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1.  A study of the dynamics of seizure propagation across micro domains in the vicinity of the seizure onset zone 
Journal of neural engineering  2015;12(4):046016.
The use of micro-electrode arrays to measure electrical activity from the surface of the brain is increasingly being investigated as a means to improve seizure onset zone localization. In this work, we used a multivariate autoregressive model to determine the evolution of seizure dynamics in the 70 – 110 Hz high frequency band across micro-domains sampled by such micro-electrode arrays.
We used 7 complex partial seizures recorded from 4 patients undergoing intracranial monitoring for surgical evaluation to reconstruct the seizure propagation pattern over sliding windows using a directed transfer function measure.
Main results
We showed that a directed transfer function can be used to estimate the flow of seizure activity in a set of simulated micro-electrode data with known propagation pattern. In general, depending on the location of the micro-electrode grid with respect to the clinical seizure onset zone and the time from seizure onset, ictal propagation changed in directional characteristics over a 2 to 10 seconds time scale, with gross directionality limited to spatial dimensions of approximately 9mm2. It was also seen that the strongest seizure patterns in the high frequency band and their sources over such micro-domains are more stable over time and across seizures bordering the clinically determined seizure onset zone than inside.
This type of propagation analysis might in future provide an additional tool to epileptologists for characterizing epileptogenic tissue. This will potentially help narrowing down resection zones without compromising essential brain functions as well as provide important information about targeting anti-epileptic stimulation devices.
PMCID: PMC4531844  PMID: 26061006
3.  Reliability of Early Cortical Auditory Gamma-Band Responses 
To evaluate the test-retest reliability of event-related power changes in the 30–150 Hz gamma frequency range occurring in the first 150 ms after presentation of an auditory stimulus.
Repeat intracranial electrocorticographic (ECoG) recordings were performed with 12 epilepsy patients, at ≥ 1-day intervals, using a passive odd-ball paradigm with steady-state tones. Time-frequency matching pursuit analysis was used to quantify changes in gamma-band power relative to pre-stimulus baseline. Test-retest reliability was estimated based on within-subject comparisons (paired t-test, McNemar’s test) and correlations (Spearman rank correlations, intra-class correlations) across sessions, adjusting for within-session variability. Reliability estimates of gamma-band response robustness, spatial concordance, and reproducibility were compared with corresponding measurements from concurrent auditory evoked N1 responses.
All patients showed increases in gamma-band power, 50–120 ms post-stimulus onset, that were highly robust across recordings, comparable to the evoked N1 responses. Gamma-band responses occurred regardless of patients’ performance on behavioral tests of auditory processing, medication changes, seizure focus, or duration of test-retest interval. Test-retest reproducibility was greatest for the timing of peak power changes in the high-gamma range (65–150 Hz). Reliability of low-gamma responses and evoked N1 responses improved at higher signal-to-noise levels.
Early cortical auditory gamma-band responses are robust, spatially concordant, and reproducible over time.
These test-retest ECoG results confirm the reliability of auditory gamma-band responses, supporting their utility as objective measures of cortical processing in clinical and research studies.
PMCID: PMC3468656  PMID: 22771035
Auditory Cortex; Gamma-Band; Reliability; Auditory Processing; Variability
4.  Epileptic Seizures From Abnormal Networks: Why Some Seizures Defy Predictability 
Epilepsy Research  2011;99(3):202-213.
Seizure prediction has proven to be difficult in clinically realistic environments. Is it possible that fluctuations in cortical firing could influence the onset of seizures in an ictal zone? To test this, we have now used neural network simulations in a computational model of cortex having a total of 65,536 neurons with intercellular wiring patterned after histological data. A spatially distributed Poisson driven background input representing the activity of neighboring cortex affected 1% of the neurons. Gamma distributions were fit to the interbursting phase intervals, a non-parametric test for randomness was applied, and a dynamical systems analysis was performed to search for period-1 orbits in the intervals. The non-parametric analysis suggests that intervals are being drawn at random from their underlying joint distribution and the dynamical systems analysis is consistent with a nondeterministic dynamical interpretation of the generation of bursting phases. These results imply that in a region of cortex with abnormal connectivity analogous to a seizure focus, it is possible to initiate seizure activity with fluctuations of input from the surrounding cortical regions. These findings suggest one possibility for ictal generation from abnormal focal epileptic networks. This mechanism additionally could help explain the difficulty in predicting partial seizures in some patients.
PMCID: PMC3312991  PMID: 22169211
Computational simulation; neural network model; seizure prediction; seizure generation
5.  Connectivity between Perisylvian and Bilateral Basal Temporal Cortices 
Cerebral Cortex (New York, NY)  2011;22(4):918-925.
