Rapid intravenous loading of brivaracetam during invasive and non-invasive video-EEG monitoring.

PURPOSE: The pharmacokinetics of Brivaracetam (BRV) and its ability to penetrate the blood-brain barrier quickly make it a suitable drug for emergencies. In this study, our aim was to investigate the tolerability, safety, and acute efficacy of rapid intravenous (IV) loading of BRV during invasive and non-invasive video-EEG monitoring in patients with drug-resistant focal epilepsy (DRFE). METHODS: Eleven adult patients, six during stereo-electroencephalography (SEEG) and five in scalp video-EEG evaluation, received a 10-minute IV infusion of BRV 100 mg after a period of total withdrawal from antiseizure medications (ASMs). The ictal and interictal EEG activity was assessed through visual and spectrographic analysis before and after intravenous BRV administration. Patients completed the Liverpool Adverse Events Profile (LAEP) scale to evaluate tolerability and adverse events. RESULTS: Rapid BRV IV infusion was well tolerated in all patients. The mean LAEP values showed no significant differences (p = 0.40). Loading BRV resulted in a reduction in interictal activity in six patients. The mean seizure frequency significantly decreased five hours after BRV administration (a 79.2 % reduction across the entire group, p = 0.027). A significant change in spectral band analysis was observed ten minutes after BRV administration. CONCLUSION: Our data suggest that rapid BRV IV infusion has a favorable safety profile and is effective in controlling seizure series in the short term. The electrophysiological changes observed ten minutes after the BRV load correlate with its effects on brain dynamics after blood-brain barrier diffusion.

Bringing rehabilitation home with an e-health platform to treat stroke patients: study protocol of a randomized clinical trial (RGS@home).

BACKGROUND: There is a pressing need for scalable healthcare solutions and a shift in the rehabilitation paradigm from hospitals to homes to tackle the increase in stroke incidence while reducing the practical and economic burden for patients, hospitals, and society. Digital health technologies can contribute to addressing this challenge; however, little is known about their effectiveness in at-home settings. In response, we have designed the RGS@home study to investigate the effectiveness, acceptance, and cost of a deep tech solution called the Rehabilitation Gaming System (RGS). RGS is a cloud-based system for delivering AI-enhanced rehabilitation using virtual reality, motion capture, and wearables that can be used in the hospital and at home. The core principles of the brain theory-based RGS intervention are to deliver rehabilitation exercises in the form of embodied, goal-oriented, and task-specific action. METHODS: The RGS@home study is a randomized longitudinal clinical trial designed to assess whether the combination of the RGS intervention with standard care is superior to standard care alone for the functional recovery of stroke patients at the hospital and at home. The study is conducted in collaboration with hospitals in Spain, Sweden, and France and includes inpatients and outpatients at subacute and chronic stages post-stroke. The intervention duration is 3 months with assessment at baseline and after 3, 6, and 12 months. The impact of RGS is evaluated in terms of quality of life measurements, usability, and acceptance using standardized clinical scales, together with health economic analysis. So far, one-third of the patients expected to participate in the study have been recruited (N = 90, mean age 60, days after stroke ≥ 30 days). The trial will end in July 2023. DISCUSSION: We predict an improvement in the patients' recovery, high acceptance, and reduced costs due to a soft landing from the clinic to home rehabilitation. In addition, the data provided will allow us to assess whether the prescription of therapy at home can counteract deterioration and improve quality of life while also identifying new standards for online and remote assessment, diagnostics, and intervention across European hospitals. TRIAL REGISTRATION: C linicalTrials.gov NCT04620707. Registered on November 3, 2020.

Validation of direct cortical stimulation in presurgical evaluation of epilepsy.

