Elliot H. Smith

The ictal wavefront is the spatiotemporal source of discharges during spontaneous human seizures

The extensive distribution and simultaneous termination of seizures across cortical areas has led to the hypothesis that seizures are caused by large-scale coordinated networks spanning these areas. This view, however, is difficult to reconcile with most proposed mechanisms of seizure spread and termination, which operate on a cellular scale. We hypothesize that seizures evolve into self-organized structures wherein a small seizing territory projects high-intensity electrical signals over a broad cortical area. Here we investigate human seizures on both small and large electrophysiological scales. We show that the migrating edge of the seizing territory is the source of travelling waves of synaptic activity into adjacent cortical areas. As the seizure progresses, slow dynamics in induced activity from these waves indicate a weakening and eventual failure of their source. These observations support a parsimonious theory for how large-scale evolution and termination of seizures are driven from a small, migrating cortical area.

Single unit action potentials in humans and the effect of seizure activity.

See Kimchi and Cash (doi:10.1093/awv264) for a scientific commentary on this article. In patients undergoing surgical evaluation of focal neocortical epilepsies, Merricks et al. perform the first single-unit recordings of neurons in the ictal core and contrast their activity patterns with those of the penumbra. Single-unit spiking recovers rapidly after seizure termination, suggesting a network rather than cellular cause of post-ictal dysfunction.

Frequency-Dependent Representation of Reinforcement-Related Information in the Human Medial and Lateral Prefrontal Cortex.

The feedback-related negativity (FRN) is a commonly observed potential in scalp electroencephalography (EEG) studies related to the valence of feedback about a subjects performance. This potential classically manifests as a negative deflection in medial frontocentral EEG contacts following negative feedback. Recent work has shown prominence of theta power in the spectral composition of the FRN, placing it within the larger class of “frontal midline theta” cognitive control signals. Although the dorsal anterior cingulate cortex (dACC) is thought to be the cortical generator of the FRN, conclusive data regarding its origin and propagation are lacking. Here we examine intracranial electrophysiology from the human medial and lateral prefrontal cortex (PFC) to better understand the anatomical localization and communication patterns of the FRN. We show that the FRN is evident in both low- and high-frequency local field potentials (LFPs) recorded on electrocorticography. The FRN is larger in medial compared with lateral PFC, and coupling between theta band phase and high-frequency LFP power is also greater in medial PFC. Using Granger causality and conditional mutual information analyses, we provide evidence that feedback-related information propagates from medial to lateral PFC, and that this information transfer oscillates with theta-range periodicity. These results provide evidence for the dACC as the cortical source of the FRN, provide insight into the local computation of frontal midline theta, and have implications for reinforcement learning models of cognitive control. SIGNIFICANCE STATEMENT Using intracranial electrophysiology in humans, this work addresses questions about a frequently studied feedback-related electroencephalographic signal, illuminating anatomical and functional properties of the representation of feedback-related reinforcement during decision-making across the medial to lateral extent of the human prefrontal cortex.

Seeing is believing: neural representations of visual stimuli in human auditory cortex correlate with illusory auditory perceptions.

In interpersonal communication, the listener can often see as well as hear the speaker. Visual stimuli can subtly change a listener’s auditory perception, as in the McGurk illusion, in which perception of a phoneme’s auditory identity is changed by a concurrent video of a mouth articulating a different phoneme. Studies have yet to link visual influences on the neural representation of language with subjective language perception. Here we show that vision influences the electrophysiological representation of phonemes in human auditory cortex prior to the presentation of the auditory stimulus. We used the McGurk effect to dissociate the subjective perception of phonemes from the auditory stimuli. With this paradigm we demonstrate that neural representations in auditory cortex are more closely correlated with the visual stimuli of mouth articulation, which drive the illusory subjective auditory perception, than the actual auditory stimuli. Additionally, information about visual and auditory stimuli transfer in the caudal–rostral direction along the superior temporal gyrus during phoneme perception as would be expected of visual information flowing from the occipital cortex into the ventral auditory processing stream. These results show that visual stimuli influence the neural representation in auditory cortex early in sensory processing and may override the subjective auditory perceptions normally generated by auditory stimuli. These findings depict a marked influence of vision on the neural processing of audition in tertiary auditory cortex and suggest a mechanistic underpinning for the McGurk effect.

