Oscillatory Waveform Shape and Temporal Spike Correlations Differ across Bat Frontal and Auditory Cortex.

Neural oscillations are associated with diverse computations in the mammalian brain. The waveform shape of oscillatory activity measured in the cortex relates to local physiology and can be informative about aberrant or dynamically changing states. However, how waveform shape differs across distant yet functionally and anatomically related cortical regions is largely unknown. In this study, we capitalize on simultaneous recordings of local field potentials (LFPs) in the auditory and frontal cortices of awake, male Carollia perspicillata bats to examine, on a cycle-by-cycle basis, waveform shape differences across cortical regions. We find that waveform shape differs markedly in the fronto-auditory circuit even for temporally correlated rhythmic activity in comparable frequency ranges (i.e., in the delta and gamma bands) during spontaneous activity. In addition, we report consistent differences between areas in the variability of waveform shape across individual cycles. A conceptual model predicts higher spike-spike and spike-LFP correlations in regions with more asymmetric shapes, a phenomenon that was observed in the data: spike-spike and spike-LFP correlations were higher in the frontal cortex. The model suggests a relationship between waveform shape differences and differences in spike correlations across cortical areas. Altogether, these results indicate that oscillatory activity in the frontal and auditory cortex possesses distinct dynamics related to the anatomical and functional diversity of the fronto-auditory circuit.

Corticospinal excitability is highest at the early rising phase of sensorimotor µ-rhythm.

Alpha oscillations are thought to reflect alternating cortical states of excitation and inhibition. Studies of perceptual thresholds and evoked potentials have shown the scalp EEG negative phase of the oscillation to correspond to a short-lasting low-threshold and high-excitability state of underlying visual, somatosensory, and primary motor cortex. The negative peak of the oscillation is assumed to correspond to the state of highest excitability based on biophysical considerations and considerable effort has been made to improve the extraction of a predictive signal by individually optimizing EEG montages. Here, we investigate whether it is the negative peak of sensorimotor µ-rhythm that corresponds to the highest corticospinal excitability, and whether this is consistent between individuals. In 52 adult participants, a standard 5-channel surface Laplacian EEG montage was used to extract sensorimotor µ-rhythm during transcranial magnetic stimulation (TMS) of primary motor cortex. Post-hoc trials were sorted from 800 TMS-evoked motor potentials (MEPs) according to the pre-stimulus EEG (estimated instantaneous phase) and MEP amplitude (as an index of corticospinal excitability). Different preprocessing transformations designed to improve the accuracy by which µ-alpha phase predicts excitability were also tested. By fitting a sinusoid to the MEP amplitudes, sorted according to pre-stimulus EEG-phase, we found that excitability was highest during the early rising phase, at a significant delay with respect to the negative peak by on average 45° or 10 ms. The individual phase of highest excitability was consistent across study participants and unaffected by two different EEG-cleaning methods that utilize 64 channels to improve signal quality by compensating for individual noise level and channel covariance. Personalized transformations of the montage did not yield better prediction of excitability from µ-alpha phase. The relationship between instantaneous phase of a brain oscillation and fluctuating cortical excitability appears to be more complex than previously hypothesized. In TMS of motor cortex, a standard surface Laplacian 5-channel EEG montage is effective in extracting a predictive signal and the phase corresponding to the highest excitability appears to be consistent between individuals. This is an encouraging result with respect to the clinical potential of therapeutic personalized brain interventions in the motor system. However, it remains to be investigated, whether similar results can be obtained for other brain areas and brain oscillations targeted with EEG and TMS.

Is sensor space analysis good enough? Spatial patterns as a tool for assessing spatial mixing of EEG/MEG rhythms.

