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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.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

The hemodynamic signal as a first-order low-pass temporal filter: Evidence and implications for neuroimaging studies

Neuronal activation triggers blood flow and hemoglobin deoxygenation. These hemodynamic signals can be recorded through magnetic resonance or optical imaging, and allows inferring neural activity in response to stimuli. These techniques are widely used to uncover functional brain architectures. However, their accuracy suffers from distortions inherent to hemodynamic responses and noise. The analysis of these signals currently relies on models of impulse hemodynamic responses to brief stimuli. Here, in order to infer precise functional architectures, we focused on integrated signals associated to the dynamical response of functional maps. To this end, we recorded orientation and direction maps in cat primary visual cortex and confronted two protocols: the conventional episodic stimulation technique and a continuous, periodic stimulation paradigm. Conventional methods show that the dynamics of activation and deactivation of the functional maps follows a linear first-order differential equation representing a low-pass filter. Comparison with the periodic stimulation methods confirmed this observation: the phase shifts and magnitude attenuations extracted at various frequencies were consistent with a low-pass filter with a 5 s time constant. This dynamics open new avenues in the analysis of neuroimaging data that differs from common methods based on the hemodynamic response function. In particular, we demonstrate that inverting this first-order low-pass filter minimized the distortions of the signal and enabled a much faster and accurate reconstruction of functional maps.

Neuroscience↗

bioRxiv2016

An odor delivery system for arbitrary time-varying patterns of odors, mixtures and concentrations

Odor stimuli in the natural environment are intermittent and the concentration of any given odor fluctuates rapidly over time. Further, even in the simplest scenario, the olfactory sensors receive uncorrelated, intermittent inputs in the form of odor plumes arising from several odor sources in the local environment. However, typically used odor stimuli under laboratory settings are restricted to long-duration (~seconds), single pulse of one odor at a time that are rarely encountered in nature. This inadequate choice of odor stimuli is due to the dearth of affordable odor delivery systems that can generate plume-like, naturalistic stimuli with high reproducibility such as to allow for repeat measurements under laboratory conditions. We thus developed an odor delivery system that generates arbitrary time-varying patterns of individual odors and ternary mixtures at time scales of ~20 Hz. Here, we provide a detailed description of the construction and output characterization of our odor delivery system.

Neuroscience↗

bioRxiv2016

Developmental dysfunction of VIP interneurons impairs cortical circuits

Current evidence suggests that dysregulation of GABAergic interneurons contributes to neural and behavioral deficits in several neurodevelopmental disorders, including schizophrenia. However, there are multiple populations of interneurons and their respective roles in psychiatric disease remain poorly explored. Neuregulin 1 (NRG1) and its interneuron-specific tyrosine kinase receptor ERBB4 are risk genes for schizophrenia, and the Nrg1/ErbB4 pathway is important for normal cortical development. Using a conditional ErbB4 deletion model, we directly tested the role of vasoactive intestinal peptide (VIP)-expressing interneurons in schizophrenia-related deficits in vivo. ErbB4 removal from VIP interneurons during development leads to changes in their activity, along with severe dysregulation of the temporal organization and state-dependence of cortical activity. As a result of these neural circuit alterations, animals in which VIP interneurons lack ErbB4 exhibit behavioral abnormalities, reduced cortical responses to sensory stimuli, and impaired sensory learning. Our data support a key role for VIP interneurons in normal cortical circuit development and suggest that their disruption contributes to pathophysiology in the ErbB4 model of schizophrenia. These findings provide a new perspective on the role of GABAergic interneuron diversity in the disruption of cortical function in complex psychiatric diseases.

Neuroscience↗

bioRxiv2016

Can we test the influence of prosociality on high frequency heart rate variability? A double-blind sham-controlled approach.

The polyvagal theory (Porges, 2007) proposes that physiological flexibility dependent on heart- brain interactions is associated with prosociality. So far, whether prosociality has a causal effect on physiological flexibility is unknown. Previous studies present mitigated results on this matter. In a randomized double-blind protocol, we used a generation of social closeness procedure against a standardized control condition in order to manipulate social affiliation as a prosocial interaction factor. High frequency heart rate variability (HF-HRV, indexing physiological flexibility), electromyographical activity of the corrugator supercilii (sensitive to the valence of the interaction) and self-reported measure of social closeness were monitored before, during, and after experimental manipulation. Cooperation was measured after the experimental manipulation as an index of behavioral prosociality. Data reveal no evidence toward and effect of the experimental manipulation on these measures. We discuss methodological aspects related to the experimental constraints observed in social psychophysiology. Implications for the experimental test of the polyvagal theory are approached within alternative theoretical frameworks.

