Growth rules for the repair of Asynchronous Irregular neuronal networks after peripheral lesions.

Several homeostatic mechanisms enable the brain to maintain desired levels of neuronal activity. One of these, homeostatic structural plasticity, has been reported to restore activity in networks disrupted by peripheral lesions by altering their neuronal connectivity. While multiple lesion experiments have studied the changes in neurite morphology that underlie modifications of synapses in these networks, the underlying mechanisms that drive these changes are yet to be explained. Evidence suggests that neuronal activity modulates neurite morphology and may stimulate neurites to selective sprout or retract to restore network activity levels. We developed a new spiking network model of peripheral lesioning and accurately reproduced the characteristics of network repair after deafferentation that are reported in experiments to study the activity dependent growth regimes of neurites. To ensure that our simulations closely resemble the behaviour of networks in the brain, we model deafferentation in a biologically realistic balanced network model that exhibits low frequency Asynchronous Irregular (AI) activity as observed in cerebral cortex. Our simulation results indicate that the re-establishment of activity in neurons both within and outside the deprived region, the Lesion Projection Zone (LPZ), requires opposite activity dependent growth rules for excitatory and inhibitory post-synaptic elements. Analysis of these growth regimes indicates that they also contribute to the maintenance of activity levels in individual neurons. Furthermore, in our model, the directional formation of synapses that is observed in experiments requires that pre-synaptic excitatory and inhibitory elements also follow opposite growth rules. Lastly, we observe that our proposed structural plasticity growth rules and the inhibitory synaptic plasticity mechanism that also balances our AI network both contribute to the restoration of the network to pre-deafferentation stable activity levels.

Review of combinations of experimental and computational techniques to identify and understand genes involved in innate immunity and effector-triggered defence.

The innate immune system includes a first layer of defence that recognises conserved pathogen-associated molecular patterns that are essential for microbial fitness. Resistance (R) gene-based recognition of pathogen effectors, which function in modulation or avoidance of host immunity, activates a second layer of plant defence. In this review, experimental and computational techniques are considered to improve understanding of the plant immune system. Biocomputation contributes to discovery of the molecular genetic basis of host resistance against pathogens. Sequenced genomes have been used to identify R genes in plants. Resistance gene enrichment sequencing based on conserved protein domains has increased the number of R genes with nucleotide-binding site and leucine-rich repeat domains. Network analysis will contribute to an improved understanding of the innate immune system and identify novel genes for partial disease resistance. Machine learning algorithms are expected to become important in defining aspects of the immune system that are less well characterised, including identification of R genes that lack conserved protein domains.

Cerebellar output controls generalized spike-and-wave discharge occurrence.

OBJECTIVE: Disrupting thalamocortical activity patterns has proven to be a promising approach to stop generalized spike-and-wave discharges (GSWDs) characteristic of absence seizures. Here, we investigated to what extent modulation of neuronal firing in cerebellar nuclei (CN), which are anatomically in an advantageous position to disrupt cortical oscillations through their innervation of a wide variety of thalamic nuclei, is effective in controlling absence seizures. METHODS: Two unrelated mouse models of generalized absence seizures were used: the natural mutant tottering, which is characterized by a missense mutation in Cacna1a, and inbred C3H/HeOuJ. While simultaneously recording single CN neuron activity and electrocorticogram in awake animals, we investigated to what extent pharmacologically increased or decreased CN neuron activity could modulate GSWD occurrence as well as short-lasting, on-demand CN stimulation could disrupt epileptic seizures. RESULTS: We found that a subset of CN neurons show phase-locked oscillatory firing during GSWDs and that manipulating this activity modulates GSWD occurrence. Inhibiting CN neuron action potential firing by local application of the γ-aminobutyric acid type A (GABA-A) agonist muscimol increased GSWD occurrence up to 37-fold, whereas increasing the frequency and regularity of CN neuron firing with the use of GABA-A antagonist gabazine decimated its occurrence. A single short-lasting (30-300 milliseconds) optogenetic stimulation of CN neuron activity abruptly stopped GSWDs, even when applied unilaterally. Using a closed-loop system, GSWDs were detected and stopped within 500 milliseconds. INTERPRETATION: CN neurons are potent modulators of pathological oscillations in thalamocortical network activity during absence seizures, and their potential therapeutic benefit for controlling other types of generalized epilepsies should be evaluated.

