally isolated effort valuation from reward and choice difficulty, a function that is commonly ascribed to this region. We used functional magnetic resonance imaging (fMRI) to monitor brain activity while human participants engaged in uncertain choices for prospective physical effort. Our task was designed to examine effort-based decision making in the absence of reward and separated from choice difficulty - allowing us to investigate the brains role in effort valuation, independent of these other factors. Participants exhibited subjectivity in their decision-making, displaying increased sensitivity to changes in subjective effort as objective effort levels increased. Analysis of blood-oxygenation level dependent (BOLD) activity revealed that the ventromedial prefrontal cortex (vmPFC) encoded the subjective valuation of prospective effort and ACC encoded choice difficulty. These results provide insight into the processes responsible for decision-making regarding effort, dissociating the roles of vmPFC and ACC in prospective valuation of effort and choice difficulty.

Neuroscience↗

bioRxiv2016

A causal role of the right superior temporal sulcus in emotion recognition from biological motion

Understanding the emotions of others through nonverbal cues is critical for successful social interactions. The right posterior superior temporal sulcus (rpSTS) is one brain region thought to be key in the recognition of the mental states of others based on body language and facial expression. In the present study, we temporarily disrupted functional activity of the rpSTS by using continuous, theta-burst transcranial magnetic stimulation (cTBS) to test the hypothesis that the rpSTS plays a causal role in emotion recognition from body movements. Participants (N=23) received cTBS of the rpSTS, which was individually localized using fMRI, and a vertex control site. Before and after cTBS, we tested the ability of participants to identify emotions from point-light biological motion stimuli and a non-biological global motion identification task. Results revealed that the ability of participants to accurately identify emotional states from biological motion was reduced following cTBS stimulation to the rpSTS, but was unimpaired following vertex stimulation. Accuracy on the global motion tasks was unaffected by cTBS to either site. These results support the causal role of the rpSTS in decoding information about others emotional state from their body movements and gestures.

Neuroscience↗

bioRxiv2016

Alzheimer’s disease pathogenesis is dependent on neuronal receptor PTPσ

Due to limited understanding of disease mechanisms and the lack of molecular targets, translational research for Alzheimer disease has not been fruitful hitherto. Here we report findings that indicate neuronal receptor phosphatase PTP{sigma} as a potential therapeutic target for this dementia. In two TgAPP mouse models, a spectrum of Alzheimer-related pathologies, including aged-induced progression of {beta}-amyloidosis, Tau aggregation, neuroinflammation, synaptic loss, as well as behavioral deficits, all show unambiguous dependency on PTP{sigma}. APP amyloidogenic metabolites diminish upon PTP{sigma} genetic depletion or pharmacological inhibition. Binding to APP in the brain, PTP{sigma} regulates APP proteolytic metabolism via its phosphatase activity, likely through downstream signaling that modulates APP membrane localization and affinity to the {beta}-secretase, in a specific manner that does not broadly affect {beta}- and {gamma}-secretase processing of other major substrates. Together, these findings unveil a gatekeeping role of PTP{sigma} upstream in Alzheimer-like pathogenic pathway.

Neuroscience↗

bioRxiv2016

Temporal and spatial localization of prediction-error signals in the visual brain

It has been suggested that the brain pre-empts changes in the visual environment through generating predictions, although real-time eletrophysiological evidence of prediction violations remains elusive. In a series of experiments we showed participants sequences of images that followed a predictable implied sequence or whose final image violated the implied sequence. Through careful design we were able to use the same final image transitions across predictable and unpredictable conditions, ensuring that any differences in neural responses were due only to preceding context and not to the images themselves. EEG and MEG recordings showed that early/mid-latency visual evoked potentials were robustly modulated by images that violated the implied sequence across a range of types of image change (expression deformations, rigid-rotations and visual field location). This modulation occurred irrespective of stimulus object category. Although the stimuli were static images, MEG source reconstruction of the early latency signal (N/M170) localised expectancy violation signals to brain areas associated with motion perception. Our findings suggest that the N/M170 can index mismatches between predicted and actual visual inputs in a system that predicts trajectories based on ongoing context. This has important implications for understanding the N/M170 and investigating how the brain represents context to generate perceptual predictions.