Analyzing non-invasive recordings of electroencephalography (EEG) and magnetoencephalography (MEG) directly in sensor space, using the signal from individual sensors, is a convenient and standard way of working with this type of data. However, volume conduction introduces considerable challenges for sensor space analysis. While the general idea of signal mixing due to volume conduction in EEG/MEG is recognized, the implications have not yet been clearly exemplified. Here, we illustrate how different types of activity overlap on the level of individual sensors. We show spatial mixing in the context of alpha rhythms, which are known to have generators in different areas of the brain. Using simulations with a realistic 3D head model and lead field and data analysis of a large resting-state EEG dataset, we show that electrode signals can be differentially affected by spatial mixing by computing a sensor complexity measure. While prominent occipital alpha rhythms result in less heterogeneous spatial mixing on posterior electrodes, central electrodes show a diversity of rhythms present. This makes the individual contributions, such as the sensorimotor mu-rhythm and temporal alpha rhythms, hard to disentangle from the dominant occipital alpha. Additionally, we show how strong occipital rhythms can contribute the majority of activity to frontal channels, potentially compromising analyses that are solely conducted in sensor space. We also outline specific consequences of signal mixing for frequently used assessment of power, power ratios and connectivity profiles in basic research and for neurofeedback application. With this work, we hope to illustrate the effects of volume conduction in a concrete way, such that the provided practical illustrations may be of use to EEG researchers to in order to evaluate whether sensor space is an appropriate choice for their topic of investigation.

Methodological considerations for studying neural oscillations.

Neural oscillations are ubiquitous across recording methodologies and species, broadly associated with cognitive tasks, and amenable to computational modelling that investigates neural circuit generating mechanisms and neural population dynamics. Because of this, neural oscillations offer an exciting potential opportunity for linking theory, physiology and mechanisms of cognition. However, despite their prevalence, there are many concerns-new and old-about how our analysis assumptions are violated by known properties of field potential data. For investigations of neural oscillations to be properly interpreted, and ultimately developed into mechanistic theories, it is necessary to carefully consider the underlying assumptions of the methods we employ. Here, we discuss seven methodological considerations for analysing neural oscillations. The considerations are to (1) verify the presence of oscillations, as they may be absent; (2) validate oscillation band definitions, to address variable peak frequencies; (3) account for concurrent non-oscillatory aperiodic activity, which might otherwise confound measures; measure and account for (4) temporal variability and (5) waveform shape of neural oscillations, which are often bursty and/or nonsinusoidal, potentially leading to spurious results; (6) separate spatially overlapping rhythms, which may interfere with each other; and (7) consider the required signal-to-noise ratio for obtaining reliable estimates. For each topic, we provide relevant examples, demonstrate potential errors of interpretation, and offer suggestions to address these issues. We primarily focus on univariate measures, such as power and phase estimates, though we discuss how these issues can propagate to multivariate measures. These considerations and recommendations offer a helpful guide for measuring and interpreting neural oscillations.

Enhancing oscillations in intracranial electrophysiological recordings with data-driven spatial filters.

In invasive electrophysiological recordings, a variety of neural oscillations can be detected across the cortex, with overlap in space and time. This overlap complicates measurement of neural oscillations using standard referencing schemes, like common average or bipolar referencing. Here, we illustrate the effects of spatial mixing on measuring neural oscillations in invasive electrophysiological recordings and demonstrate the benefits of using data-driven referencing schemes in order to improve measurement of neural oscillations. We discuss referencing as the application of a spatial filter. Spatio-spectral decomposition is used to estimate data-driven spatial filters, a computationally fast method which specifically enhances signal-to-noise ratio for oscillations in a frequency band of interest. We show that application of these data-driven spatial filters has benefits for data exploration, investigation of temporal dynamics and assessment of peak frequencies of neural oscillations. We demonstrate multiple use cases, exploring between-participant variability in presence of oscillations, spatial spread and waveform shape of different rhythms as well as narrowband noise removal with the aid of spatial filters. We find high between-participant variability in the presence of neural oscillations, a large variation in spatial spread of individual rhythms and many non-sinusoidal rhythms across the cortex. Improved measurement of cortical rhythms will yield better conditions for establishing links between cortical activity and behavior, as well as bridging scales between the invasive intracranial measurements and noninvasive macroscale scalp measurements.