Dendritic morphology predicts pattern recognition performance in multi-compartmental model neurons with and without active conductances.

In this paper we examine how a neuron's dendritic morphology can affect its pattern recognition performance. We use two different algorithms to systematically explore the space of dendritic morphologies: an algorithm that generates all possible dendritic trees with 22 terminal points, and one that creates representative samples of trees with 128 terminal points. Based on these trees, we construct multi-compartmental models. To assess the performance of the resulting neuronal models, we quantify their ability to discriminate learnt and novel input patterns. We find that the dendritic morphology does have a considerable effect on pattern recognition performance and that the neuronal performance is inversely correlated with the mean depth of the dendritic tree. The results also reveal that the asymmetry index of the dendritic tree does not correlate with the performance for the full range of tree morphologies. The performance of neurons with dendritic tapering is best predicted by the mean and variance of the electrotonic distance of their synapses to the soma. All relationships found for passive neuron models also hold, even in more accentuated form, for neurons with active membranes.

Synaptic depression enables neuronal gain control.

To act as computational devices, neurons must perform mathematical operations as they transform synaptic and modulatory input into output firing rate. Experiments and theory indicate that neuronal firing typically represents the sum of synaptic inputs, an additive operation, but multiplication of inputs is essential for many computations. Multiplication by a constant produces a change in the slope, or gain, of the input-output relationship, amplifying or scaling down the sensitivity of the neuron to changes in its input. Such gain modulation occurs in vivo, during contrast invariance of orientation tuning, attentional scaling, translation-invariant object recognition, auditory processing and coordinate transformations. Moreover, theoretical studies highlight the necessity of gain modulation in several of these tasks. Although potential cellular mechanisms for gain modulation have been identified, they often rely on membrane noise and require restrictive conditions to work. Because nonlinear components are used to scale signals in electronics, we examined whether synaptic nonlinearities are involved in neuronal gain modulation. We used synaptic stimulation and the dynamic-clamp technique to investigate gain modulation in granule cells in acute slices of rat cerebellum. Here we show that when excitation is mediated by synapses with short-term depression (STD), neuronal gain is controlled by an inhibitory conductance in a noise-independent manner, allowing driving and modulatory inputs to be multiplied together. The nonlinearity introduced by STD transforms inhibition-mediated additive shifts in the input-output relationship into multiplicative gain changes. When granule cells were driven with bursts of high-frequency mossy fibre input, as observed in vivo, larger inhibition-mediated gain changes were observed, as expected with greater STD. Simulations of synaptic integration in more complex neocortical neurons suggest that STD-based gain modulation can also operate in neurons with large dendritic trees. Our results establish that neurons receiving depressing excitatory inputs can act as powerful multiplicative devices even when integration of postsynaptic conductances is linear.

A defined heteromeric KV1 channel stabilizes the intrinsic pacemaking and regulates the output of deep cerebellar nuclear neurons to thalamic targets.

The output of the cerebellum to the motor axis of the central nervous system is orchestrated mainly by synaptic inputs and intrinsic pacemaker activity of deep cerebellar nuclear (DCN) projection neurons. Herein, we demonstrate that the soma of these cells is enriched with K(V)1 channels produced by mandatory multi-merization of K(V)1.1, 1.2 α and KV ß2 subunits. Being constitutively active, the K(+) current (IK(V)1) mediated by these channels stabilizes the rate and regulates the temporal precision of self-sustained firing of these neurons. Placed strategically, IK(V)1 provides a powerful counter-balance to prolonged depolarizing inputs, attenuates the rebound excitation, and dampens the membrane potential bi-stability. Somatic location with low activation threshold render IK(V)1 instrumental in voltage-dependent de-coupling of the axon initial segment from the cell body of projection neurons, impeding invasion of back-propagating action potentials into the somato-dendritic compartment. The latter is also demonstrated to secure the dominance of clock-like somatic pacemaking in driving the regenerative firing activity of these neurons, to encode time variant inputs with high fidelity. Through the use of multi-compartmental modelling and retro-axonal labelling, the physiological significance of the described functions for processing and communication of information from the lateral DCN to thalamic relay nuclei is established.

An integrator circuit in cerebellar cortex.