Neuroscience↗

bioRxiv2016

Long-range suppressive influences from the visual surround can be explained by anatomically plausible recruitment of local competition in a model of columnar cortex

Although neurons in columns of visual cortex of adult carnivores and primates share similar orientation tuning preferences, responses of nearby neurons are surprisingly sparse and temporally uncorrelated, especially in response to complex visual scenes. The mechanisms underlying this counter-intuitive combination of response properties are still unknown. Here we present a computational model of columnar visual cortex which explains experimentally observed integration of complex features across the visual field, and which is consistent with anatomical and physiological profiles of cortical excitation and inhibition. In this model, sparse local excitatory connections within columns, coupled with strong unspecific local inhibition and functionally-specific long-range excitatory connections across columns, give rise to competitive dynamics that reproduce experimental observations. Our results explain surround modulation of responses to simple and complex visual stimuli, including reduced correlation of nearby excitatory neurons, increased excitatory response selectivity, increased inhibitory selectivity, and complex orientation-tuning of surround modulation.

neuroscience↗

bioRxiv2016

Connecting myelin-related and synaptic dysfunction in schizophrenia with SNP-rich gene expression hubs

The recent availability of several genome-wide data sets such as genome-wide mapping of SNP-rich regions and differentially methylated genes in schizophrenic individuals and gene expression data in all brain compartments across the span of human life prompted us to integrate these datasets to gain a better insight into the underlying gene networks driving this enigmatic disease.\n\nWe summed up the differentially methylated \"expression neighbors\" (i.e. genes with positively or negatively correlating expression values) of genes that fall into one of 108 distinct schizophrenia-associated genetic loci with high number of SNPs in schizophrenic patients derived from a large cohort of pooled sequencing experiments. Surprisingly, the number of expression neighbors (with a Pearson correlation of R>=0.8 or R<=-0.7) of the genes falling into the 108 genomic regions were about 35 times higher for the positively correlating genes and 32 times higher for the negatively correlating ones than for the rest of the ~16000 genes outside these loci. While the genes in the 108 loci have relatively little known impact in schizophrenia, using this approach we identified many more known schizophrenia-related important genes with a high degree of connectedness to other genes and high scores of differentially methylated probes for their expression neighbors (such as MBP, MOBP, GRIA1, COMT, SYNGR1, MAP2 and DGCR6), validating our approach.\n\nThe analysis revealed that the most positively correlating as well as the most negatively correlating genes affect synapse-related genes the most, offering an explanation and a unified view into the root cause of schizophrenia.

Neuroscience↗

bioRxiv2016

Multiplexed computations in retinal ganglion cells of a single type

In the early visual system, cells of the same type perform the same computation in dierent places of the visual field. How these cells code together a complex visual scene is unclear. A common assumption is that cells of the same type will extract a single stimulus feature to form a feature map, but this has rarely been observed directly. Using large-scale recordings in the rat retina, we show that a homogeneous population of fast OFF ganglion cells simultaneously encodes two radically different features of a visual scene. Cells close to a moving object code linearly for its position, while distant cells remain largely invariant to the objects position and, instead, respond non-linearly to changes in the objects speed. Cells switch between these two computations depending on the stimulus. We developed a quantitative model that accounts for this effect and identified a likely disinhibitory circuit that mediates it. Ganglion cells of a single type thus do not code for one, but two features simultaneously. This richer, flexible neural map might also be present in other sensory systems.