Language processing requires the orchestrated action of different neuronal populations, and some studies suggest that the role of the basal temporal (BT) cortex in language processing is bilaterally distributed. Our aim was to demonstrate connectivity between perisylvian cortex and both BT areas. We recorded corticocortical evoked potentials (CCEPs) in 8 patients with subdural electrodes implanted for surgical evaluation of intractable epilepsy. Four patients had subdural grids over dominant perisylvian and BT areas, and 4 had electrode strips over both BT areas and left posterior superior temporal gyrus (LPSTG). After electrocortical mapping, patients with grids had 1-Hz stimulation of language areas. Patients with strips did not undergo mapping but had 1-Hz stimulation of the LPSTG. Posterior language area stimulation elicited CCEPs in ipsilateral BT cortex in 3/4 patients with left hemispheric grids. CCEPs were recorded in bilateral BT cortices in 3/4 patients with strips upon stimulation of the LPSTG, and in the LPSTG in the fourth patient upon stimulation of either BT area. This is the first in vivo demonstration of connectivity between LPSTG and both BT cortices. The role of BT cortex in language processing may be bilaterally distributed and related to linking visual information with phonological representations stored in the LPSTG.
PMCID: PMC3306577  PMID: 21715651
basal temporal language area; connectivity; cortical mapping; epilepsy; evoked potentials
6.  Improving Early Seizure Detection 
Epilepsy & behavior : E&B  2011;22(Suppl 1):S44-S48.
Over the last decade, the search for a method able to reliably predict seizures hours in advance has been largely replaced by a more realistic goal of very early detection of seizure onset which would allow therapeutic or warning devices to be triggered prior to the onset of disabling clinical symptoms. We explore in this article the steps along the pathway from data acquisition to closed loop applications that can and should be considered to design the most efficient early seizure detection. Microelectrodes, high-frequency oscillations, high sampling rate, high-density arrays, and modern analysis techniques are all elements of the recording and detection process that in combination with modeling studies can provide new insights into the dynamics of seizure onsets. Each of these step needs to be considered if one wants to implement improved detection devices that will favorably impact the quality of life of patients.
PMCID: PMC3233224  PMID: 22078518
seizure onset; early detection; EEG acquisition; warning devices; therapeutic devices
7.  Dynamics of large-scale cortical interactions at high gamma frequencies during word production: Event related causality (ERC) analysis of human electrocorticography (ECoG) 
NeuroImage  2011;56(4):2218-2237.
Intracranial EEG studies in humans have shown that functional brain activation in a variety of functional-anatomic domains of human cortex is associated with an increase in power at a broad range of high gamma (> 60 Hz) frequencies. Although these electrophysiological responses are highly specific for the location and timing of cortical processing and in animal recordings are highly correlated with increased population firing rates, there has been little direct empirical evidence for causal interactions between different recording sites at high gamma frequencies. Such causal interactions are hypothesized to occur during cognitive tasks that activate multiple brain regions. To determine whether such causal interactions occur at high gamma frequencies and to investigate their functional significance, we used event-related causality (ERC) analysis to estimate the dynamics, directionality, and magnitude of event-related causal interactions using subdural electrocorticography (ECoG) recorded during two word production tasks: picture naming and auditory word repetition. A clinical subject who had normal hearing but was skilled in American Signed Language (ASL) provided a unique opportunity to test our hypothesis with reference to a predictable pattern of causal interactions, i.e. that language cortex interacts with different areas of sensorimotor cortex during spoken vs. signed responses. Our ERC analyses confirmed this prediction. During word production with spoken responses, perisylvian language sites had prominent causal interactions with mouth/tongue areas of motor cortex, and when responses were gestured in sign language, the most prominent interactions involved hand and arm areas of motor cortex. Furthermore, we found that the sites from which the most numerous and prominent causal interactions originated, i.e. sites with a pattern of ERC “divergence”, were also sites where high gamma power increases were most prominent and where electrocortical stimulation mapping interfered with word production. These findings suggest that the number, strength and directionality of event-related causal interactions may help identify network nodes that are not only activated by a task but are critical to its performance.
PMCID: PMC3105123  PMID: 21419227
effective connectivity; Granger causality; large-scale brain networks; high gamma oscillations; language mapping
8.  Partial Seizures Are Associated with Early Increases in Signal Complexity 
Partial seizures are often believed to be associated with EEG signals of low complexity because seizures are associated with increased neural network synchrony. The investigations reported here provide an assessment of the signal complexity of epileptic seizure onsets using newly developed quantitative measures.