Neuroscience↗

bioRxiv2016

Theta Oscillations in the Human Medial Temporal Lobe during Real World Ambulatory Movement

Theta oscillations play a critical role in learning and memory by coordinating the spiking activity of neuronal ensembles via mechanisms such as spike timing dependent plasticity1-7. This rhythm is present in rodents where it is continuously evident during movement at frequencies within 6-12Hz8,9. In humans, however, the presence of continuous theta rhythm has been elusive; indeed, a functionally similar theta is thought to occur at lower frequency ranges (3-7Hz) and in shorter bouts10-12. This lower frequency theta rhythm is observed during a variety of behaviors, including virtual navigation, but has never been tested during real world ambulatory movement. Here we examined the oscillatory properties of theta within the human medial temporal lobe (MTL) in freely moving human subjects chronically implanted with the clinical NeuroPace RNS(R) responsive neurostimulator device, capable of wireless recordings of continuous intracranial deep brain electroencephalographic (iEEG) activity. MTL iEEG recordings, together with sub-millimeter position tracking, revealed the presence of high frequency theta oscillations (6-12Hz) during ambulation. The prevalence of these oscillations was increased during fast movement compared to slow movement. These theta bouts, although occurring more frequently, were not significantly different in durations during fast versus slow movements. In a rare opportunity to study one subject with congenital blindness, we found that both the prevalence and duration of theta bouts were much greater than those in sighted subjects. Our results suggest that higher frequency theta indeed exists in humans during movement providing critical support for conserved neurobiological mechanisms for spatial navigation. The precise link between this pattern and its behavioral correlates will be an exciting area for future studies given this novel methodology for simultaneous motion capture and long term chronic recordings from deep brain targets during ambulatory human behavior.

Neuroscience↗

bioRxiv2016

A Rapid Subcortical Amygdala Route for Faces Irrespective of Spatial Frequency and Emotion

There is significant controversy over the anatomical existence and potential function of a direct subcortical visual pathway to the amygdala. It is thought that this pathway rapidly transmits low spatial frequency information to the amygdala independently of the cortex and yet this function has never been causally determined. In this study, neural activity was measured using magnetoencephalography (MEG) while participants discriminated the gender of neutral and fearful faces filtered for low or high spatial frequencies. Dynamic causal modelling (DCM) revealed that the most likely underlying neural network consisted of a subcortical pulvino-amygdala connection that was not modulated by spatial frequency or emotion and a cortico-amygdala connection that conveyed predominantly high spatial frequencies. Crucially, data-driven neural simulations demonstrated a clear temporal advantage of the subcortical route (70ms) over the cortical route (155ms) in influencing amygdala activity. Thus, our findings support the existence of a rapid functional subcortical pathway that is unselective of the spatial frequency or emotional content of faces.

Neuroscience↗

bioRxiv2016

A forward model at Purkinje cell synapses facilitates cerebellar anticipatory motor control

How does our motor system solve the problem of anticipatory control in spite of a wide spectrum of response dynamics from different musculo-skeletal systems, transport delays as well as response latencies throughout the central nervous system? To a great extent, our highly-skilled motor responses are a result of a reactive feedback system, originating in the brain-stem and spinal cord, combined with a feed-forward anticipatory system, that is adaptively fine-tuned by sensory experience and originates in the cerebellum. Based on that interaction we design the counterfactual predictive control (CFPC) architecture, an anticipatory adaptive motor control scheme, in which a feed-forward module, based on the cerebellum, steers an error feedback controller with counterfactual error signals. Those are signals that trigger reactions as actual errors would, but that do not code for any current of forthcoming errors. In order to determine the optimal learning strategy, we derive a novel learning rule for the feed-forward module that involves an eligibility trace and operates at the synaptic level. In particular, our eligibility trace provides a mechanism beyond co-incidence detection in that it convolves a history of prior synaptic inputs with error signals. In the context of cerebellar physiology, this solution implies that Purkinje cell synapses should generate eligibility traces using a forward model of the system being controlled. From an engineering perspective, CFPC provides a general-purpose anticipatory control architecture equipped with a learning rule that exploits the full dynamics of the closed-loop system.

