Summary The ability to focus on and understand one talker in a noisy social environment is a critical social-cognitive capacity, whose underlying neuronal mechanisms are unclear. We investigated the manner in which speech streams are represented in brain activity and the way that selective attention governs the brain’s representation of speech using a ‘Cocktail Party’ Paradigm, coupled with direct recordings from the cortical surface in surgical epilepsy patients. We find that brain activity dynamically tracks speech streams using both low frequency phase and high frequency amplitude fluctuations, and that optimal encoding likely combines the two. In and near low level auditory cortices, attention ‘modulates’ the representation by enhancing cortical tracking of attended speech streams, but ignored speech remains represented. In higher order regions, the representation appears to become more ‘selective,’ in that there is no detectable tracking of ignored speech. This selectivity itself seems to sharpen as a sentence unfolds.

The location and trajectory of seizure activity is of great importance, yet our ability to map such activity remains primitive. Recently, the development of multi-electrode arrays for use in humans has provided new levels of temporal and spatial resolution for recording seizures. Here, we show that there is a sharp delineation between areas showing intense, hypersynchronous firing indicative of recruitment to the seizure, and adjacent territories where there is only low-level, unstructured firing. Thus, there is a core territory of recruited neurons and a surrounding 'ictal penumbra'. The defining feature of the 'ictal penumbra' is the contrast between the large amplitude EEG signals and the low-level firing there. Our human recordings bear striking similarities with animal studies of an inhibitory restraint, indicating that they can be readily understood in terms of this mechanism. These findings have important implications for how we localize seizure activity and map its spread.

In this and two companion papers, we report on an extended empirical study of the simulated annealing approach to combinatorial optimization proposed by S. Kirkpatrick et al. That study investigated how best to adapt simulated annealing to particular problems and compared its performance to that of more traditional algorithms. This paper (Part I) discusses annealing and our parameterized generic implementation of it, describes how we adapted this generic algorithm to the graph partitioning problem, and reports how well it compared to standard algorithms like the Kernighan-Lin algorithm. (For sparse random graphs, it tended to outperform Kernighan-Lin as the number of vertices become large, even when its much greater running time was taken into account. It did not perform nearly so well, however, on graphs generated with a built-in geometric structure.) We also discuss how we went about optimizing our implementation, and describe the effects of changing the various annealing parameters or varying the basic annealing algorithm itself.

Epilepsy has been historically seen as a functional brain disorder associated with excessive synchronization of large neuronal populations leading to a hypersynchronous state. Recent evidence showed that epileptiform phenomena, particularly seizures, result from complex interactions between neuronal networks characterized by heterogeneity of neuronal firing and dynamical evolution of synchronization. Desynchronization is often observed preceding seizures or during their early stages; in contrast, high levels of synchronization observed towards the end of seizures may facilitate termination. In this review we discuss cellular and network mechanisms responsible for such complex changes in synchronization. Recent work has identified cell-type-specific inhibitory and excitatory interactions, the dichotomy between neuronal firing and the non-local measurement of local field potentials distant to that firing, and the reflection of the neuronal dark matter problem in non-firing neurons active in seizures. These recent advances have challenged long-established views and are leading to a more rigorous and realistic understanding of the pathophysiology of epilepsy.

This is the second in a series of three papers that empirically examine the competitiveness of simulated annealing in certain well-studied domains of combinatorial optimization. Simulated annealing is a randomized technique proposed by S. Kirkpatrick, C. D. Gelatt and M. P. Vecchi for improving local optimization algorithms. Here we report on experiments at adapting simulated annealing to graph coloring and number partitioning, two problems for which local optimization had not previously been thought suitable. For graph coloring, we report on three simulated annealing schemes, all of which can dominate traditional techniques for certain types of graphs, at least when large amounts of computing time are available. For number partitioning, simulated annealing is not competitive with the differencing algorithm of N. Karmarkar and R. M. Karp, except on relatively small instances. Moreover, if running time is taken into account, natural annealing schemes cannot even outperform multiple random runs of the local optimization algorithms on which they are based, in sharp contrast to the observed performance of annealing on other problems.

High frequency oscillations have been proposed as a clinically useful biomarker of seizure generating sites. We used a unique set of human microelectrode array recordings (four patients, 10 seizures), in which propagating seizure wavefronts could be readily identified, to investigate the basis of ictal high frequency activity at the cortical (subdural) surface. Sustained, repetitive transient increases in high gamma (80-150 Hz) amplitude, phase-locked to the low-frequency (1-25 Hz) ictal rhythm, correlated with strong multi-unit firing bursts synchronized across the core territory of the seizure. These repetitive high frequency oscillations were seen in recordings from subdural electrodes adjacent to the microelectrode array several seconds after seizure onset, following ictal wavefront passage. Conversely, microelectrode recordings demonstrating only low-level, heterogeneous neural firing correlated with a lack of high frequency oscillations in adjacent subdural recording sites, despite the presence of a strong low-frequency signature. Previously, we reported that this pattern indicates a failure of the seizure to invade the area, because of a feedforward inhibitory veto mechanism. Because multi-unit firing rate and high gamma amplitude are closely related, high frequency oscillations can be used as a surrogate marker to distinguish the core seizure territory from the surrounding penumbra. We developed an efficient measure to detect delayed-onset, sustained ictal high frequency oscillations based on cross-frequency coupling between high gamma amplitude and the low-frequency (1-25 Hz) ictal rhythm. When applied to the broader subdural recording, this measure consistently predicted the timing or failure of ictal invasion, and revealed a surprisingly small and slowly spreading seizure core surrounded by a far larger penumbral territory. Our findings thus establish an underlying neural mechanism for delayed-onset, sustained ictal high frequency oscillations, and provide a practical, efficient method for using them to identify the small ictal core regions. Our observations suggest that it may be possible to reduce substantially the extent of cortical resections in epilepsy surgery procedures without compromising seizure control.

Previous studies raise the hypothesis that attentional bias in the phase of neocortical excitability fluctuations (oscillations) represents a fundamental mechanism for tuning the brain to the temporal dynamics of task-relevant event patterns. To evaluate this hypothesis, we recorded intracranial electrocortical activity in human epilepsy patients while they performed an audiovisual stream selection task. Consistent with our hypothesis, (1) attentional modulation of oscillatory entrainment operates in a distinct network of areas including auditory, visual, posterior parietal, inferior motor, inferior frontal and superior midline frontal cortex, (2) the degree of oscillatory entrainment depends on the predictability of the stimulus stream, and (3) the attentional phase shift of entrained oscillation cooccurs with classical attentional effects observed on phase-locked evoked activity in sensory-specific areas but seems to operate on entrained low-frequency oscillations that cannot be explained by sensory activity evoked at the rate of stimulation. Thus, attentional entrainment appears to tune a network of brain areas to the temporal dynamics of behaviorally relevant event streams, contributing to its perceptual and behavioral selection.

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.