OBJECTIVE: Direct cortical stimulation (DCS) is standard for intracranial presurgical evaluation in drug-resistant epilepsy (DRE). Few studies have reported levels of concordance between spontaneous seizure generators and triggered seizures during DCS. The present work reports validity measures of DCS for detecting the seizure onset zone (SOZ) during stereoelectroencephalography (SEEG). METHODS: We evaluated all patients who underwent SEEG evaluation at our epilepsy center between 2013 and 2019. Data were analyzed using contingency tables. Validity measures of the diagnostic test were computed for all patients evaluated with DCS and for seizure free patients. RESULTS: Fifty-eight consecutive patients were evaluated through DCS. One hundred seventy-three clinical seizures were elicited with DCS. Electroclinical identical to spontaneous seizures were considered true positive (TP) seizures. They showed a high specificity (96.9%) for detecting the SOZ in patients that remained seizure free one year after treatment. Sensitivity was low (23.0%), and a high percentage of false-negative stimulations was documented in the SOZ. The accuracy was 87.9%. CONCLUSIONS: DCS is a technique with high specificity but a low sensitivity for the localization of the SOZ. The DCS validity measures need to be known when considered for surgical decisions. The interpretation of DCS-triggered seizures and the differentiation of true-positive vs false-positive seizures should be carefully evaluated. SIGNIFICANCE: DCS seizure triggering is highly specific for SOZ localization.

Mood Disturbances, Anxiety, and Impact on Quality of Life in Patients Admitted to Epilepsy Monitoring Units.

Introduction: The overall combined prevalence of anxiety and depression in patients with epilepsy has been estimated at 20.2 and 22.9%, respectively, and is considered more severe in drug-refractory epilepsy. Patients admitted to epilepsy monitoring units constitute a particular group. Also, patients with psychogenic non-epileptic seizures can reach more than 20% of all admissions. This study aims to characterize these symptoms in a large cohort of patients admitted for evaluation in a tertiary epilepsy center. Materials and Methods: The study was conducted among 493 consecutive patients (age: 38.78 ± 12.7, 57% females) admitted for long-term video EEG from January 2013 to February 2021. Demographic, clinical, and mood disorder patients' data were collected. Anxiety and depression symptoms were assessed through the Hospital Anxiety Depression Scale (HADS-A and HADS-D), the State Trait Anxiety Inventory (STAI), and Beck Depression Inventory (BDI-II). Quality of life was determined using the QOLIE-10. Patients were divided into three groups: patients with epilepsy (n = 395), psychogenic non-epileptic seizures (PNES) (n = 56), and combined (n = 33). A univariate and multivariate regression analysis was performed for variables associated with quality of life. Results: Of 493 patients, 45.0% had structural etiology, and considering epilepsy classification, 43.6% were of temporal lobe origin. In addition, 32.45% of patients had a previous psychiatric history, 49.9% of patients had depressive symptoms in BDI, and 30.9% according to HADS-D; 56.42 and 52.63% of patients presented pathological anxiety scores in STAI-T and STAI-S, respectively; and 44.78% according to HADS-A. PNES and combined groups revealed a higher incidence of pathologic BDI scores (64.29 and 78.79%, p < 0.001) as well as pathologic HADS-A scores (p = 0.001). Anxiety and depression pathologic results are more prevalent in females, HADS-A (females = 50.7%, males = 36.8%; p = 0.0027) and BDI > 13 (females = 56.6%, males = 41.0%; p = 0.0006). QOLIE-10 showed that 71% of the patients had their quality of life affected with significantly higher scores in the combined group than in the epilepsy and PNES groups (p = 0.0015). Conclusions: Subjective anxiety, depression, and reduced quality of life are highly prevalent in patients with refractory epilepsy. These symptoms are more evident when PNES are associated with epilepsy and more severe among female patients. Most of the cases were not previously diagnosed. These factors should be considered in everyday clinical practice, and specific approaches might be adapted depending on the patient's profile.

Volitional learning promotes theta phase coding in the human hippocampus.

