Search

Rolandic epilepsy is the most common form of epileptic encephalopathy, characterized by sleep-potentiated inferior Rolandic epileptiform spikes, seizures, and cognitive deficits in school-age children that spontaneously resolve by adolescence. We recently identified a paucity of sleep spindles, physiological thalamocortical rhythms associated with sleep-dependent learning, in the Rolandic cortex during the active phase of this disease. Because spindles are generated in the thalamus and amplified through regional thalamocortical circuits, we hypothesized that: 1) deficits in spindle rate would involve but extend beyond the inferior Rolandic cortex in active epilepsy and 2) regional spindle deficits would better predict cognitive function than inferior Rolandic spindle deficits alone. To test these hypotheses, we obtained high-resolution MRI, high-density EEG recordings, and focused neuropsychological assessments in children with Rolandic epilepsy during active (n = 8, age 9–14.7 years, 3F) and resolved (seizure free for > 1 year, n = 10, age 10.3–16.7 years, 1F) stages of disease and age-matched controls (n = 8, age 8.9–14.5 years, 5F). Using a validated spindle detector applied to estimates of electrical source activity in 31 cortical regions, including the inferior Rolandic cortex, during stages 2 and 3 of non-rapid eye movement sleep, we compared spindle rates in each cortical region across groups. Among detected spindles, we compared spindle features (power, duration, coherence, bilateral synchrony) between groups. We then used regression models to examine the relationship between spindle rate and cognitive function (fine motor dexterity, phonological processing, attention, and intelligence, and a global measure of all functions). We found that spindle rate was reduced in the inferior Rolandic cortices in active but not resolved disease (active P = 0.007; resolved P = 0.2) compared to controls. Spindles in this region were less synchronous between hemispheres in the active group (P = 0.005; resolved P = 0.1) compared to controls; but there were no differences in spindle power, duration, or coherence between groups. Compared to controls, spindle rate in the active group was also reduced in the prefrontal, insular, superior temporal, and posterior parietal regions (i.e., “regional spindle rate”, P

Epilepsy biomarkers from electroencephalogram recordings are routinely used to assess seizure risk and localization. Two widely adopted biomarkers include: (i) interictal spikes, and (ii) high frequency ripple oscillations. The combination of these two biomarkers, ripples co-occurring with spikes (spike ripples), has been proposed as an improved biomarker for the epileptogenic zone and epileptogenicity in humans and rodent models. Whether spike ripples translate to predict seizure risk in rodent seizure models is unknown. Further, recent evidence suggests ictal networks can include deep gray nuclei in humans. Whether pathologic spike ripples and seizures are also observed in the basal ganglia in rodent models has not been explored. We addressed these questions using local field potential recordings from mice with and without striatal seizures after carbachol or 6-hydroxydopamine infusions into the striatum. We found increased spike ripples in the interictal and ictal periods in mice with seizures compared to pre-infusion and post-infusion seizure-free recordings. These data provide evidence of electrographic seizures involving the striatum in mice and support the candidacy of spike ripples as a translational biomarker for seizure risk in mouse models.

Representations related to past experiences play a critical role in memory and decision-making processes. The rat hippocampus expresses these types of representations during sharp-wave ripple (SWR) events, and previous work identified a minority of SWRs that contain ‘replay’ of spatial trajectories at ∼20x the movement speed of the animal. Efforts to understand replay typically make multiple assumptions about which events to examine and what sorts of representations constitute replay. We therefore lack a clear understanding of both the prevalence and the range of representational dynamics associated with replay. Here, we develop a state space model that uses a combination of movement dynamics of different speeds to capture the spatial content and time evolution of replay during SWRs. Using this model, we find that the large majority of replay events contain spatially coherent, interpretable content. Furthermore, many events progress at real-world, rather than accelerated, movement speeds, consistent with actual experiences.