The brain builds dynamic models of the body and the outside world to predict the consequences of actions and stimuli. A well-known example is the oculomotor integrator, which anticipates the position-dependent elasticity forces acting on the eye ball by mathematically integrating over time oculomotor velocity commands. Many models of neural integration have been proposed, based on feedback excitation, lateral inhibition or intrinsic neuronal nonlinearities. We report here that a computational model of the cerebellar cortex, a structure thought to implement dynamic models, reveals a hitherto unrecognized integrator circuit. In this model, comprising Purkinje cells, molecular layer interneurons and parallel fibres, Purkinje cells were able to generate responses lasting more than 10 s, to which both neuronal and network mechanisms contributed. Activation of the somatic fast sodium current by subthreshold voltage fluctuations was able to maintain pulse-evoked graded persistent activity, whereas lateral inhibition among Purkinje cells via recurrent axon collaterals further prolonged the responses to step and sine wave stimulation. The responses of Purkinje cells decayed with a time-constant whose value depended on their baseline spike rate, with integration vanishing at low (< 1 per s) and high rates (> 30 per s). The model predicts that the apparently fast circuit of the cerebellar cortex may control the timing of slow processes without having to rely on sensory feedback. Thus, the cerebellar cortex may contain an adaptive temporal integrator, with the sensitivity of integration to the baseline spike rate offering a potential mechanism of plasticity of the response time-constant.

Creating, documenting and sharing network models.

As computational neuroscience matures, many simulation environments are available that are useful for neuronal network modeling. However, methods for successfully documenting models for publication and for exchanging models and model components among these projects are still under development. Here we briefly review existing software and applications for network model creation, documentation and exchange. Then we discuss a few of the larger issues facing the field of computational neuroscience regarding network modeling and suggest solutions to some of these problems, concentrating in particular on standardized network model terminology, notation, and descriptions and explicit documentation of model scaling. We hope this will enable and encourage computational neuroscientists to share their models more systematically in the future.

The effect of alterations of schizophrenia-associated genes on gamma band oscillations.

Abnormalities in the synchronized oscillatory activity of neurons in general and, specifically in the gamma band, might play a crucial role in the pathophysiology of schizophrenia. While these changes in oscillatory activity have traditionally been linked to alterations at the synaptic level, we demonstrate here, using computational modeling, that common genetic variants of ion channels can contribute strongly to this effect. Our model of primary auditory cortex highlights multiple schizophrenia-associated genetic variants that reduce gamma power in an auditory steady-state response task. Furthermore, we show that combinations of several of these schizophrenia-associated variants can produce similar effects as the more traditionally considered synaptic changes. Overall, our study provides a mechanistic link between schizophrenia-associated common genetic variants, as identified by genome-wide association studies, and one of the most robust neurophysiological endophenotypes of schizophrenia.

neuroConstruct: a tool for modeling networks of neurons in 3D space.

Conductance-based neuronal network models can help us understand how synaptic and cellular mechanisms underlie brain function. However, these complex models are difficult to develop and are inaccessible to most neuroscientists. Moreover, even the most biologically realistic network models disregard many 3D anatomical features of the brain. Here, we describe a new software application, neuroConstruct, that facilitates the creation, visualization, and analysis of networks of multicompartmental neurons in 3D space. A graphical user interface allows model generation and modification without programming. Models within neuroConstruct are based on new simulator-independent NeuroML standards, allowing automatic generation of code for NEURON or GENESIS simulators. neuroConstruct was tested by reproducing published models and its simulator independence verified by comparing the same model on two simulators. We show how more anatomically realistic network models can be created and their properties compared with experimental measurements by extending a published 1D cerebellar granule cell layer model to 3D.

Cerebellar LTD and pattern recognition by Purkinje cells.

Many theories of cerebellar function assume that long-term depression (LTD) of parallel fiber (PF) synapses enables Purkinje cells to learn to recognize PF activity patterns. We have studied the LTD-based recognition of PF patterns in a biophysically realistic Purkinje-cell model. With simple-spike firing as observed in vivo, the presentation of a pattern resulted in a burst of spikes followed by a pause. Surprisingly, the best criterion to distinguish learned patterns was the duration of this pause. Moreover, our simulations predicted that learned patterns elicited shorter pauses, thus increasing Purkinje-cell output. We tested this prediction in Purkinje-cell recordings both in vitro and in vivo. In vitro, we found a shortening of pauses when decreasing the number of active PFs or after inducing LTD. In vivo, we observed longer pauses in LTD-deficient mice. Our results suggest a novel form of neural coding in the cerebellar cortex.