Electrophysiological studies in rodents show that active navigation enhances hippocampal theta oscillations (4-12 Hz), providing a temporal framework for stimulus-related neural codes. Here we show that active learning promotes a similar phase coding regime in humans, although in a lower frequency range (3-8 Hz). We analyzed intracranial electroencephalography (iEEG) from epilepsy patients who studied images under either volitional or passive learning conditions. Active learning increased memory performance and hippocampal theta oscillations and promoted a more accurate reactivation of stimulus-specific information during memory retrieval. Representational signals were clustered to opposite phases of the theta cycle during encoding and retrieval. Critically, during active but not passive learning, the temporal structure of intracycle reactivations in theta reflected the semantic similarity of stimuli, segregating conceptually similar items into more distant theta phases. Taken together, these results demonstrate a multilayered mechanism by which active learning improves memory via a phylogenetically old phase coding scheme.

Non-Invasive Estimation of Intracranial Pressure by Diffuse Optics: A Proof-of-Concept Study.

Intracranial pressure (ICP) is an important parameter to monitor in several neuropathologies. However, because current clinically accepted methods are invasive, its monitoring is limited to patients in critical conditions. On the other hand, there are other less critical conditions for which ICP monitoring could still be useful; therefore, there is a need to develop non-invasive methods. We propose a new method to estimate ICP based on the analysis of the non-invasive measurement of pulsatile, microvascular cerebral blood flow with diffuse correlation spectroscopy. This is achieved by training a recurrent neural network using only the cerebral blood flow as the input. The method is validated using a 50% split sample method using the data from a proof-of-concept study. The study involved a population of infants (n = 6) with external hydrocephalus (initially diagnosed as benign enlargement of subarachnoid spaces) as well as a population of adults (n = 6) with traumatic brain injury. The algorithm was applied to each cohort individually to obtain a model and an ICP estimate. In both diverse cohorts, the non-invasive estimation of ICP was achieved with an accuracy of <4 mm Hg and a negligible small bias. Further, we have achieved a good correlation (Pearson's correlation coefficient >0.9) and good concordance (Lin's concordance correlation coefficient >0.9) in comparison with standard clinical, invasive ICP monitoring. This preliminary work paves the way for further investigations of this tool for the non-invasive, bedside assessment of ICP.

Modulating grid cell scale and intrinsic frequencies via slow high-threshold conductances: A simplified model.

Grid cells in the medial entorhinal cortex (MEC) have known spatial periodic firing fields which provide a metric for the representation of self-location and path planning. The hexagonal tessellation pattern of grid cells scales up progressively along the MEC's layer II dorsal-to-ventral axis. This scaling gradient has been hypothesized to originate either from inter-population synaptic dynamics as postulated by attractor networks, or from projected theta frequency waves to different axis levels, as in oscillatory models. Alternatively, cellular dynamics and specifically slow high-threshold conductances have been proposed to have an impact on the grid cell scale. To test the hypothesis that intrinsic hyperpolarization-activated cation currents account for both the scaled gradient and the oscillatory frequencies observed along the dorsal-to-ventral axis, we have modeled and analyzed data from a population of grid cells simulated with spiking neurons interacting through low-dimensional attractor dynamics. We observed that the intrinsic neuronal membrane properties of simulated cells were sufficient to induce an increase in grid scale and potentiate differences in the membrane potential oscillatory frequency. Overall, our results suggest that the after-spike dynamics of cation currents may play a major role in determining the grid cells' scale and that oscillatory frequencies are a consequence of intrinsic cellular properties that are specific to different levels of the dorsal-to-ventral axis in the MEC layer II.

A computational analysis of dynamic, multi-organ inflammatory crosstalk induced by endotoxin in mice.

Bacterial lipopolysaccharide (LPS) induces an acute inflammatory response across multiple organs, primarily via Toll-like receptor 4 (TLR4). We sought to define novel aspects of the complex spatiotemporal dynamics of LPS-induced inflammation using computational modeling, with a special focus on the timing of pathological systemic spillover. An analysis of principal drivers of LPS-induced inflammation in the heart, gut, lung, liver, spleen, and kidney to assess organ-specific dynamics, as well as in the plasma (as an assessment of systemic spillover), was carried out using data on 20 protein-level inflammatory mediators measured over 0-48h in both C57BL/6 and TLR4-null mice. Using a suite of computational techniques, including a time-interval variant of Principal Component Analysis, we confirm key roles for cytokines such as tumor necrosis factor-α and interleukin-17A, define a temporal hierarchy of organ-localized inflammation, and infer the point at which organ-localized inflammation spills over systemically. Thus, by employing a systems biology approach, we obtain a novel perspective on the time- and organ-specific components in the propagation of acute systemic inflammation.