Brain rhythms have been proposed to facilitate brain function, with an especially important role attributed to the phase of low-frequency rhythms. Understanding the role of phase in neural function requires interventions that perturb neural activity at a target phase, necessitating estimation of phase in real-time. Current methods for real-time phase estimation rely on bandpass filtering, which assumes narrowband signals and couples the signal and noise in the phase estimate, adding noise to the phase and impairing detections of relationships between phase and behavior. To address this, we propose a state space phase estimator for real-time tracking of phase. By tracking the analytic signal as a latent state, this framework avoids the requirement of bandpass filtering, separately models the signal and the noise, accounts for rhythmic confounds, and provides credible intervals for the phase estimate. We demonstrate in simulations that the state space phase estimator outperforms current state-of-the-art real-time methods in the contexts of common confounds such as broadband rhythms, phase resets, and co-occurring rhythms. Finally, we show applications of this approach to in vivo data. The method is available as a ready-to-use plug-in for the Open Ephys acquisition system, making it widely available for use in experiments.

Censored data occur commonly in trial-structured behavioral experiments and many other forms of longitudinal data. They can lead to severe bias and reduction of statistical power in subsequent analyses. Principled approaches for dealing with censored data, such as data imputation and methods based on the complete data’s likelihood, work well for estimating fixed features of statistical models but have not been extended to dynamic measures, such as serial estimates of an underlying latent variable over time. Here we propose an approach to the censored-data problem for dynamic behavioral signals. We developed a state-space modeling framework with a censored observation process at the trial timescale. We then developed a filter algorithm to compute the posterior distribution of the state process using the available data. We showed that special cases of this framework can incorporate the three most common approaches to censored observations: ignoring trials with censored data, imputing the censored data values, or using the full information available in the data likelihood. Finally, we derived a computationally efficient approximate Gaussian filter that is similar in structure to a Kalman filter, but that efficiently accounts for censored data. We compared the performances of these methods in a simulation study and provide recommendations of approaches to use, based on the expected amount of censored data in an experiment. These new techniques can broadly be applied in many research domains in which censored data interfere with estimation, including survival analysis and other clinical trial applications.

The authors record both local and long-range neural activity during human epileptic seizures to study the underlying multi-scale dynamics. They find that coupling of activity across spatial scales increases during seizures through propagating waves that are fit by a model that combines neural activity and potassium concentration dynamics.

Cross frequency coupling (CFC) is emerging as a fundamental feature of brain activity, correlated with brain function and dysfunction. Many different types of CFC have been identified through application of numerous data analysis methods, each developed to characterize a specific CFC type. Choosing an inappropriate method weakens statistical power and introduces opportunities for confounding effects. To address this, we propose a statistical modeling framework to estimate high frequency amplitude as a function of both the low frequency amplitude and low frequency phase; the result is a measure of phase-amplitude coupling that accounts for changes in the low frequency amplitude. We show in simulations that the proposed method successfully detects CFC between the low frequency phase or amplitude and the high frequency amplitude, and outperforms an existing method in biologically-motivated examples. Applying the method to in vivo data, we illustrate examples of CFC during a seizure and in response to electrical stimuli.

Mathematical modeling of behavior during a psychophysical task, referred to as “computational psychiatry,” could greatly improve our understanding of mental disorders. One barrier to the broader adoption of computational methods, is that they often require advanced statistical modeling and mathematical skills. Biological and behavioral signals often show skewed or non-Gaussian distributions, and very few toolboxes and analytical platforms are capable of processing such signal categories. We developed the Computational Psychiatry Adaptive State-Space (COMPASS) toolbox, an open-source MATLAB-based software package. This toolbox is easy to use and capable of integrating signals with a variety of distributions. COMPASS has the tools to process signals with continuous-valued and binary measurements, or signals with incomplete—missing or censored—measurements, which makes it well-suited for processing those signals captured during a psychophysical task. After specifying a few parameters in a small set of user-friendly functions, COMPASS allows users to efficiently apply a wide range of computational behavioral models. The model output can be analyzed as an experimental outcome or used as a regressor for neural data and can also be tested using the goodness-of-fit measurement. Here, we demonstrate that COMPASS can replicate two computational behavioral analyses from different groups. COMPASS replicates and can slightly improve on the original modeling results. We also demonstrate the use of COMPASS application in a censored-data problem and compare its performance result with naïve estimation methods. This flexible, general-purpose toolkit should accelerate the use of computational modeling in psychiatric neuroscience.