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.

Cortico-cortical evoked potentials in response to varying stimulation intensity improves seizure localization.

OBJECTIVE: As single pulse electrical stimulation (SPES) is increasingly utilized to help localize the seizure onset zone (SOZ), it is important to understand how stimulation intensity can affect the ability to use cortico-cortical evoked potentials (CCEPs) to delineate epileptogenic regions. METHODS: We studied 15 drug-resistant epilepsy patients undergoing intracranial EEG monitoring and SPES with titrations of stimulation intensity. The N1 amplitude and distribution of CCEPs elicited in the SOZ and non-seizure onset zone (nSOZ) were quantified at each intensity. The separability of the SOZ and nSOZ using N1 amplitudes was compared between models using responses to titrations, responses to one maximal intensity, or both. RESULTS: At 2 mA and above, the increase in N1 amplitude with current intensity was greater for responses within the SOZ, and SOZ response distribution was maximized by 4-6 mA. Models incorporating titrations achieved better separability of SOZ and nSOZ compared to those using one maximal intensity. CONCLUSIONS: We demonstrated that differences in CCEP amplitude over a range of current intensities can improve discriminability of SOZ regions. SIGNIFICANCE: This study provides insight into the underlying excitability of the SOZ and how differences in current-dependent amplitudes of CCEPs may be used to help localize epileptogenic sites.

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.

Effects of stimulation intensity on intracranial cortico-cortical evoked potentials: A titration study.

OBJECTIVE: The aim of the present study was to investigate the optimal stimulation parameters for eliciting cortico-cortical evoked potentials (CCEPs) for mapping functional and epileptogenic networks. METHODS: We studied 13 patients with refractory epilepsy undergoing intracranial EEG monitoring. We systematically titrated the intensity of single-pulse electrical stimulation at multiple sites to assess the effect of increasing current on salient features of CCEPs such as N1 potential magnitude, signal to noise ratio, waveform similarity, and spatial distribution of responses. Responses at each incremental stimulation setting were compared to each other and to a final set of responses at the maximum intensity used in each patient (3.5-10 mA, median 6 mA). RESULTS: We found that with a biphasic 0.15 ms/phase pulse at least 2-4 mA is needed to differentiate between non-responsive and responsive sites, and that stimulation currents of 6-7 mA are needed to maximize amplitude and spatial distribution of N1 responses and stabilize waveform morphology. CONCLUSIONS: We determined a minimum stimulation threshold necessary for eliciting CCEPs, as well as a point at which the current-dependent relationship of several response metrics all saturate. SIGNIFICANCE: This titration study provides practical, immediate guidance on optimal stimulation parameters to study specific features of CCEPs, which have been increasingly used to map both functional and epileptic brain networks in humans.

Graph theoretical analysis of evoked potentials shows network influence of epileptogenic mesial temporal region.

It is now widely accepted that seizures arise from the coordinated activity of epileptic networks, and as a result, traditional methods of analyzing seizures have been augmented by techniques like single-pulse electrical stimulation (SPES) that estimate effective connectivity in brain networks. We used SPES and graph analytics in 18 patients undergoing intracranial EEG monitoring to investigate effective connectivity between recording sites within and outside mesial temporal structures. We compared evoked potential amplitude, network density, and centrality measures inside and outside the mesial temporal region (MTR) across three patient groups: focal epileptogenic MTR, multifocal epileptogenic MTR, and non-epileptogenic MTR. Effective connectivity within the MTR had significantly greater magnitude (evoked potential amplitude) and network density, regardless of epileptogenicity. However, effective connectivity between MTR and surrounding non-epileptogenic regions was of greater magnitude and density in patients with focal epileptogenic MTR compared to patients with multifocal epileptogenic MTR and those with non-epileptogenic MTR. Moreover, electrodes within focal epileptogenic MTR had significantly greater outward network centrality compared to electrodes outside non-epileptogenic regions and to multifocal and non-epileptogenic MTR. Our results indicate that the MTR is a robustly connected subnetwork that can exert an overall elevated propagative influence over other brain regions when it is epileptogenic. Understanding the underlying effective connectivity and roles of epileptogenic regions within the larger network may provide insights that eventually lead to improved surgical outcomes.

Spatial-Temporal Functional Mapping Combined With Cortico-Cortical Evoked Potentials in Predicting Cortical Stimulation Results.

Functional human brain mapping is commonly performed during invasive monitoring with intracranial electroencephalographic (iEEG) electrodes prior to resective surgery for drug- resistant epilepsy. The current gold standard, electrocortical stimulation mapping (ESM), is time -consuming, sometimes elicits pain, and often induces after discharges or seizures. Moreover, there is a risk of overestimating eloquent areas due to propagation of the effects of stimulation to a broader network of language cortex. Passive iEEG spatial-temporal functional mapping (STFM) has recently emerged as a potential alternative to ESM. However, investigators have observed less correspondence between STFM and ESM maps of language than between their maps of motor function. We hypothesized that incongruities between ESM and STFM of language function may arise due to propagation of the effects of ESM to cortical areas having strong effective connectivity with the site of stimulation. We evaluated five patients who underwent invasive monitoring for seizure localization, whose language areas were identified using ESM. All patients performed a battery of language tasks during passive iEEG recordings. To estimate the effective connectivity of stimulation sites with a broader network of task-activated cortical sites, we measured cortico-cortical evoked potentials (CCEPs) elicited across all recording sites by single-pulse electrical stimulation at sites where ESM was performed at other times. With the combination of high gamma power as well as CCEPs results, we trained a logistic regression model to predict ESM results at individual electrode pairs. The average accuracy of the classifier using both STFM and CCEPs results combined was 87.7%, significantly higher than the one using STFM alone (71.8%), indicating that the correspondence between STFM and ESM results is greater when effective connectivity between ESM stimulation sites and task-activated sites is taken into consideration. These findings, though based on a small number of subjects to date, provide preliminary support for the hypothesis that incongruities between ESM and STFM may arise in part from propagation of stimulation effects to a broader network of cortical language sites activated by language tasks, and suggest that more studies, with larger numbers of patients, are needed to understand the utility of both mapping techniques in clinical practice.

Sensory stimulation enhances phantom limb perception and movement decoding.

OBJECTIVE: A major challenge for controlling a prosthetic arm is communication between the device and the user's phantom limb. We show the ability to enhance phantom limb perception and improve movement decoding through targeted transcutaneous electrical nerve stimulation in individuals with an arm amputation. APPROACH: Transcutaneous nerve stimulation experiments were performed with four participants with arm amputation to map phantom limb perception. We measured myoelectric signals during phantom hand movements before and after participants received sensory stimulation. Using electroencephalogram (EEG) monitoring, we measured the neural activity in sensorimotor regions during phantom movements and stimulation. In one participant, we also tracked sensory mapping over 2 years and movement decoding performance over 1 year. MAIN RESULTS: Results show improvements in the participants' ability to perceive and move the phantom hand as a result of sensory stimulation, which leads to improved movement decoding. In the extended study with one participant, we found that sensory mapping remains stable over 2 years. Sensory stimulation improves within-day movement decoding while performance remains stable over 1 year. From the EEG, we observed cortical correlates of sensorimotor integration and increased motor-related neural activity as a result of enhanced phantom limb perception. SIGNIFICANCE: This work demonstrates that phantom limb perception influences prosthesis control and can benefit from targeted nerve stimulation. These findings have implications for improving prosthesis usability and function due to a heightened sense of the phantom hand.