Absence of Parallel Fibre to Purkinje Cell LTD During Eyeblink Conditioning.

Long-term depression (LTD) of parallel fibre/Purkinje cell synapses has been the favoured explanation for cerebellar motor learning such as classical eyeblink conditioning. Previous evidence against this interpretation has been contested. Here we wanted to test whether a classical conditioning protocol causes LTD. We applied a conditioning protocol, using a train of electrical pulses to the parallel fibres as the conditional stimulus. In order to rule out indirect effects caused by antidromic granule cell activation or output from Purkinje cells that might produce changes in Purkinje cell responsiveness, we focused the analysis on the first pulse in the conditional stimulus, that is, before any indirect effects would have time to occur. Purkinje cells learned to respond with a firing pause to the conditional stimulus. Yet, there was no depression of parallel fibre excitation after training.

Size Matters: How Scaling Affects the Interaction between Grid and Border Cells.

Many hippocampal cell types are characterized by a progressive increase in scale along the dorsal-to-ventral axis, such as in the cases of head-direction, grid and place cells. Also located in the medial entorhinal cortex (MEC), border cells would be expected to benefit from such scale modulations. However, this phenomenon has not been experimentally observed. Grid cells in the MEC of mammals integrate velocity related signals to map the environment with characteristic hexagonal tessellation patterns. Due to the noisy nature of these input signals, path integration processes tend to accumulate errors as animals explore the environment, leading to a loss of grid-like activity. It has been suggested that border-to-grid cells' associations minimize the accumulated grid cells' error when rodents explore enclosures. Thus, the border-grid interaction for error minimization is a suitable scenario to study the effects of border cell scaling within the context of spatial representation. In this study, we computationally address the question of (i) border cells' scale from the perspective of their role in maintaining the regularity of grid cells' firing fields, as well as (ii) what are the underlying mechanisms of grid-border associations relative to the scales of both grid and border cells. Our results suggest that for optimal contribution to grid cells' error minimization, border cells should express smaller firing fields relative to those of the associated grid cells, which is consistent with the hypothesis of border cells functioning as spatial anchoring signals.

Consensus Paper: Towards a Systems-Level View of Cerebellar Function: the Interplay Between Cerebellum, Basal Ganglia, and Cortex.

Despite increasing evidence suggesting the cerebellum works in concert with the cortex and basal ganglia, the nature of the reciprocal interactions between these three brain regions remains unclear. This consensus paper gathers diverse recent views on a variety of important roles played by the cerebellum within the cerebello-basal ganglia-thalamo-cortical system across a range of motor and cognitive functions. The paper includes theoretical and empirical contributions, which cover the following topics: recent evidence supporting the dynamical interplay between cerebellum, basal ganglia, and cortical areas in humans and other animals; theoretical neuroscience perspectives and empirical evidence on the reciprocal influences between cerebellum, basal ganglia, and cortex in learning and control processes; and data suggesting possible roles of the cerebellum in basal ganglia movement disorders. Although starting from different backgrounds and dealing with different topics, all the contributors agree that viewing the cerebellum, basal ganglia, and cortex as an integrated system enables us to understand the function of these areas in radically different ways. In addition, there is unanimous consensus between the authors that future experimental and computational work is needed to understand the function of cerebellar-basal ganglia circuitry in both motor and non-motor functions. The paper reports the most advanced perspectives on the role of the cerebellum within the cerebello-basal ganglia-thalamo-cortical system and illustrates other elements of consensus as well as disagreements and open questions in the field.

The Impact of Cortical Lesions on Thalamo-Cortical Network Dynamics after Acute Ischaemic Stroke: A Combined Experimental and Theoretical Study.