Longitudinal changes in aperiodic and periodic activity in electrophysiological recordings in the first seven months of life.

Neuronal oscillations emerge in early human development. These periodic oscillations are thought to rapidly change in infancy and stabilize during maturity. Given their numerous connections to physiological and cognitive processes, understanding the trajectory of oscillatory development is important for understanding healthy human brain development. This understanding is complicated by recent evidence that assessment of periodic neuronal oscillations is confounded by aperiodic neuronal activity, an inherent feature of electrophysiological recordings. Recent cross-sectional evidence shows that this aperiodic signal progressively shifts from childhood through early adulthood, and from early adulthood into later life. None of these studies, however, have been performed in infants, nor have they been examined longitudinally. Here, we analyzed longitudinal non-invasive EEG data from 22 typically developing infants, ranging between 38 and 203 days old. We show that the progressive flattening of the EEG power spectrum begins in very early development, continuing through the first months of life. These results highlight the importance of separating the periodic and aperiodic neuronal signals, because the aperiodic signal can bias measurement of neuronal oscillations. Given the infrequent, bursting nature of oscillations in infants, we recommend using quantitative time domain approaches that isolate bursts and uncover changes in waveform properties of oscillatory bursts.

Spatial neuronal synchronization and the waveform of oscillations: Implications for EEG and MEG.

Neuronal oscillations are ubiquitous in the human brain and are implicated in virtually all brain functions. Although they can be described by a prominent peak in the power spectrum, their waveform is not necessarily sinusoidal and shows rather complex morphology. Both frequency and temporal descriptions of such non-sinusoidal neuronal oscillations can be utilized. However, in non-invasive EEG/MEG recordings the waveform of oscillations often takes a sinusoidal shape which in turn leads to a rather oversimplified view on oscillatory processes. In this study, we show in simulations how spatial synchronization can mask non-sinusoidal features of the underlying rhythmic neuronal processes. Consequently, the degree of non-sinusoidality can serve as a measure of spatial synchronization. To confirm this empirically, we show that a mixture of EEG components is indeed associated with more sinusoidal oscillations compared to the waveform of oscillations in each constituent component. Using simulations, we also show that the spatial mixing of the non-sinusoidal neuronal signals strongly affects the amplitude ratio of the spectral harmonics constituting the waveform. Finally, our simulations show how spatial mixing can affect the strength and even the direction of the amplitude coupling between constituent neuronal harmonics at different frequencies. Validating these simulations, we also demonstrate these effects in real EEG recordings. Our findings have far reaching implications for the neurophysiological interpretation of spectral profiles, cross-frequency interactions, as well as for the unequivocal determination of oscillatory phase.

EEG-triggered TMS reveals stronger brain state-dependent modulation of motor evoked potentials at weaker stimulation intensities.

BACKGROUND: Corticospinal excitability depends on the current brain state. The recent development of real-time EEG-triggered transcranial magnetic stimulation (EEG-TMS) allows studying this relationship in a causal fashion. Specifically, it has been shown that corticospinal excitability is higher during the scalp surface negative EEG peak compared to the positive peak of µ-oscillations in sensorimotor cortex, as indexed by larger motor evoked potentials (MEPs) for fixed stimulation intensity. OBJECTIVE: We further characterize the effect of µ-rhythm phase on the MEP input-output (IO) curve by measuring the degree of excitability modulation across a range of stimulation intensities. We furthermore seek to optimize stimulation parameters to enable discrimination of functionally relevant EEG-defined brain states. METHODS: A real-time EEG-TMS system was used to trigger MEPs during instantaneous brain-states corresponding to µ-rhythm surface positive and negative peaks with five different stimulation intensities covering an individually calibrated MEP IO curve in 15 healthy participants. RESULTS: MEP amplitude is modulated by µ-phase across a wide range of stimulation intensities, with larger MEPs at the surface negative peak. The largest relative MEP-modulation was observed for weak intensities, the largest absolute MEP-modulation for intermediate intensities. These results indicate a leftward shift of the MEP IO curve during the µ-rhythm negative peak. CONCLUSION: The choice of stimulation intensity influences the observed degree of corticospinal excitability modulation by µ-phase. Lower stimulation intensities enable more efficient differentiation of EEG µ-phase-defined brain states.

