Towards optimizing single pulse electrical stimulation: High current intensity, short pulse width stimulation most effectively elicits evoked potentials.

BACKGROUND: While single pulse electrical stimulation (SPES) is increasingly used to study effective connectivity, the effects of varying stimulation parameters on the resulting cortico-cortical evoked potentials (CCEPs) have not been systematically explored. OBJECTIVE: We sought to understand the interacting effects of stimulation pulse width, current intensity, and charge on CCEPs through an extensive testing of this parameter space and analysis of several response metrics. METHODS: We conducted SPES in 11 patients undergoing intracranial EEG monitoring using five combinations of current intensity (1.5, 2.0, 3.0, 5.0, and 7.5 mA) and pulse width at each of three charges (0.750, 1.125, and 1.500 µC/phase) to study how CCEP amplitude, distribution, latency, morphology, and stimulus artifact amplitude vary with each parameter. RESULTS: Stimulations with a greater charge or a greater current intensity and shorter pulse width at a given charge generally resulted in greater CCEP amplitudes and spatial distributions, shorter latencies, and increased waveform correlation. These effects interacted such that stimulations with the lowest charge and highest current intensities resulted in greater response amplitudes and spatial distributions than stimulations with the highest charge and lowest current intensities. Stimulus artifact amplitude increased with charge, but this could be mitigated by using shorter pulse widths. CONCLUSIONS: Our results indicate that individual combinations of current intensity and pulse width, in addition to charge, are important determinants of CCEP magnitude, morphology, and spatial extent. Together, these findings suggest that high current intensity, short pulse width stimulations are optimal SPES settings for eliciting strong and consistent responses while minimizing charge.

Stimulating native seizures with neural resonance: a new approach to localize the seizure onset zone.

Successful outcomes in epilepsy surgery rely on the accurate localization of the seizure onset zone. Localizing the seizure onset zone is often a costly and time-consuming process wherein a patient undergoes intracranial EEG monitoring, and a team of clinicians wait for seizures to occur. Clinicians then analyse the intracranial EEG before each seizure onset to identify the seizure onset zone and localization accuracy increases when more seizures are captured. In this study, we develop a new approach to guide clinicians to actively elicit seizures with electrical stimulation. We propose that a brain region belongs to the seizure onset zone if a periodic stimulation at a particular frequency produces large amplitude oscillations in the intracranial EEG network that propagate seizure activity. Such responses occur when there is 'resonance' in the intracranial EEG network, and the resonant frequency can be detected by observing a sharp peak in the magnitude versus frequency response curve, called a Bode plot. To test our hypothesis, we analysed single-pulse electrical stimulation response data in 32 epilepsy patients undergoing intracranial EEG monitoring. For each patient and each stimulated brain region, we constructed a Bode plot by estimating a transfer function model from the intracranial EEG 'impulse' or single-pulse electrical stimulation response. The Bode plots were then analysed for evidence of resonance. First, we showed that when Bode plot features were used as a marker of the seizure onset zone, it distinguished successful from failed surgical outcomes with an area under the curve of 0.83, an accuracy that surpassed current methods of analysis with cortico-cortical evoked potential amplitude and cortico-cortical spectral responses. Then, we retrospectively showed that three out of five native seizures accidentally triggered in four patients during routine periodic stimulation at a given frequency corresponded to a resonant peak in the Bode plot. Last, we prospectively stimulated peak resonant frequencies gleaned from the Bode plots to elicit seizures in six patients, and this resulted in an induction of three seizures and three auras in these patients. These findings suggest neural resonance as a new biomarker of the seizure onset zone that can guide clinicians in eliciting native seizures to more quickly and accurately localize the seizure onset zone.

Transfer Function Models for the Localization of Seizure Onset Zone From Cortico-Cortical Evoked Potentials.