Neuroscience↗

bioRxiv2016

AN OSCILLATORY NETWORK MODEL OF HEAD DIRECTION, SPATIALLY PERIODIC CELLS AND PLACE CELLS USING LOCOMOTOR INPUTS

We propose a computational modeling approach that explains the formation of a range of spatial cells like head direction cells, grid cells, border cells and place cells which are believed to play a pivotal role in the spatial navigation of an animal. Most existing models insert special symmetry conditions in the models in order to obtain such symmetries in the outcome; our models do not require such symmetry assumptions. Our modeling approach is embodied in two models: a simple one (Model #1) and a more detailed version (Model #2). In Model #1, velocity input is presented to a layer of Head Direction cells, with no special topology requirements, the outputs of which are presented to a layer of Path Integration neurons. A variety of spatially periodic responses resembling grid cells, are obtained using the Principal Components of Path Integration layer. In Model #2, the input consists of the locomotor rhythms from the four legs of a virtual animal. These rhythms are integrated into the phases of a layer of oscillatory neurons, whose outputs drive a layer of Head Direction cells. The Head Direction cells in turn drive a layer of Path Integration neurons, which in turn project to two successive layers of Lateral Anti Hebbian Networks (LAHN). Cells in the first LAHN resemble grid cells (with both hexagonal and square gridness), and border cells. Cells in the second LAHN exhibit place cell behaviour and a new cell type known as corner cell. Both grid cells and place cells exhibit phase precession in 1D and 2D spaces. The models outline the neural hierarchy necessary to obtain the complete range of spatial cell responses found in the hippocampal system.

Neuroscience↗

bioRxiv2016

Association of polygenic risk for major psychiatric illness with subcortical volumes and white matter integrity in UK Biobank

Major depressive disorder (MDD), schizophrenia (SCZ) and bipolar disorder (BP) are common, disabling and heritable psychiatric diseases with a complex overlapping polygenic architecture. Individuals with these disorders, as well as their unaffected relatives, show widespread structural differences in corticostriatal and limbic networks. Structural variation in many of these brain regions is also heritable and polygenic but whether their genetic architecture overlaps with major psychiatric disorders is unknown. We sought to address this issue by examining the impact of polygenic risk of MDD, SCZ, and BP on subcortical brain volumes and white matter (WM) microstructure in a large single sample of neuroimaging data; the UK Biobank Imaging study. The first release of UK Biobank imaging data compromised participants with overlapping genetic data and subcortical volumes (N = 978) and WM measures (N = 816). Our, findings however, indicated no statistically significant associations between either subcortical volumes or WM microstructure, and polygenic risk for MDD, SCZ or BP. In the current study, we found little or no evidence for genetic overlap between major psychiatric disorders and structural brain measures. These findings suggest that subcortical brain volumes and WM microstructure may not be closely linked to the genetic mechanisms of major psychiatric disorders.

Neuroscience↗

bioRxiv2016

Recall without Hippocampal Engagement

The hippocampus is considered pivotal to recall, allowing retrieval of information not available in the immediate environment. In contrast, neocortex is thought to signal familiarity, and to contribute to recall only when called upon by the hippocampus. However, this view is not compatible with representational accounts of memory, which reject the mapping of cognitive processes onto brain regions. According to representational accounts, the hippocampus is not engaged by recall per se, rather it is engaged whenever hippocampal representations are required. To test whether hippocampus is engaged by recall when hippocampal representations are not required, we used functional imaging and a non-associative recall task, with images (objects, scenes) studied in isolation, and image-patches used as cues. As predicted by a representational account, hippocampal activation increased during recall of scenes - which are known to be processed by hippocampus - but not during recall of objects. Object recall instead engaged neocortical regions known to be involved in object-processing. Further supporting the representational account, effective connectivity analyses revealed that recall was associated with increased information flow out of lateral occipital cortex (object recall) and parahippocampal cortex (scene recall), suggesting that recall-related activation spread from neocortex to hippocampus, not the reverse.