Using the Gabor atom density (GAD) measure of signal complexity, 339 partial seizures in 45 patients with intracranial electrode arrays were analyzed. Segmentation procedures were applied to determine the timing and amplitude of GAD changes relative to the electrographic onset of the seizure.
330 out of 339 seizures have significant complexity level changes, with 319 (97%) having an increase in complexity. GAD increases occur within seconds of the onset of the partial seizure but are not observed in channels remote from the focus. The complexity increase is similar for seizures from mesial temporal origin, neocortical temporal and extra-temporal origin.
Partial onset seizures are associated with early increases in signal complexity as measured by GAD. This increase is independent of the location of the seizure focus.
Despite the often predominant rhythmic activity that characterizes onset and early evolution of epileptic seizures, partial seizure onset is associated with an early increase in complexity. These changes are common to partial seizures originating from different brain regions, indicating a similar seizure dynamic.
PMCID: PMC2818227  PMID: 19910249
Epilepsy; Seizures; Complexity; Signal Processing; EEG; Matching Pursuit
9.  Language Mapping in Multilingual Patients: Electrocorticography and Cortical Stimulation During Naming 
Multilingual patients pose a unique challenge when planning epilepsy surgery near language cortex because the cortical representations of each language may be distinct. These distinctions may not be evident with routine electrocortical stimulation mapping (ESM). Electrocorticography (ECoG) has recently been used to detect task-related spectral perturbations associated with functional brain activation. We hypothesized that using broadband high gamma augmentation (HGA, 60–150 Hz) as an index of cortical activation, ECoG would complement ESM in discriminating the cortical representations of first (L1) and second (L2) languages. We studied four adult patients for whom English was a second language, in whom subdural electrodes (a total of 358) were implanted to guide epilepsy surgery. Patients underwent ECoG recordings and ESM while performing the same visual object naming task in L1 and L2. In three of four patients, ECoG found sites activated during naming in one language but not the other. These language-specific sites were not identified using ESM. In addition, ECoG HGA was observed at more sites during L2 versus L1 naming in two patients, suggesting that L2 processing required additional cortical resources compared to L1 processing in these individuals. Post-operative language deficits were identified in three patients (one in L2 only). These deficits were predicted by ECoG spectral mapping but not by ESM. These results suggest that pre-surgical mapping should include evaluation of all utilized languages to avoid post-operative functional deficits. Finally, this study suggests that ECoG spectral mapping may potentially complement the results of ESM of language.
PMCID: PMC3044479  PMID: 21373361
multilingual; naming; electrocorticography; ECoG; high gamma; functional mapping; electrocortical stimulation mapping; epilepsy surgery
10.  Phase-dependent stimulation effects on bursting activity in a neural network cortical simulation 
Epilepsy research  2009;84(1):42-55.
A neural network simulation with realistic cortical architecture has been used to study synchronized bursting as a seizure representation. This model has the property that bursting epochs arise and cease spontaneously, and bursting epochs can be induced by external stimulation. We have used this simulation to study the time-frequency properties of the evolving bursting activity, as well as effects due to network stimulation.
The model represents a cortical region of 1.6 mm × 1.6 mm, and includes seven neuron classes organized by cortical layer, inhibitory or excitatory properties, and electrophysiological characteristics. There are a total of 65, 536 modeled single compartment neurons that operate according to a version of Hodgkin-Huxley dynamics. The intercellular wiring is based on histological studies and our previous modeling efforts.
The bursting phase is characterized by a flat frequency spectrum. Stimulation pulses are applied to this modeled network, with an electric field provided by a 1 mm radius circular electrode represented mathematically in the simulation. A phase dependence to the post-stimulation quiescence is demonstrated, with local relative maxima in efficacy occurring before or during the network depolarization phase in the underlying activity. Brief periods of network insensitivity to stimulation are also demonstrated. The phase dependence was irregular and did not reach statistical significance when averaged over the full 2.5 seconds of simulated bursting investigated. This result provides comparison with previous in vivo studies which have also demonstrated increased efficacy of stimulation when pulses are applied at the peak of the local field potential during cortical afterdischarges. The network bursting is synchronous when comparing the different neuron classes represented up to an uncertainty of 10 msec. Studies performed with an excitatory chandelier cell component demonstrated increased synchronous bursting in the model, as predicted from experimental work.
This large scale multi-neuron neural network simulation reproduces many aspects of evolving cortical bursting behaviour as well as the timing-dependent effects of electrical stimulation on that bursting.