Determinants of synaptic integration and heterogeneity in rebound firing explored with data-driven models of deep cerebellar nucleus cells.

Significant inroads have been made to understand cerebellar cortical processing but neural coding at the output stage of the cerebellum in the deep cerebellar nuclei (DCN) remains poorly understood. The DCN are unlikely to just present a relay nucleus because Purkinje cell inhibition has to be turned into an excitatory output signal, and DCN neurons exhibit complex intrinsic properties. In particular, DCN neurons exhibit a range of rebound spiking properties following hyperpolarizing current injection, raising the question how this could contribute to signal processing in behaving animals. Computer modeling presents an ideal tool to investigate how intrinsic voltage-gated conductances in DCN neurons could generate the heterogeneous firing behavior observed, and what input conditions could result in rebound responses. To enable such an investigation we built a compartmental DCN neuron model with a full dendritic morphology and appropriate active conductances. We generated a good match of our simulations with DCN current clamp data we recorded in acute slices, including the heterogeneity in the rebound responses. We then examined how inhibitory and excitatory synaptic input interacted with these intrinsic conductances to control DCN firing. We found that the output spiking of the model reflected the ongoing balance of excitatory and inhibitory input rates and that changing the level of inhibition performed an additive operation. Rebound firing following strong Purkinje cell input bursts was also possible, but only if the chloride reversal potential was more negative than -70 mV to allow de-inactivation of rebound currents. Fast rebound bursts due to T-type calcium current and slow rebounds due to persistent sodium current could be differentially regulated by synaptic input, and the pattern of these rebounds was further influenced by HCN current. Our findings suggest that active properties of DCN neurons could play a crucial role for signal processing in the cerebellum.

STD-dependent and independent encoding of input irregularity as spike rate in a computational model of a cerebellar nucleus neuron.

Neurons in the cerebellar nuclei (CN) receive inhibitory inputs from Purkinje cells in the cerebellar cortex and provide the major output from the cerebellum, but their computational function is not well understood. It has recently been shown that the spike activity of Purkinje cells is more regular than previously assumed and that this regularity can affect motor behaviour. We use a conductance-based model of a CN neuron to study the effect of the regularity of Purkinje cell spiking on CN neuron activity. We find that increasing the irregularity of Purkinje cell activity accelerates the CN neuron spike rate and that the mechanism of this recoding of input irregularity as output spike rate depends on the number of Purkinje cells converging onto a CN neuron. For high convergence ratios, the irregularity induced spike rate acceleration depends on short-term depression (STD) at the Purkinje cell synapses. At low convergence ratios, or for synchronised Purkinje cell input, the firing rate increase is independent of STD. The transformation of input irregularity into output spike rate occurs in response to artificial input spike trains as well as to spike trains recorded from Purkinje cells in tottering mice, which show highly irregular spiking patterns. Our results suggest that STD may contribute to the accelerated CN spike rate in tottering mice and they raise the possibility that the deficits in motor control in these mutants partly result as a pathological consequence of this natural form of plasticity.

Transtibial versus anteromedial portal reaming in anterior cruciate ligament reconstruction: an anatomic and biomechanical evaluation of surgical technique.