The neocortex and thalamus provide a core substrate for perception, cognition, and action, and are interconnected through different direct and indirect pathways that maintain specific dynamics associated with functional states including wakefulness and sleep. It has been shown that a lack of excitation, or enhanced subcortical inhibition, can disrupt this system and drive thalamic nuclei into an attractor state of low-frequency bursting and further entrainment of thalamo-cortical circuits, also called thalamo-cortical dysrhythmia (TCD). The question remains however whether similar TCD-like phenomena can arise with a cortical origin. For instance, in stroke, a cortical lesion could disrupt thalamo-cortical interactions through an attenuation of the excitatory drive onto the thalamus, creating an imbalance between excitation and inhibition that can lead to a state of TCD. Here we tested this hypothesis by comparing the resting-state EEG recordings of acute ischaemic stroke patients (N = 21) with those of healthy, age-matched control-subjects (N = 17). We observed that these patients displayed the hallmarks of TCD: a characteristic downward shift of dominant α-peaks in the EEG power spectra, together with increased power over the lower frequencies (δ and θ-range). Contrary to general observations in TCD, the patients also displayed a broad reduction in ß-band activity. In order to explain the genesis of this stroke-induced TCD, we developed a biologically constrained model of a general thalamo-cortical module, allowing us to identify the specific cellular and network mechanisms involved. Our model showed that a lesion in the cortical component leads to sustained cell membrane hyperpolarization in the corresponding thalamic relay neurons, that in turn leads to the de-inactivation of voltage-gated T-type Ca2+-channels, switching neurons from tonic spiking to a pathological bursting regime. This thalamic bursting synchronises activity on a population level through divergent intrathalamic circuits, and entrains thalamo-cortical pathways by means of propagating low-frequency oscillations beyond the restricted region of the lesion. Hence, pathological stroke-induced thalamo-cortical dynamics can be the source of diaschisis, and account for the dissociation between lesion location and non-specific symptoms of stroke such as neuropathic pain and hemispatial neglect.

Climbing Fiber Regulation of Spontaneous Purkinje Cell Activity and Cerebellum-Dependent Blink Responses(1,2,3).

It has been known for a long time that GABAergic Purkinje cells in the cerebellar cortex, as well as their target neurons in the cerebellar nuclei, are spontaneously active. The cerebellar output will, therefore, depend on how input is integrated into this spontaneous activity. It has been shown that input from climbing fibers originating in the inferior olive controls the spontaneous activity in Purkinje cells. While blocking climbing fiber input to the Purkinje cells causes a dramatic increase in the firing rate, increased climbing fiber activity results in reduced Purkinje cell activity. However, the exact calibration of this regulation has not been examined systematically. Here we examine the relation between climbing fiber stimulation frequency and Purkinje cell activity in unanesthetized decerebrated ferrets. The results revealed a gradual suppression of Purkinje cell activity, starting at climbing fiber stimulation frequencies as low as 0.5 Hz. At 4 Hz, Purkinje cells were completely silenced. This effect lasted an average of 2 min after the stimulation rate was reduced to a lower level. We also examined the effect of sustained climbing fiber stimulation on overt behavior. Specifically, we analyzed conditioned blink responses, which are known to be dependent on the cerebellum, while stimulating the climbing fibers at different frequencies. In accordance with the neurophysiological data, the conditioned blink responses were suppressed at stimulation frequencies of ≥4 Hz.

Purkinje cell activity during classical conditioning with different conditional stimuli explains central tenet of Rescorla­Wagner model [corrected].

A central tenet of Rescorla and Wagner's model of associative learning is that the reinforcement value of a paired trial diminishes as the associative strength between the presented stimuli increases. Despite its fundamental importance to behavioral sciences, the neural mechanisms underlying the model have not been fully explored. Here, we present findings that, taken together, can explain why a stronger association leads to a reduced reinforcement value, within the context of eyeblink conditioning. Specifically, we show that learned pause responses in Purkinje cells, which trigger adaptively timed conditioned eyeblinks, suppress the unconditional stimulus (US) signal in a graded manner. Furthermore, by examining how Purkinje cells respond to two distinct conditional stimuli and to a compound stimulus, we provide evidence that could potentially help explain the somewhat counterintuitive overexpectation phenomenon, which was derived from the Rescorla-Wagner model.