PMCID: PMC2738625  PMID: 19185465
Seizure simulation; neural network modeling; cortical stimulation; computer modeling
11.  Quantifying Auditory Event-Related Responses in Multichannel Human Intracranial Recordings 
Multichannel intracranial recordings are used increasingly to study the functional organization of human cortex. Intracranial recordings of event-related activity, or electrocorticography (ECoG), are based on high density electrode arrays implanted directly over cortex, combining good temporal and spatial resolution. Developing appropriate statistical methods for analyzing event-related responses in these high dimensional ECoG datasets remains a major challenge for clinical and systems neuroscience. We present a novel methodological framework that combines complementary, existing methods adapted for statistical analysis of auditory event-related responses in multichannel ECoG recordings. This analytic framework integrates single-channel (time-domain, time–frequency) and multichannel analyses of event-related ECoG activity to determine statistically significant evoked responses, induced spectral responses, and effective (causal) connectivity. Implementation of this quantitative approach is illustrated using multichannel ECoG data from recent studies of auditory processing in patients with epilepsy. Methods described include a time–frequency matching pursuit algorithm adapted for modeling brief, transient cortical spectral responses to sound, and a recently developed method for estimating effective connectivity using multivariate autoregressive modeling to measure brief event-related changes in multichannel functional interactions. A semi-automated spatial normalization method for comparing intracranial electrode locations across patients is also described. The individual methods presented are published and readily accessible. We discuss the benefits of integrating multiple complementary methods in a unified and comprehensive quantitative approach. Methodological considerations in the analysis of multichannel ECoG data, including corrections for multiple comparisons are discussed, as well as remaining challenges in the development of new statistical approaches.
PMCID: PMC2859880  PMID: 20428513
electrocorticography; auditory; matching pursuit; multivariate autoregressive modeling; epilepsy; statistical testing
12.  Neural correlates of high-gamma oscillations (60–200 Hz) in macaque local field potentials and their potential implications in electrocorticography 
Recent studies using electrocorticographic (ECoG) recordings in humans have shown that functional activation of cortex is associated with an increase in power in the high-gamma frequency range (∼60–200 Hz). Here we investigate the neural correlates of this high-gamma activity in local field potential (LFP). Single units and LFP were recorded with microelectrodes from the hand region of macaque SII cortex while vibrotactile stimuli of varying intensities were presented to the hand. We found that high-gamma power in the LFP was strongly correlated with the average firing rate recorded by the microelectrodes, both temporally and on a trial-by-trial basis. In comparison, the correlation between firing rate and low-gamma power (40–80 Hz) was much smaller. In order to explore the potential effects of neuronal firing on ECoG, we developed a model to estimate ECoG power generated by different firing patterns of the underlying cortical population and studied how ECoG power varies with changes in firing rate versus the degree of synchronous firing between neurons in the population. Both an increase in firing rate and neuronal synchrony increased high-gamma power in the simulated ECoG data. However, ECoG high-gamma activity was much more sensitive to increases in neuronal synchrony than firing rate.
PMCID: PMC2715840  PMID: 18987189
Secondary somatosensory cortex; gamma; high-gamma; local field potential; ECoG; synchrony
13.  Effect of stimulus intensity on spike-LFP relationship in Secondary Somatosensory cortex 
Neuronal oscillations in the gamma frequency range have been reported in many cortical areas, but the role they play in cortical processing remains unclear. We tested a recently proposed hypothesis that the intensity of sensory input is coded in the timing of action potentials relative to the phase of gamma oscillations, thus converting amplitude information to a temporal code. We recorded spikes and local field potential (LFP) from secondary somatosensory (SII) cortex in awake monkeys while presenting a vibratory stimulus at different amplitudes. We developed a novel technique based on matching pursuit to study the interaction between the highly transient gamma oscillations and spikes with high time-frequency resolution. We found that spikes were weakly coupled to LFP oscillations in the gamma frequency range (40−80 Hz), and strongly coupled to oscillations in higher gamma frequencies. However, the phase relationship of neither low-gamma nor high-gamma oscillations changed with stimulus intensity, even with a ten-fold increase. We conclude that, in SII, gamma oscillations are synchronized with spikes, but their phase does not vary with stimulus intensity. Furthermore, high-gamma oscillations (>60 Hz) appear to be closely linked to the occurrence of action potentials, suggesting that LFP high-gamma power could be a sensitive index of the population firing rate near the microelectrode.
PMCID: PMC2597587  PMID: 18632937
Secondary somatosensory cortex; gamma; high-gamma; phase coding; local field potential; matching pursuit

Results 1-13 (13)