Neuroscience↗

bioRxiv2017

Activation of the hypothalamic feeding centre upon visual prey detection

The visual system plays a major role in food/prey recognition in diurnal animals, and food intake is regulated by the hypothalamus. However, whether and how visual information about prey is conveyed to the hypothalamic feeding centre is largely unknown. Here we perform real-time imaging of neuronal activity in freely behaving or constrained zebrafish larvae and demonstrate that prey or prey-like visual stimuli activate the hypothalamic feeding centre. Furthermore, we identify prey detector neurons in the pretectal area that project to the hypothalamic feeding centre. Ablation of the pretectum completely abolishes prey capture behaviour and neurotoxin expression in the hypothalamic area also reduces feeding. Taken together, these results suggest that the pretecto-hypothalamic pathway plays a crucial role in conveying visual information to the feeding centre. Thus, this pathway possibly converts visual food detection into feeding motivation in zebrafish.

neuroscience↗

bioRxiv2016

A Saposin deficiency model in Drosophila: lysosomal storage, progressive neurodegeneration, sensory physiological decline and defective calcium homeostasis

Saposin deficiency is a childhood neurodegenerative lysosomal storage disorder (LSD) that can cause premature death within three months of life. Saposins are activator proteins that promote the function of lysosomal hydrolases in the degradation of sphingolipids. There are four saposin proteins in humans, which are encoded by the prosaposin gene. Mutations causing an absence of individual saposins or the whole prosaposin gene lead to distinct LSDs due to the storage of different classes of sphingolipids. The pathological events leading to neuronal dysfunction induced by lysosomal storage of sphingolipids are as yet poorly defined. We have generated and characterised a Drosophila model of saposin deficiency that shows striking similarities to the human diseases. Drosophila saposin-related (dSap-r) mutants show a reduced longevity, progressive neurodegeneration, lysosomal storage, dramatic swelling of neuronal soma, perturbations in sphingolipid catabolism, and sensory physiological deterioration. We have also revealed a genetic interaction with a calcium exchanger (CalX), suggesting that calcium homeostasis may be altered in saposin deficiency. Together these findings support the use of dSap-r mutants in advancing our understanding of the cellular pathology implicated in saposin deficiency and related LSDs.

Neuroscience↗

bioRxiv2016

Targeted electrical stimulation of active brain sources using reciprocity

To demonstrate causal relationships between brain and behavior, investigators would like to guide brain stimulation using measurements of neural activity. Particularly promising in this context are electroen-cephalography (EEG) and transcranial electrical stimulation (TES), as they are linked by a reciprocity principle which, despite being known for decades, has not led to a formalism for relating EEG recordings to optimal stimulation parameters. Here we derive a closed-form expression for the TES configuration that optimally stimulates (i.e., targets) the sources of recorded EEG, without making assumptions about source location or distribution. We also derive a duality between TES targeting and EEG source localization, and demonstrate that in cases where source localization fails, so does the proposed targeting. Numerical simulations with realistic head models confirm these theoretical predictions and quantify the achieved stimulation in terms of focality and intensity. We show that constraining the stimulation currents automatically selects optimal montages that involve only a few (4-7) electrodes, with only incremental loss in performance. The proposed technique allows brain scientists and clinicians to rationally target the sources of observed EEG and thus overcomes a major obstacle to the realization of individualized or closed-loop brain stimulation.

Neuroscience↗

bioRxiv2016

Combining Multiscale Diffusion Kernels for Learning the Structural and Functional Brain Connectivity

The activation of the brain at rest is thought to be at the core of cognitive functions. There have been many attempts at characterizing the functional connectivity at rest from the structure. Recent attempts with diffusion kernel models point to the possibility of a single diffusion kernel that can give a good estimate of the functional connectivity. But our empirical investigations revealed that the hypothesis of a single scale best-fitting kernel across subjects is not tenable. Further, our experiments demonstrate that structure-function relationship across subjects seems to obey a multi-scale diffusion phenomenon. Based on this insight, we propose a multiple diffusion kernel model (MKL) along with a learning framework for estimating the optimal model parameters. We tested our hypothesis on 124 subjects data from publicly available NKI_Rockland database. The results establish the viability of the proposed model and also demonstrate several promising features as compared to the single kernel approach. One of the key strengths of the proposed approach is that it does not require hand-tuning of model parameters but actually learns them as part of the optimization process. The learned parameters may be suitable candidates for future investigation of their role in distinguishing health and disease.

