Flexible, high-resolution cortical arrays with large coverage capture microscale high-frequency oscillations in patients with epilepsy.

OBJECTIVE: Effective surgical treatment of drug-resistant epilepsy depends on accurate localization of the epileptogenic zone (EZ). High-frequency oscillations (HFOs) are potential biomarkers of the EZ. Previous research has shown that HFOs often occur within submillimeter areas of brain tissue and that the coarse spatial sampling of clinical intracranial electrode arrays may limit the accurate capture of HFO activity. In this study, we sought to characterize microscale HFO activity captured on thin, flexible microelectrocorticographic (µECoG) arrays, which provide high spatial resolution over large cortical surface areas. METHODS: We used novel liquid crystal polymer thin-film µECoG arrays (.76-1.72-mm intercontact spacing) to capture HFOs in eight intraoperative recordings from seven patients with epilepsy. We identified ripple (80-250 Hz) and fast ripple (250-600 Hz) HFOs using a common energy thresholding detection algorithm along with two stages of artifact rejection. We visualized microscale subregions of HFO activity using spatial maps of HFO rate, signal-to-noise ratio, and mean peak frequency. We quantified the spatial extent of HFO events by measuring covariance between detected HFOs and surrounding activity. We also compared HFO detection rates on microcontacts to simulated macrocontacts by spatially averaging data. RESULTS: We found visually delineable subregions of elevated HFO activity within each µECoG recording. Forty-seven percent of HFOs occurred on single 200-µm-diameter recording contacts, with minimal high-frequency activity on surrounding contacts. Other HFO events occurred across multiple contacts simultaneously, with covarying activity most often limited to a .95-mm radius. Through spatial averaging, we estimated that macrocontacts with 2-3-mm diameter would only capture 44% of the HFOs detected in our µECoG recordings. SIGNIFICANCE: These results demonstrate that thin-film microcontact surface arrays with both highresolution and large coverage accurately capture microscale HFO activity and may improve the utility of HFOs to localize the EZ for treatment of drug-resistant epilepsy.

Single-Trial Cognitive Stress Classification Using Portable Wireless Electroencephalography.

This work used a low-cost wireless electroencephalography (EEG) headset to quantify the human response to different cognitive stress states on a single-trial basis. We used a Stroop-type color⁻word interference test to elicit mild stress responses in 18 subjects while recording scalp EEG. Signals recorded from thirteen scalp locations were analyzed using an algorithm that computes the root mean square voltages in the theta (4⁻8 Hz), alpha (8⁻13 Hz), and beta (13⁻30 Hz) bands immediately following the initiation of Stroop stimuli; the mean of the Teager energy in each of these three bands; and the wideband EEG signal line-length and number of peaks. These computational features were extracted from the EEG signals on thirteen electrodes during each stimulus presentation and used as inputs to logistic regression, quadratic discriminant analysis, and k-nearest neighbor classifiers. Two complementary analysis methodologies indicated classification accuracies over subjects of around 80% on a balanced dataset for the logistic regression classifier when information from all electrodes was taken into account simultaneously. Additionally, we found evidence that stress responses were preferentially time-locked to stimulus presentation, and that certain electrode⁻feature combinations worked broadly well across subjects to distinguish stress states.

Temporal changes of neocortical high-frequency oscillations in epilepsy.

High-frequency (100-500 Hz) oscillations (HFOs) recorded from intracranial electrodes are a potential biomarker for epileptogenic brain. HFOs are commonly categorized as ripples (100-250 Hz) or fast ripples (250-500 Hz), and a third class of mixed frequency events has also been identified. We hypothesize that temporal changes in HFOs may identify periods of increased the likelihood of seizure onset. HFOs (86,151) from five patients with neocortical epilepsy implanted with hybrid (micro + macro) intracranial electrodes were detected using a previously validated automated algorithm run over all channels of each patient's entire recording. HFOs were characterized by extracting quantitative morphologic features and divided into four time epochs (interictal, preictal, ictal, and postictal) and three HFO clusters (ripples, fast ripples, and mixed events). We used supervised classification and nonparametric statistical tests to explore quantitative changes in HFO features before, during, and after seizures. We also analyzed temporal changes in the rates and proportions of events from each HFO cluster during these periods. We observed patient-specific changes in HFO morphology linked to fluctuation in the relative rates of ripples, fast ripples, and mixed frequency events. These changes in relative rate occurred in pre- and postictal periods up to thirty min before and after seizures. We also found evidence that the distribution of HFOs during these different time periods varied greatly between individual patients. These results suggest that temporal analysis of HFO features has potential for designing custom seizure prediction algorithms and for exploring the relationship between HFOs and seizure generation.

