Weakly Correlated Local Cortical State Switches under Anesthesia Lead to Strongly Correlated Global States.

During recovery from anesthesia, brain activity switches abruptly between a small set of discrete states. Surprisingly, this switching also occurs under constant doses of anesthesia, even in the absence of stimuli. These metastable states and the transitions between them are thought to form a "scaffold" that ultimately guides the brain back to wakefulness. The processes that constrain cortical activity patterns to these states and govern how states are coordinated between different cortical regions are unknown. If state transitions were driven by subcortical modulation, different cortical sites should exhibit near-synchronous state transitions. Conversely, spatiotemporal heterogeneity would suggest that state transitions are coordinated through corticocortical interactions. To differentiate between these hypotheses, we quantified synchrony of brain states in male rats exposed to a fixed isoflurane concentration. States were defined from spectra of local field potentials recorded across layers of visual and motor cortices. A transition synchrony measure shows that most state transitions are highly localized. Furthermore, while most pairs of cortical sites exhibit statistically significant coupling of both states and state transition times, coupling strength is typically weak. States and state transitions in the thalamic input layer (L4) are particularly decoupled from those in supragranular and infragranular layers. This suggests that state transitions are not imposed on the cortex by broadly projecting modulatory systems. Although each pairwise interaction is typically weak, we show that the multitude of such weak interactions is sufficient to confine global activity to a small number of discrete states.SIGNIFICANCE STATEMENT The brain consistently recovers to wakefulness after anesthesia, but this process is poorly understood. Previous work revealed that, during recovery from anesthesia, corticothalamic activity falls into one of several discrete patterns. The neuronal mechanisms constraining the cortex to just a few discrete states remain unknown. Global states could be coordinated by fluctuations in subcortical nuclei that project broadly to the cortex. Alternatively, these states may emerge from interactions within the cortex itself. Here, we provide evidence for the latter possibility by demonstrating that most pairs of cortical sites exhibit weak coupling. We thereby lay groundwork for future investigations of the specific cellular and network mechanisms of corticocortical activity state coupling.

Toolkit for Oscillatory Real-time Tracking and Estimation (TORTE).

BACKGROUND: Closing the loop between brain activity and behavior is one of the most active areas of development in neuroscience. There is particular interest in developing closed-loop control of neural oscillations. Many studies report correlations between oscillations and functional processes. Oscillation-informed closed-loop experiments might determine whether these relationships are causal and would provide important mechanistic insights which may lead to new therapeutic tools. These closed-loop perturbations require accurate estimates of oscillatory phase and amplitude, which are challenging to compute in real time. NEW METHOD: We developed an easy to implement, fast and accurate Toolkit for Oscillatory Real-time Tracking and Estimation (TORTE). TORTE operates with the open-source Open Ephys GUI (OEGUI) system, making it immediately compatible with a wide range of acquisition systems and experimental preparations. RESULTS: TORTE efficiently extracts oscillatory phase and amplitude from a target signal and includes a variety of options to trigger closed-loop perturbations. Implementing these tools into existing experiments is easy and adds minimal latency to existing protocols. COMPARISON WITH EXISTING METHODS: Most labs use in-house lab-specific approaches, limiting replication and extension of their experiments by other groups. Accuracy of the extracted analytic signal and accuracy of oscillation-informed perturbations with TORTE match presented results by these groups. However, TORTE provides access to these tools in a flexible, easy to use toolkit without requiring proprietary software. CONCLUSION: We hope that the availability of a high-quality, open-source, and broadly applicable toolkit will increase the number of labs able to perform oscillatory closed-loop experiments, and will improve the replicability of protocols and data across labs.

A statistical framework to assess cross-frequency coupling while accounting for confounding analysis effects.

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.