Toward a Mechanistic Understanding of Epileptic Networks.

Focal epileptic seizures have long been considered to arise from a small susceptible brain area and spread through uninvolved regions. In the past decade, the idea that focal seizures instead arise from coordinated activity across large-scale epileptic networks has become widely accepted. Understanding the network model’s applicability is critical, due to its increasing influence on clinical research and surgical treatment paradigms. In this review, we examine the origins of the concept of epileptic networks as the nidus for recurring seizures. We summarize analytical and methodological elements of epileptic network studies and discuss findings from recent detailed electrophysiological investigations. Our review highlights the strengths and limitations of the epileptic network theory as a metaphor for the complex interactions that occur during seizures. We present lines of investigation that may usefully probe these interactions and thus serve to advance our understanding of the long-range effects of epileptiform activity.

Decoding stimulus identity from multi-unit activity and local field potentials along the ventral auditory stream in the awake primate: implications for cortical neural prostheses

OBJECTIVE Hierarchical processing of auditory sensory information is believed to occur in two streams: a ventral stream responsible for stimulus identity and a dorsal stream responsible for processing spatial elements of a stimulus. The objective of the current study is to examine neural coding in this processing stream in the context of understanding the possibility for an auditory cortical neural prosthesis. APPROACH We examined the selectivity for species-specific primate vocalizations in the ventral auditory processing stream by applying a statistical classifier to neural data recorded from microelectrode arrays. Multi-unit activity (MUA) and local field potential (LFP) data recorded simultaneously from primary auditory complex (AI) and rostral parabelt (PBr) were decoded on a trial-by-trial basis. MAIN RESULTS While decode performance in AI was well above chance, mean performance in PBr did not deviate >15% from chance level. Mean performance levels were similar for MUA and LFP decodes. Increasing the spectral and temporal resolution improved decode performance; while inter-electrode spacing could be as large as 1.14 mm without degrading decode performance. SIGNIFICANCE These results serve as preliminary guidance for a human auditory cortical neural prosthesis; instructing interface implementation, microstimulation patterns and anatomical placement.

Multiscale Aspects of Generation of High-Gamma Activity during Seizures in Human Neocortex

Visual Abstract High-gamma (HG; 80-150 Hz) activity in macroscopic clinical records is considered a marker for critical brain regions involved in seizure initiation; it is correlated with pathological multiunit firing during neocortical seizures in the seizure core, an area identified by correlated multiunit spiking and low frequency seizure activity. High-gamma (HG; 80-150 Hz) activity in macroscopic clinical records is considered a marker for critical brain regions involved in seizure initiation; it is correlated with pathological multiunit firing during neocortical seizures in the seizure core, an area identified by correlated multiunit spiking and low frequency seizure activity. However, the effects of the spatiotemporal dynamics of seizure on HG power generation are not well understood. Here, we studied HG generation and propagation, using a three-step, multiscale signal analysis and modeling approach. First, we analyzed concurrent neuronal and microscopic network HG activity in neocortical slices from seven intractable epilepsy patients. We found HG activity in these networks, especially when neurons displayed paroxysmal depolarization shifts and network activity was highly synchronized. Second, we examined HG activity acquired with microelectrode arrays recorded during human seizures (n = 8). We confirmed the presence of synchronized HG power across microelectrode records and the macroscale, both specifically associated with the core region of the seizure. Third, we used volume conduction-based modeling to relate HG activity and network synchrony at different network scales. We showed that local HG oscillations require high levels of synchrony to cross scales, and that this requirement is met at the microscopic scale, but not within macroscopic networks. Instead, we present evidence that HG power at the macroscale may result from harmonics of ongoing seizure activity. Ictal HG power marks the seizure core, but the generating mechanism can differ across spatial scales.