Data mining neocortical high-frequency oscillations in epilepsy and controls.

Transient high-frequency (100-500 Hz) oscillations of the local field potential have been studied extensively in human mesial temporal lobe. Previous studies report that both ripple (100-250 Hz) and fast ripple (250-500 Hz) oscillations are increased in the seizure-onset zone of patients with mesial temporal lobe epilepsy. Comparatively little is known, however, about their spatial distribution with respect to seizure-onset zone in neocortical epilepsy, or their prevalence in normal brain. We present a quantitative analysis of high-frequency oscillations and their rates of occurrence in a group of nine patients with neocortical epilepsy and two control patients with no history of seizures. Oscillations were automatically detected and classified using an unsupervised approach in a data set of unprecedented volume in epilepsy research, over 12 terabytes of continuous long-term micro- and macro-electrode intracranial recordings, without human preprocessing, enabling selection-bias-free estimates of oscillation rates. There are three main results: (i) a cluster of ripple frequency oscillations with median spectral centroid = 137 Hz is increased in the seizure-onset zone more frequently than a cluster of fast ripple frequency oscillations (median spectral centroid = 305 Hz); (ii) we found no difference in the rates of high frequency oscillations in control neocortex and the non-seizure-onset zone neocortex of patients with epilepsy, despite the possibility of different underlying mechanisms of generation; and (iii) while previous studies have demonstrated that oscillations recorded by parenchyma-penetrating micro-electrodes have higher peak 100-500 Hz frequencies than penetrating macro-electrodes, this was not found for the epipial electrodes used here to record from the neocortical surface. We conclude that the relative rate of ripple frequency oscillations is a potential biomarker for epileptic neocortex, but that larger prospective studies correlating high-frequency oscillations rates with seizure-onset zone, resected tissue and surgical outcome are required to determine the true predictive value.

Dissolvable films of silk fibroin for ultrathin conformal bio-integrated electronics.

Electronics that are capable of intimate, non-invasive integration with the soft, curvilinear surfaces of biological tissues offer important opportunities for diagnosing and treating disease and for improving brain/machine interfaces. This article describes a material strategy for a type of bio-interfaced system that relies on ultrathin electronics supported by bioresorbable substrates of silk fibroin. Mounting such devices on tissue and then allowing the silk to dissolve and resorb initiates a spontaneous, conformal wrapping process driven by capillary forces at the biotic/abiotic interface. Specialized mesh designs and ultrathin forms for the electronics ensure minimal stresses on the tissue and highly conformal coverage, even for complex curvilinear surfaces, as confirmed by experimental and theoretical studies. In vivo, neural mapping experiments on feline animal models illustrate one mode of use for this class of technology. These concepts provide new capabilities for implantable and surgical devices.

Unsupervised classification of high-frequency oscillations in human neocortical epilepsy and control patients.

High-frequency oscillations (HFOs) have been observed in animal and human intracranial recordings during both normal and aberrant brain states. It has been proposed that the relationship between subclasses of these oscillations can be used to identify epileptic brain. Studies of HFOs in epilepsy have been hampered by selection bias arising primarily out of the need to reduce the volume of data so that clinicians can manually review it. In this study, we introduce an algorithm for detecting and classifying these signals automatically and demonstrate the tractability of analyzing a data set of unprecedented size, over 31,000 channel-hours of intracranial electroencephalographic (iEEG) recordings from micro- and macroelectrodes in humans. Using an unsupervised approach that does not presuppose a specific number of clusters in the data, we show direct evidence for the existence of distinct classes of transient oscillations within the 100- to 500-Hz frequency range in a population of nine neocortical epilepsy patients and two controls. The number of classes we find, four (three plus one putative artifact class), is consistent with prior studies that identify "ripple" and "fast ripple" oscillations using human-intensive methods and, additionally, identifies a less examined class of mixed-frequency events.

Combined assessment of attentional reserve and cognitive-motor effort under various levels of challenge with a dry EEG system.