Neuroscience↗

bioRxiv2016

A shared representation of order between encoding and recognition in visual short-term memory

Most complex tasks require people to bind individual stimuli into a sequence in short term memory (STM). For this purpose information about the order of the individual stimuli in the sequence needs to be in active and accessible form in STM over a period of few seconds. Here we investigated how the temporal order information is shared between the presentation and response phases of an STM task. We trained a classification algorithm on the fMRI activity patterns from the presentation phase of the STM task to predict the order of the items during the subsequent recognition phase. While voxels in a number of brain regions represented positional information during either presentation and recognition phases, only voxels in the lateral prefrontal cortex (PFC) and the anterior temporal lobe (ATL) represented position consistently across task phases. A shared positional code in the ATL might reflect verbal recoding of visual sequences to facilitate the maintenance of order information over several seconds.

Neuroscience↗

bioRxiv2016

Genetic,transcriptome, proteomic and epidemiological evidence for blood brain barrier disruption and polymicrobial brain invasion as determinant factors in Alzheimers disease.

Multiple pathogens have been detected in Alzheimers disease (AD) brains. A bioinformatics approach was used to assess relationships between pathogens and AD genes (GWAS), the AD hippocampal transcriptome and plaque or tangle proteins. Host/pathogen interactomes (C.albicans, C.Neoformans, Bornavirus, B.Burgdorferri, cytomegalovirus, Ebola virus, HSV-1, HERV-W, HIV-1, Epstein-Barr, hepatitis C, influenza, C.Pneumoniae, P.Gingivalis, H.Pylori, T.Gondii, T.Cruzi) significantly overlap with misregulated AD hippocampal genes, with plaque and tangle proteins and, except Bornavirus, Ebola and HERV-W, with AD genes. Upregulated AD hippocampal genes match those upregulated by multiple bacteria, viruses, fungi or protozoa in immunocompetent blood cells. AD genes are enriched in bone marrow and immune locations and in GWAS datasets reflecting pathogen diversity, suggesting selection for pathogen resistance. The age of AD patients implies resistance to infections afflicting the younger. APOE4 protects against malaria and hepatitis C, and immune/inflammatory gain of function applies to APOE4, CR1, TREM2 and presenilin variants. 30/78 AD genes are expressed in the blood brain barrier (BBB), which is disrupted by AD risk factors (ageing, alcohol, aluminium, concussion, cerebral hypoperfusion, diabetes, homocysteine, hypercholesterolaemia, hypertension, obesity, pesticides, pollution, physical inactivity, sleep disruption and smoking). The BBB and AD benefit from statins, NSAIDs, oestrogen, melatonin and the Mediterranean diet. Polymicrobial involvement is supported by the upregulation of pathogen sensors/defenders (bacterial, fungal, viral) in the AD brain, blood or CSF. Cerebral pathogen invasion permitted by BBB inadequacy, activating a hyper-efficient immune/inflammatory system, betaamyloid and other antimicrobial defence may be responsible for AD which may respond to antibiotic, antifungal or antiviral therapy.

Neuroscience↗

bioRxiv2016

Human anterolateral entorhinal cortex volumes are associated with preclinical cognitive decline

We investigated whether older adults without subjective memory complaints, but who present with cognitive decline in the laboratory, demonstrate atrophy in medial temporal lobe (MTL) subregions associated with Alzheimer's disease. Forty community-dwelling older adults were categorized based on Montreal Cognitive Assessment (MoCA) performance. Total grey/white matter, cerebrospinal fluid, and white matter hyperintensity load were quantified from whole-brain T1-weighted and FLAIR magnetic resonance imaging scans, while hippocampal subfields and MTL cortical subregion volumes (CA1, dentate gyrus/CA2/3, subiculum, anterolateral and posteromedial entorhinal, perirhinal, and parahippocampal cortices) were quantified using high-resolution T2-weighted scans. Cognitive status was evaluated using standard neuropsychological assessments. No significant differences were found in the whole-brain measures. However, MTL volumetry revealed that anterolateral entorhinal cortex (alERC) volume -- the same region in which Alzheimer's pathology originates -- was strongly associated with MoCA performance. This is the first study to demonstrate that alERC volume is related to cognitive decline in preclinical, community-dwelling older adults.

Neuroscience↗