Surgical resection of the seizure onset zone (SOZ) could potentially lead to seizure-freedom in medically refractory epilepsy patients. However, localizing the SOZ can be a time consuming and tedious process involving visual inspection of intracranial electroencephalographic (iEEG) recordings captured during passive patient monitoring. Cortical stimulation is currently performed on patients undergoing invasive EEG monitoring for the main purpose of mapping functional brain networks such as language and motor networks. We hypothesized that evoked responses from single pulse electrical stimulation (SPES) can also be used to localize the SOZ as they may express the natural frequencies and connectivity of the iEEG network. To test our hypothesis, we constructed patient specific transfer function models from the evoked responses recorded from 22 epilepsy patients that underwent SPES evaluation and iEEG monitoring. We then computed the frequency and connectivity dependent "peak gain" of the system as measured by the H ∞    norm from systems theory. We found that in cases for which clinicians had high confidence in localizing the SOZ, the highest peak gain transfer functions with the smallest "floor gain" (gain at which the dipped H ∞    3dB below DC gain) corresponded to when the clinically annotated SOZ and early spread regions were stimulated. In more complex cases, there was a large spread of the peak-to-floor (PF) ratios when the clinically annotated SOZ was stimulated. Interestingly for patients who had successful surgeries, our ratio of gains, agreed with clinical localization, no matter the complexity of the case. For patients with failed surgeries, the PF ratio did not match clinical annotations. Our findings suggest that transfer function gains and their corresponding frequency responses computed from SPES evoked responses may improve SOZ localization and thus surgical outcomes.

State-space models of evoked potentials to localize the seizure onset zone.

Surgical removal of the seizure onset zone (SOZ) in epilepsy patients is a potentially curative treatment, but the process heavily relies on accurate localization of the SOZ via visual inspection. SPES (Single-pulse electrical stimulation) is a method recently used to explore inter-areal connectivity in vivo to probe functional brain networks such as language and motor networks, and to a much lesser degree, seizure networks. We hypothesized that a dynamical quantification of the connectivity networks derived from the evoked responses induced by SPES could also be used to localize the SOZ. To test our hypothesis, we used an intracranial EEG (iEEG) data set in which five epilepsy patients underwent extensive SPES evaluation. For each patient, and for each dataset that stimulated a different pair of electrodes, we constructed a state-space model from the patient's data. Specifically, we simultaneously estimated model parameters under an exogenous pulse input to a dynamical system whose state vector consisted of the response iEEG signals. Then, the size of the reachable state space, as quantified by the maximum singular value of the reachability matrix, σmax(R), was computed and denoted as the "largest" network response possible when stimulating the given pair. Our results suggest high agreement between σmax(R) and clinically annotated SOZ for patients with localizable SOZs.Clinical Relevance- Our study applies dynamical systems theory to identify epileptogenic brain regions, creating a novel tool that clinicians may use in surgical planning for medically-refractory epilepsy patients.

Localizing the seizure onset zone from single pulse electrical stimulation responses using transfer function models.

Surgical resection of the seizure onset zone (SOZ) could potentially lead to seizure-freedom in medically refractory epilepsy patients. However, localizing the SOZ can be a time consuming and tedious process involving visual inspection of intracranial electroencephalographic (iEEG) recordings captured during passive patient monitoring. Single pulse electrical stimulation (SPES) is currently performed on patients undergoing invasive EEG monitoring for the main purposes of mapping functional brain networks such as language and motor networks. We hypothesize that evoked responses from SPES can also be used to localize the SOZ as they may express the natural frequencies and connectivity of the iEEG network. To test our hypothesis, we construct patient specific single-input multi-output transfer function models from the evoked responses recorded from five epilepsy patients that underwent SPES evaluation and iEEG monitoring. Our preliminary results suggest that the stimulation electrodes that produced the highest gain transfer functions, as measured by the ${\mathcal{H}_\infty }$ norm, correspond to those electrodes clinically defined in the SOZ in successfully treated patients.Clinical Relevance- This study creates an innovative tool that allows clinicians to identify the seizure onset zone in medically refractory epilepsy patients using quantitative metrics thereby increasing surgical success outcomes, mitigating patient risks, and decreasing costs.