PURPOSE: The purpose of this study was to objectively evaluate the anatomic and biomechanical outcomes of anterior cruciate ligament (ACL) reconstruction with transtibial versus anteromedial portal drilling of the femoral tunnel. METHODS: Ten human cadaveric knees (5 matched pairs) without ligament injury or pre-existing arthritis underwent ACL reconstruction by either a transtibial or anteromedial portal technique. A medial arthrotomy was created in all cases before reconstruction to determine the center of the native ACL tibial and femoral footprints. A 10-mm tibial tunnel directed toward the center of the tibial footprint was prepared in an identical fashion, starting at the anterior border of the medial collateral ligament in all cases. For transtibial femoral socket preparation (n = 5), a guidewire was placed as close to the center of the femoral footprint as possible. With anteromedial portal reconstruction (n = 5), the guidewire was positioned centrally in the femoral footprint and the tunnel drilled through the medial portal in hyperflexion. An identical graft was fixed and tensioned, and knee stability was assessed with the following standardized examinations: (1) anterior drawer, (2) Lachman, (3) maximal internal rotation at 30°, (4) manual pivot shift, and (5) instrumented pivot shift. Distance from the femoral guidewire to the center of the femoral footprint and dimensions of the tibial tunnel intra-articular aperture were measured for all specimens. Statistical analysis was completed with a repeated-measures analysis of variance and Tukey multiple comparisons test with P ≤ .05 defined as significant. RESULTS: The anteromedial portal ACL reconstruction controlled tibial translation significantly more than the transtibial reconstruction with anterior drawer, Lachman, and pivot-shift examinations of knee stability (P ≤ .05). Anteromedial portal ACL reconstruction restored the Lachman and anterior drawer examinations to those of the intact condition and constrained translation with the manual and instrumented pivot-shift examinations more than the native ACL (P ≤ .05). Despite optimal guidewire positioning, the transtibial technique resulted in a mean position 1.94 mm anterior and 3.26 mm superior to the center of the femoral footprint. The guidewire was positioned at the center of the femoral footprint through the anteromedial portal in all cases. The tibial tunnel intra-articular aperture was 38% larger in the anteroposterior dimension with the transtibial versus anteromedial portal technique (mean, 14.9 mm v 10.8 mm; P ≤ .05). CONCLUSIONS: The anteromedial portal drilling technique allows for accurate positioning of the femoral socket in the center of the native footprint, resulting in secondary improvement in time-zero control of tibial translation with Lachman and pivot-shift testing compared with conventional transtibial ACL reconstruction. This technique respects the native ACL anatomy but cannot restore it with a single-bundle ACL reconstruction. Eccentric, posterolateral positioning of the guidewire in the tibial tunnel with the transtibial technique results in iatrogenic re-reaming of the tibial tunnel and significant intra-articular aperture expansion. CLINICAL RELEVANCE: Anteromedial portal drilling of the femoral socket may allow for improved restoration of anatomy and stability with ACL reconstruction compared with conventional transtibial drilling techniques.

The beta component of gamma-band auditory steady-state responses in patients with schizophrenia.

The mechanisms underlying circuit dysfunctions in schizophrenia (SCZ) remain poorly understood. Auditory steady-state responses (ASSRs), especially in the gamma and beta band, have been suggested as a potential biomarker for SCZ. While the reduction of 40 Hz power for 40 Hz drive has been well established and replicated in SCZ patients, studies are inconclusive when it comes to an increase in 20 Hz power during 40 Hz drive. There might be several factors explaining the inconsistencies, including differences in the sensitivity of the recording modality (EEG vs MEG), differences in stimuli (click-trains vs amplitude-modulated tones) and large differences in the amplitude of the stimuli. Here, we used a computational model of ASSR deficits in SCZ and explored the effect of three SCZ-associated microcircuit alterations: reduced GABA activity, increased GABA decay times and NMDA receptor hypofunction. We investigated the effect of input strength on gamma (40 Hz) and beta (20 Hz) band power during gamma ASSR stimulation and saw that the pronounced increase in beta power during gamma stimulation seen experimentally could only be reproduced in the model when GABA decay times were increased and only for a specific range of input strengths. More specifically, when the input was in this specific range, the rhythmic drive at 40 Hz produced a strong 40 Hz rhythm in the control network; however, in the 'SCZ-like' network, the prolonged inhibition led to a so-called 'beat-skipping', where the network would only strongly respond to every other input. This mechanism was responsible for the emergence of the pronounced 20 Hz beta peak in the power spectrum. The other two microcircuit alterations were not able to produce a substantial 20 Hz component but they further narrowed the input strength range for which the network produced a beta component when combined with increased GABAergic decay times. Our finding that the beta component only existed for a specific range of input strengths might explain the seemingly inconsistent reporting in experimental studies and suggests that future ASSR studies should systematically explore different amplitudes of their stimuli. Furthermore, we provide a mechanistic link between a microcircuit alteration and an electrophysiological marker in schizophrenia and argue that more complex ASSR stimuli are needed to disentangle the nonlinear interactions of microcircuit alterations. The computational modelling approach put forward here is ideally suited to facilitate the development of such stimuli in a theory-based fashion.