Network dynamics with BrainX(3): a large-scale simulation of the human brain network with real-time interaction.

BrainX(3) is a large-scale simulation of human brain activity with real-time interaction, rendered in 3D in a virtual reality environment, which combines computational power with human intuition for the exploration and analysis of complex dynamical networks. We ground this simulation on structural connectivity obtained from diffusion spectrum imaging data and model it on neuronal population dynamics. Users can interact with BrainX(3) in real-time by perturbing brain regions with transient stimulations to observe reverberating network activity, simulate lesion dynamics or implement network analysis functions from a library of graph theoretic measures. BrainX(3) can thus be used as a novel immersive platform for exploration and analysis of dynamical activity patterns in brain networks, both at rest or in a task-related state, for discovery of signaling pathways associated to brain function and/or dysfunction and as a tool for virtual neurosurgery. Our results demonstrate these functionalities and shed insight on the dynamics of the resting-state attractor. Specifically, we found that a noisy network seems to favor a low firing attractor state. We also found that the dynamics of a noisy network is less resilient to lesions. Our simulations on TMS perturbations show that even though TMS inhibits most of the network, it also sparsely excites a few regions. This is presumably due to anti-correlations in the dynamics and suggests that even a lesioned network can show sparsely distributed increased activity compared to healthy resting-state, over specific brain areas.

Inference of human affective states from psychophysiological measurements extracted under ecologically valid conditions.

Compared to standard laboratory protocols, the measurement of psychophysiological signals in real world experiments poses technical and methodological challenges due to external factors that cannot be directly controlled. To address this problem, we propose a hybrid approach based on an immersive and human accessible space called the eXperience Induction Machine (XIM), that incorporates the advantages of a laboratory within a life-like setting. The XIM integrates unobtrusive wearable sensors for the acquisition of psychophysiological signals suitable for ambulatory emotion research. In this paper, we present results from two different studies conducted to validate the XIM as a general-purpose sensing infrastructure for the study of human affective states under ecologically valid conditions. In the first investigation, we recorded and classified signals from subjects exposed to pictorial stimuli corresponding to a range of arousal levels, while they were free to walk and gesticulate. In the second study, we designed an experiment that follows the classical conditioning paradigm, a well-known procedure in the behavioral sciences, with the additional feature that participants were free to move in the physical space, as opposed to similar studies measuring physiological signals in constrained laboratory settings. Our results indicate that, by using our sensing infrastructure, it is indeed possible to infer human event-elicited affective states through measurements of psychophysiological signals under ecological conditions.

Memory trace and timing mechanism localized to cerebellar Purkinje cells.

The standard view of the mechanisms underlying learning is that they involve strengthening or weakening synaptic connections. Learned response timing is thought to combine such plasticity with temporally patterned inputs to the neuron. We show here that a cerebellar Purkinje cell in a ferret can learn to respond to a specific input with a temporal pattern of activity consisting of temporally specific increases and decreases in firing over hundreds of milliseconds without a temporally patterned input. Training Purkinje cells with direct stimulation of immediate afferents, the parallel fibers, and pharmacological blocking of interneurons shows that the timing mechanism is intrinsic to the cell itself. Purkinje cells can learn to respond not only with increased or decreased firing but also with an adaptively timed activity pattern.

Number of spikes in climbing fibers determines the direction of cerebellar learning.

Cerebellar learning requires context information from mossy fibers and a teaching signal through the climbing fibers from the inferior olive. Although the inferior olive fires in bursts, virtually all studies have used a teaching signal consisting of a single pulse. Following a number of failed attempts to induce cerebellar learning in decerebrate ferrets with a nonburst signal, we tested the effect of varying the number of pulses in the climbing fiber teaching signal. The results show that training with a single pulse in a conditioning paradigm in vivo does not result in learning, but rather causes extinction of a previously learned response.