Lateralized hippocampal oscillations underlie distinct aspects of human spatial memory and navigation

The hippocampus plays a vital role in various aspects of cognition including both memory and spatial navigation. To understand electrophysiologically how the hippocampus supports these processes, we recorded intracranial electroencephalographic activity from 46 neurosurgical patients as they performed a spatial memory task. We measure signals from multiple brain regions, including both left and right hippocampi, and we use spectral analysis to identify oscillatory patterns related to memory encoding and navigation. We show that in the left but not right hippocampus, the amplitude of oscillations in the 1–3-Hz “low theta” band increases when viewing subsequently remembered object–location pairs. In contrast, in the right but not left hippocampus, low-theta activity increases during periods of navigation. The frequencies of these hippocampal signals are slower than task-related signals in the neocortex. These results suggest that the human brain includes multiple lateralized oscillatory networks that support different aspects of cognition.Theta oscillations are implicated in memory formation. Here, the authors show that low-theta oscillations in the hippocampus are differentially modulated between each hemisphere, with oscillations in the left increasing when successfully learning object–location pairs and in the right during spatial navigation.

Role of inhibitory control in modulating focal seizure spread

Focal seizure propagation is classically thought to be spatially contiguous. However, distribution of seizures through a large-scale epileptic network has been theorized. Here, we used a multielectrode array, wide field calcium imaging, and two-photon calcium imaging to study focal seizure propagation pathways in an acute rodent neocortical 4-aminopyridine model. Although ictal neuronal bursts did not propagate beyond a 2-3-mm region, they were associated with hemisphere-wide field potential fluctuations and parvalbumin-positive interneuron activity outside the seizure focus. While bicuculline surface application enhanced contiguous seizure propagation, focal bicuculline microinjection at sites distant to the 4-aminopyridine focus resulted in epileptic network formation with maximal activity at the two foci. Our study suggests that both classical and epileptic network propagation can arise from localized inhibition defects, and that the network appearance can arise in the context of normal brain structure without requirement for pathological connectivity changes between sites.

Multivariate regression methods for estimating velocity of ictal discharges from human microelectrode recordings

OBJECTIVE Epileptiform discharges, an electrophysiological hallmark of seizures, can propagate across cortical tissue in a manner similar to traveling waves. Recent work has focused attention on the origination and propagation patterns of these discharges, yielding important clues to their source location and mechanism of travel. However, systematic studies of methods for measuring propagation are lacking. APPROACH We analyzed epileptiform discharges in microelectrode array recordings of human seizures. The array records multiunit activity and local field potentials at 400 micron spatial resolution, from a small cortical site free of obstructions. We evaluated several computationally efficient statistical methods for calculating traveling wave velocity, benchmarking them to analyses of associated neuronal burst firing. MAIN RESULTS Over 90% of discharges met statistical criteria for propagation across the sampled cortical territory. Detection rate, direction and speed estimates derived from a multiunit estimator were compared to four field potential-based estimators: negative peak, maximum descent, high gamma power, and cross-correlation. Interestingly, the methods that were computationally simplest and most efficient (negative peak and maximal descent) offer non-inferior results in predicting neuronal traveling wave velocities compared to the other two, more complex methods. Moreover, the negative peak and maximal descent methods proved to be more robust against reduced spatial sampling challenges. Using least absolute deviation in place of least squares error minimized the impact of outliers, and reduced the discrepancies between local field potential-based and multiunit estimators. SIGNIFICANCE Our findings suggest that ictal epileptiform discharges typically take the form of exceptionally strong, rapidly traveling waves, with propagation detectable across millimeter distances. The sequential activation of neurons in space can be inferred from clinically-observable EEG data, with a variety of straightforward computation methods available. This opens possibilities for systematic assessments of ictal discharge propagation in clinical and research settings.