Neuroscience↗

bioRxiv2016

Oligodendrocytes in the mouse optic nerve originate in the preoptic area

The present study aims to examine the origin of oligodendrocyte progenitor cells (OPCs) in the mouse optic nerve (ON) by labeling OPCs in the fetal forebrain. The labeling of OPCs in the ON was performed by injection of a retrovirus vector carrying the lacZ gene into the lateral ventricle, or by inducible Cre/loxP of Olig2-positive cells. The retrovirus labeling revealed that ventricular zone-derived cells of the fetal forebrain relocated to the ON and differentiated into oligodendrocytes. In addition, lineage tracing of Olig2-positive cells and whole mount staining of PDGFR-positive cells demonstrated that OPCs appeared by E12.5 in the preoptic area, and spread caudally to enter the ON. Our results also suggest that OPCs generated during the early stage are depleted from the ON after maturation.

Neuroscience↗

bioRxiv2016

Brain activity and connectivity attributable to nociceptive signal block

Converging lines of evidence indicate that the pain experience emerges from distributed cortical nodes that share nociceptive information. While the theory of a single pain center is still not falsifiable by current neuroimaging technology, the validation of distinct brain mechanisms for acute pain and its relief is ongoing and strongly dependent on the employed experimental design. In the current study including a total of 28 subjects, a recently presented, innovative experimental approach was adopted that is able to clearly differentiate painful from non-pain perceptions without changing stimulus strength and while recording brain activity using functional magnetic resonance imaging (fMRI). Namely, we applied a repetitive and purely nociceptive stimulus to the tooth pulp with subsequent suppression of the nociceptive barrage via a regional nerve block. The study aims were 1) to replicate previous findings of acute pain demonstrating a fundamental role of the operculo-insular region and 2) to explore its functional connectivity during pain and subsequent relief. The brain activity reduction in the posterior insula (pINS) due to pain extinction was confirmed. In addition, the posterior S2 region (OP1) showed a similar activity pattern, thus confirming the relevance of the operculo-insular cortex in acute pain processing. Furthermore, the functional connectivity analysis yielded an enhanced positive coupling of the pINS with the cerebellar culmen during pain relief, whereas the OP1 demonstrated a positive coupling with the posterior midcingulate cortex during pain. The current results support the conceptual synthesis of localized specialization of pain processing with interactions across distributed neural targets.

Neuroscience↗

bioRxiv2016

Encoding of locomotion kinematics in the mouse cerebellum

The cerebellum has a well-established role in locomotion control, but how the cerebellar network regulates locomotion behaviour is still not well understood. We therefore characterized the activity of cerebellar neurons in awake mice engaged in a locomotion task, using high-density silicon electrode arrays. We characterized the activity of over 300 neurons in response to locomotion, finding tuning to speed of locomotion, turning, and phase of the step cycle. We found that the cerebellar neurons we recorded mainly encoded information about future locomotor activity. We were able to decode the speed of locomotion with a simple linear algorithm, needing relatively few well-chosen cells to provide an accurate estimate of locomotion speed. Our observation that cerebellar neuronal activity predicts locomotion in the near future, and encodes the required kinematic variables, points to this activity underlying the efference copy signal for vertebrate locomotion.

Neuroscience↗

bioRxiv2016

The Healthy Brain Network Serial Scanning Initiative: A resource for evaluating inter-individual differences and their reliabilities across scan conditions and sessions.

BackgroundAlthough typically measured during the resting state, a growing literature is illustrating the ability to map intrinsic connectivity in task and naturalistic viewing fMRI paradigms. These paradigms are drawing excitement due to their greater tolerability in clinical and developing populations and because they enable a wider range of analyses (e.g. inter-subject correlations). To be clinically useful, the test-retest reliability of connectivity measured during these paradigms needs to be established. This resource provides data for evaluating testretest reliability for full-brain connectivity patterns detected during each of four scan conditions that differ with respect to level of engagement (rest, abstract animations, movie clips, flanker task). Data is provided for thirteen participants, each scanned in twelve sessions with 10 minutes for each scan of the four conditions. Diffusion kurtosis imaging data was also obtained at each session.\n\nFindingsTechnical validation and demonstrative reliability analyses found that variation in intrinsic functional connectivity across sessions was greater than that attributable to scan condition. Between-condition reliability was generally high, particularly for the frontoparietal and default networks. Between-session reliabilities obtained separately for the different scan conditions were comparable, though notably lower than between-condition reliabilities.\n\nConclusionsThe described resource provides a test-bed for quantifying the reliability of connectivity indices across conditions and time. The resource can be used to compare and optimize different frameworks for measuring connectivity and data collection parameters such as scan length. Additionally, investigators can explore the unique perspectives of the brains functional architecture offered by each of the scan conditions.