A novel ERP approach was proposed to index variations in mental workload, particularly in attentional reserve, which is complementary to EEG spectral content thought to reflect mental effort. To our knowledge, no study has assessed mental effort and attentional reserve simultaneously in EEG gel-based and, importantly, dry systems, which are particularly well suited for real-world settings. Therefore, by systematically considering ERP, EEG spectral, and importantly the combination of both, this study examined if a small set of dry EEG electrodes could detect changes in both spectral and ERP metrics to assess the mental workload under various challenges with a similar fidelity to their gel-based counterparts in a laboratory setting. By employing both EEG gel-based and dry systems, the ERP and spectral markers were computed while participants executed a visuomotor task under three levels of challenge. For both EEG systems, more challenging levels of difficulty were associated with concomitant changes in ERP amplitude, and spectral power reflected a reduction of the attentional reserve and an increase in cognitive-motor effort, respectively. Those variations in attentional reserve and cognitive-motor effort collectively indexed mental workload with nearly identical fidelity for both gel-based and dry EEG systems. These findings promise to assess the mental workload in situations where the use of dry EEG systems could be advantageously employed to examine human cognitive-motor performance.

Millimeter-scale epileptiform spike propagation patterns and their relationship to seizures.

OBJECTIVE: Current mapping of epileptic networks in patients prior to epilepsy surgery utilizes electrode arrays with sparse spatial sampling (∼1.0 cm inter-electrode spacing). Recent research demonstrates that sub-millimeter, cortical-column-scale domains have a role in seizure generation that may be clinically significant. We use high-resolution, active, flexible surface electrode arrays with 500 µm inter-electrode spacing to explore epileptiform local field potential (LFP) spike propagation patterns in two dimensions recorded from subdural micro-electrocorticographic signals in vivo in cat. In this study, we aimed to develop methods to quantitatively characterize the spatiotemporal dynamics of epileptiform activity at high-resolution. APPROACH: We topically administered a GABA-antagonist, picrotoxin, to induce acute neocortical epileptiform activity leading up to discrete electrographic seizures. We extracted features from LFP spikes to characterize spatiotemporal patterns in these events. We then tested the hypothesis that two-dimensional spike patterns during seizures were different from those between seizures. MAIN RESULTS: We showed that spatially correlated events can be used to distinguish ictal versus interictal spikes. SIGNIFICANCE: We conclude that sub-millimeter-scale spatiotemporal spike patterns reveal network dynamics that are invisible to standard clinical recordings and contain information related to seizure-state.

Modeling the effects of biological tissue on RF propagation from a wrist-worn device.

Many wireless devices in common use today are worn either on or in close proximity to the body. Among them are a growing number of wrist-mounted devices designed for applications such as activity or vital-signs monitoring, typically using Bluetooth technology to communicate with external devices. Here, we use a tissue-mimicking phantom material in conjunction with anechoic chamber and network analyzer testing to investigate how antenna propagation patterns in one such device are influenced by the electrical properties of the human wrist. A microstrip antenna module is mounted onto phantom material of various geometries, and the resulting voltage standing wave ratio (VSWR), input impedance, and azimuth radiation pattern are recorded in both free space and real-world environments. The results of this study demonstrate how the high permittivity values of human tissue (ε(r) ≈ 16) affect the design parameters of microstrip antennas. A simulation environment using Sonnet EM software was used to further analyze the high dielectric effects of biological tissue on RF propagation.

Development of high resolution, multiplexed electrode arrays: Opportunities and challenges.

More than one third of the world's 60 million people with epilepsy have seizures that cannot be controlled by medication. Some of these individuals may be candidates for surgical removal of brain regions that generate seizures, but the chance of being seizure free after epilepsy surgery is as low as 35% in many patients. Even when surgery is successful, patients risk neurological deficits like memory loss and speech difficulties. The need for new treatments is clear. A central barrier to better treatments for epilepsy is technological: we do not have devices capable of interfacing with the brain with small enough electrodes over large enough regions to map epileptic networks in sufficient detail to enable treatment. Our collaborative group has developed new implantable brain devices to address this challenge. Our devices, made from flexible silicon nanoribbons, can record from these very small brain regions, with electrodes ½ millimeter apart or less, and can be scaled up to clinically useful sizes, on the order of 64 cm(2). They consist of thousands of individually controllable microelectrodes.

Millimeter-scale epileptiform spike patterns and their relationship to seizures.