Simulation of electromyographic recordings following transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is a technique that enables noninvasive manipulation of neural activity and holds promise in both clinical and basic research settings. The effect of TMS on the motor cortex is often measured by electromyography (EMG) recordings from a small hand muscle. However, the details of how TMS generates responses measured with EMG are not completely understood. We aim to develop a biophysically detailed computational model to study the potential mechanisms underlying the generation of EMG signals following TMS. Our model comprises a feed-forward network of cortical layer 2/3 cells, which drive morphologically detailed layer 5 corticomotoneuronal cells, which in turn project to a pool of motoneurons. EMG signals are modeled as the sum of motor unit action potentials. EMG recordings from the first dorsal interosseous muscle were performed in four subjects and compared with simulated EMG signals. Our model successfully reproduces several characteristics of the experimental data. The simulated EMG signals match experimental EMG recordings in shape and size, and change with stimulus intensity and contraction level as in experimental recordings. They exhibit cortical silent periods that are close to the biological values and reveal an interesting dependence on inhibitory synaptic transmission properties. Our model predicts several characteristics of the firing patterns of neurons along the entire pathway from cortical layer 2/3 cells down to spinal motoneurons and should be considered as a viable tool for explaining and analyzing EMG signals following TMS. NEW & NOTEWORTHY A biophysically detailed model of EMG signal generation following transcranial magnetic stimulation (TMS) is proposed. Simulated EMG signals match experimental EMG recordings in shape and amplitude. Motor-evoked potential and cortical silent period properties match experimental data. The model is a viable tool to analyze, explain, and predict EMG signals following TMS.

Ongoing brain rhythms shape I-wave properties in a computational model.

BACKGROUND: Responses to transcranial magnetic stimulation (TMS) are notoriously variable. Previous studies have observed a dependence of TMS-induced responses on ongoing brain activity, for instance sensorimotor rhythms. This suggests an opportunity for the development of more effective stimulation protocols through closed-loop TMS-EEG. However, it is not yet clear how features of ongoing activity affect the responses of cortical circuits to TMS. OBJECTIVE/HYPOTHESIS: Here we investigate the dependence of TMS-responses on power and phase of ongoing oscillatory activity in a computational model of TMS-induced I-waves. METHODS: The model comprises populations of cortical layer 2/3 (L2/3) neurons and a population of cortical layer 5 (L5) neurons and generates I-waves in response to TMS. Oscillatory input to the L2/3 neurons induces rhythmic fluctuations in activity of L5 neurons. TMS pulses are simulated at different phases and amplitudes of the ongoing rhythm. RESULTS: The model shows a robust dependence of I-wave properties on phase and power of ongoing rhythms, with the strongest response occurring for TMS at maximal L5 depolarization. The amount of phase-modulation depends on stimulation intensity, with stronger modulation for lower intensity. CONCLUSION: The model predicts that responses to TMS are highly variable for low stimulation intensities if ongoing brain rhythms are not taken into account. Closed-loop TMS-EEG holds promise for obtaining more reliable TMS effects.

µ-Rhythm Extracted With Personalized EEG Filters Correlates With Corticospinal Excitability in Real-Time Phase-Triggered EEG-TMS.