Neuroscience↗

bioRxiv2016

A network of topographic numerosity maps in human association cortex

Sensory and motor cortices each contain multiple topographic maps with the structure of sensory organs (such as the retina or cochlea) mapped onto the cortical surface. These sensory maps are hierarchically organized. For example, visual field maps contain neurons that represent increasing large parts of visual space with increasingly complex responses. Some visual neurons respond to stimuli with a particular numerosity, the number of objects in a set. We recently discovered a parietal topographic numerosity map where neural numerosity preferences progress gradually across the cortical surface, analogous to sensory maps. Following this analogy, we hypothesised that there may be multiple numerosity maps. Numerosity perception is implicated in many cognitive functions including foraging, multiple object tracking, dividing attention, decision making and mathematics. Here we use ultra-high-field (7T) fMRI and neural model-based analyses to reveal numerosity-selective neural populations organized into six widely separated topographic maps in each hemisphere. Although we describe subtle differences between these maps, their properties are very similar, unlike in sensory map hierarchies. These maps are found in areas implicated in object recognition, motion perception, attention control, decision-making and mathematics. Multiple numerosity maps may allow interactions with these many cognitive systems, suggesting a broad role for quantity processing in supporting many perceptual and cognitive functions.

Neuroscience↗

bioRxiv2016

On the Effectiveness of Event-related Beta tACS on Episodic Memory Formation and Motor Cortex Excitability

BackgroundTranscranial alternating current stimulation (tACS) is widely used to entrain or modulate brain oscillations in order to investigate causal relationships between oscillations and cognition.\n\nObjectiveIn a series of experiments we here addressed the question of whether event-related, transient tACS in the beta frequency range can be used to entrain beta oscillations in two different domains: episodic memory formation and motor cortex excitability.\n\nMethodsIn experiments 1 and 2, 72 healthy human participants engaged in an incidental encoding task of verbal and non-verbal material while receiving tACS to the left and right inferior frontal gyrus (IFG) at 6.8Hz, 10.7Hz, 18.5Hz, 30Hz, 48Hz and sham stimulation for 2s during stimulus presentation.\n\nIn experiment 3, tACS was administered to M1 at the individual motor beta frequency of eight subjects. We investigated the relationship between the size of TMS induced MEPs and tACS phase.\n\nResultsBeta tACS did not affect memory performance compared to sham stimulation in experiments 1 and 2. Likewise, in experiment 3, MEP size was not modulated by the tACS phase.\n\nConclusionsOur findings suggest that event-related, transient tACS in the beta frequency range cannot be used to modulate the formation of episodic memories or motor cortex excitability. These null-results question the effectiveness of event-related tACS to entrain beta oscillations and modulate cognition.

Neuroscience↗

bioRxiv2016

How Transcranial Magnetic Stimulation over Early Visual Cortex impacts short-term memory precision and guess rate

Neuroimaging studies have demonstrated that activity patterns in early visual areas predict stimulus properties actively maintained in visual short-term memory. Yet, the mechanisms by which such information is represented remain largely unknown. In this study, observers remembered the orientations of 4 briefly presented gratings, one in each quadrant of the visual field. A 10Hz Transcranial Magnetic Stimulation (TMS) triplet was applied directly at stimulus offset, or midway through a 2-second delay, targeting early visual cortex corresponding retinotopically to a sample item in the lower hemifield. Memory for one of the four gratings was probed at random, and participants reported this orientation via method of adjustment. Replication errors were smaller when the visual field location targeted by TMS overlapped with that of the cued memory item, compared to errors for stimuli probed diagonally to TMS. This implied topographic storage of orientation information, and a memory-enhancing effect at the targeted location. Furthermore, early pulses impaired performance at all four locations, compared to late pulses. Next, response errors were fit empirically using a mixture model analysis to characterize memory precision and guess rates. Memory was more precise for items proximal to the pulse location, irrespective of pulse timing. Guesses were more probable with early TMS pulses, regardless of stimulus location. Thus, whereas TMS administered at the offset of the stimulus array might disrupt early-phase consolidation in a topographically unspecific manner, TMS also boosts the precise representation of an item at its targeted retinotopic location, perhaps by increasing attentional resources or by injecting a beneficial amount of noise.

Neuroscience↗