Advances in neural electrode technology are enabling brain recordings with increasingly fine spatial and temporal resolution. We explore spatio-temporal (ST) patterns of local field potential spikes using a new high-density active electrode array with 500 µm resolution. We record subdural micro-electrocorticographic (µECoG) signals in vivo from a feline model of acute neocortical epileptiform spikes and seizures induced with local administration of the GABA antagonist, picrotoxin. We employ a clustering algorithm to separate 2-dimensional (2-D) spike patterns to isolate distinct classes of spikes unique to the interictal and ictal states. Our findings indicate that the 2-D patterns can be used to distinguish seizures from non-seizure state. We find two statistically significant ST patterns that uniquely characterize ictal epochs. We conclude that millimeter-scale ST spike dynamics contain useful information about ictal state. This finding may be important to understanding mechanisms underlying local circuit activity during seizure generation. Further work will investigate whether patterns we identify can increase our understanding of seizure dynamics and their underlying mechanisms and inform new electrical stimulation protocols for seizure termination.

Flexible, foldable, actively multiplexed, high-density electrode array for mapping brain activity in vivo.

Arrays of electrodes for recording and stimulating the brain are used throughout clinical medicine and basic neuroscience research, yet are unable to sample large areas of the brain while maintaining high spatial resolution because of the need to individually wire each passive sensor at the electrode-tissue interface. To overcome this constraint, we developed new devices that integrate ultrathin and flexible silicon nanomembrane transistors into the electrode array, enabling new dense arrays of thousands of amplified and multiplexed sensors that are connected using fewer wires. We used this system to record spatial properties of cat brain activity in vivo, including sleep spindles, single-trial visual evoked responses and electrographic seizures. We found that seizures may manifest as recurrent spiral waves that propagate in the neocortex. The developments reported here herald a new generation of diagnostic and therapeutic brain-machine interface devices.

Mining terabytes of submillimeter-resolution ECoG datasets for neurophysiologic biomarkers.

Recent research in brain-machine interfaces and devices to treat neurological disease indicate that important network activity exists at temporal and spatial scales beyond the resolution of existing implantable devices. We present innovations in both hardware and software that allow sampling and interpretation of data from brain networks from hundreds or thousands of sensors at submillimeter resolution. These innovations consist of novel flexible, active electrode arrays and unsupervised algorithms for detecting and classifying neurophysiologic biomarkers, specifically high frequency oscillations. We propose these innovations as the foundation for a new generation of closed loop diagnostic and therapeutic medical devices, and brain-machine interfaces.

A conformal, bio-interfaced class of silicon electronics for mapping cardiac electrophysiology.

In all current implantable medical devices such as pacemakers, deep brain stimulators, and epilepsy treatment devices, each electrode is independently connected to separate control systems. The ability of these devices to sample and stimulate tissues is hindered by this configuration and by the rigid, planar nature of the electronics and the electrode-tissue interfaces. Here, we report the development of a class of mechanically flexible silicon electronics for multiplexed measurement of signals in an intimate, conformal integrated mode on the dynamic, three-dimensional surfaces of soft tissues in the human body. We demonstrate this technology in sensor systems composed of 2016 silicon nanomembrane transistors configured to record electrical activity directly from the curved, wet surface of a beating porcine heart in vivo. The devices sample with simultaneous submillimeter and submillisecond resolution through 288 amplified and multiplexed channels. We use this system to map the spread of spontaneous and paced ventricular depolarization in real time, at high resolution, on the epicardial surface in a porcine animal model. This demonstration is one example of many possible uses of this technology in minimally invasive medical devices.

Human substantia nigra neurons encode unexpected financial rewards.

The brain's sensitivity to unexpected outcomes plays a fundamental role in an organism's ability to adapt and learn new behaviors. Emerging research suggests that midbrain dopaminergic neurons encode these unexpected outcomes. We used microelectrode recordings during deep brain stimulation surgery to study neuronal activity in the human substantia nigra (SN) while patients with Parkinson's disease engaged in a probabilistic learning task motivated by virtual financial rewards. Based on a model of the participants' expected reward, we divided trial outcomes into expected and unexpected gains and losses. SN neurons exhibited significantly higher firing rates after unexpected gains than unexpected losses. No such differences were observed after expected gains and losses. This result provides critical support for the hypothesized role of the SN in human reinforcement learning.