Embodiment and Its Influence on Informational Costs of Decision Density-Atomic Actions vs. Scripted Sequences.

The importance of embodiment for effective robot performance has been postulated for a long time. Despite this, only relatively recently concrete quantitative models were put forward to characterize the advantages provided by a well-chosen embodiment. We here use one of these models, based on the concept of relevant information, to identify in a minimalistic scenario how and when embodiment affects the decision density. Concretely, we study how embodiment affects information costs when, instead of atomic actions, scripts are introduced, that is, predefined action sequences. Their inclusion can be treated as a straightforward extension of the basic action space. We will demonstrate the effect on informational decision cost of utilizing scripts vs. basic actions using a simple navigation task. Importantly, we will also employ a world with "mislabeled" actions, which we will call a "twisted" world. This is a model which had been used in an earlier study of the influence of embodiment on decision costs. It will turn out that twisted scenarios, as opposed to well-labeled ("embodied") ones, are significantly more costly in terms of relevant information. This cost is further worsened when the agent is forced to lower the decision density by employing scripts (once a script is triggered, no decisions are taken until the script has run to its end). This adds to our understanding why well-embodied (interpreted in our model as well-labeled) agents should be preferable, in a quantifiable, objective sense.

EEG Spectral Feature Modulations Associated With Fatigue in Robot-Mediated Upper Limb Gross and Fine Motor Interactions.

This paper investigates the EEG spectral feature modulations associated with fatigue induced by robot-mediated upper limb gross and fine motor interactions. Twenty healthy participants were randomly assigned to perform a gross motor interaction with HapticMASTER or a fine motor interaction with SCRIPT passive orthosis for 20 min or until volitional fatigue. Relative and ratio band power measures were estimated from the EEG data recorded before and after the robot-mediated interactions. Paired-samples t-tests found a significant increase in the relative alpha band power and a significant decrease in the relative delta band power due to the fatigue induced by the robot-mediated gross and fine motor interactions. The gross motor task also significantly increased the (θ + α)/ß and α/ß ratio band power measures, whereas the fine motor task increased the relative theta band power. Furthermore, the robot-mediated gross movements mostly changed the EEG activity around the central and parietal brain regions, whereas the fine movements mostly changed the EEG activity around the frontopolar and central brain regions. The subjective ratings suggest that the gross motor task may have induced physical fatigue, whereas the fine motor task may have induced mental fatigue. Therefore, findings affirm that changes to localised brain activity patterns indicate fatigue developed from the robot-mediated interactions. It can also be concluded that the regional differences in the prominent EEG spectral features are most likely due to the differences in the nature of the task (fine/gross motor and distal/proximal upper limb) that may have differently altered an individual's physical and mental fatigue level. The findings could potentially be used in future to detect and moderate fatigue during robot-mediated post-stroke therapies.

Adaptive robot mediated upper limb training using electromyogram-based muscle fatigue indicators.

Studies on improving the adaptability of upper limb rehabilitation training do not often consider the implications of muscle fatigue sufficiently. In this study, electromyogram features were used as fatigue indicators in the context of human-robot interaction. They were utilised for auto-adaptation of the task difficulty, which resulted in a prolonged training interaction. The electromyogram data was collected from three gross-muscles of the upper limb in 30 healthy participants. The experiment followed a protocol for increasing the muscle strength by progressive strength training, that was an implementation of a known method in sports science for muscle training, in a new domain of robotic adaptation in muscle training. The study also compared how the participants in three experimental conditions perceived the change in task difficulty levels. One task benefitted from robotic adaptation (Intervention group) where the robot adjusted the task difficulty. The other two tasks were control groups 1 and 2. There was no difficulty adjustment at all in Control 1 group and the difficulty was adjusted manually in Control 2 group. The results indicated that the participants could perform a prolonged progressive strength training exercise with more repetitions with the help of a fatigue-based robotic adaptation, compared to the training interactions, which were based on manual/no adaptation. This study showed that it is possible to alter the level of the challenge using fatigue indicators, and thus, increase the interaction time. The results of the study are expected to be extended to stroke patients in the future by utilising the potential for adapting the training difficulty according to the patient's muscular state, and also to have a large number repetitions in a robot-assisted training environment.