Ongoing brain activity has been implicated in the modulation of cortical excitability. The combination of electroencephalography (EEG) and transcranial magnetic stimulation (TMS) in a real-time triggered setup is a novel method for testing hypotheses about the relationship between spontaneous neuronal oscillations, cortical excitability, and synaptic plasticity. For this method, a reliable real-time extraction of the neuronal signal of interest from scalp EEG with high signal-to-noise ratio (SNR) is of crucial importance. Here we compare individually tailored spatial filters as computed by spatial-spectral decomposition (SSD), which maximizes SNR in a frequency band of interest, against established local C3-centered Laplacian filters for the extraction of the sensorimotor µ-rhythm. Single-pulse TMS over the left primary motor cortex was synchronized with the surface positive or negative peak of the respective extracted signal, and motor evoked potentials (MEP) were recorded with electromyography (EMG) of a contralateral hand muscle. Both extraction methods led to a comparable degree of MEP amplitude modulation by phase of the sensorimotor µ-rhythm at the time of stimulation. This could be relevant for targeting other brain regions with no working benchmark such as the local C3-centered Laplacian filter, as sufficient SNR is an important prerequisite for reliable real-time single-trial detection of EEG features.

A multi-scale computational model of the effects of TMS on motor cortex.

The detailed biophysical mechanisms through which transcranial magnetic stimulation (TMS) activates cortical circuits are still not fully understood. Here we present a multi-scale computational model to describe and explain the activation of different pyramidal cell types in motor cortex due to TMS. Our model determines precise electric fields based on an individual head model derived from magnetic resonance imaging and calculates how these electric fields activate morphologically detailed models of different neuron types. We predict neural activation patterns for different coil orientations consistent with experimental findings. Beyond this, our model allows us to calculate activation thresholds for individual neurons and precise initiation sites of individual action potentials on the neurons' complex morphologies. Specifically, our model predicts that cortical layer 3 pyramidal neurons are generally easier to stimulate than layer 5 pyramidal neurons, thereby explaining the lower stimulation thresholds observed for I-waves compared to D-waves. It also shows differences in the regions of activated cortical layer 5 and layer 3 pyramidal cells depending on coil orientation. Finally, it predicts that under standard stimulation conditions, action potentials are mostly generated at the axon initial segment of cortical pyramidal cells, with a much less important activation site being the part of a layer 5 pyramidal cell axon where it crosses the boundary between grey matter and white matter. In conclusion, our computational model offers a detailed account of the mechanisms through which TMS activates different cortical pyramidal cell types, paving the way for more targeted application of TMS based on individual brain morphology in clinical and basic research settings.

Power-law dynamics in neuronal and behavioral data introduce spurious correlations.

Relating behavioral and neuroimaging measures is essential to understanding human brain function. Often, this is achieved by computing a correlation between behavioral measures, e.g., reaction times, and neurophysiological recordings, e.g., prestimulus EEG alpha-power, on a single-trial-basis. This approach treats individual trials as independent measurements and ignores the fact that data are acquired in a temporal order. It has already been shown that behavioral measures as well as neurophysiological recordings display power-law dynamics, which implies that trials are not in fact independent. Critically, computing the correlation coefficient between two measures exhibiting long-range temporal dependencies may introduce spurious correlations, thus leading to erroneous conclusions about the relationship between brain activity and behavioral measures. Here, we address data-analytic pitfalls which may arise when long-range temporal dependencies in neural as well as behavioral measures are ignored. We quantify the influence of temporal dependencies of neural and behavioral measures on the observed correlations through simulations. Results are further supported in analysis of real EEG data recorded in a simple reaction time task, where the aim is to predict the latency of responses on the basis of prestimulus alpha oscillations. We show that it is possible to "predict" reaction times from one subject on the basis of EEG activity recorded in another subject simply owing to the fact that both measures display power-law dynamics. The same is true when correlating EEG activity obtained from different subjects. A surrogate-data procedure is described which correctly tests for the presence of correlation while controlling for the effect of power-law dynamics.