Optimization of patient-specific stereo-EEG recording sensitivity.

Stereo-EEG is a minimally invasive technique used to localize the origin of epileptic activity (the epileptogenic zone) in patients with drug-resistant epilepsy. However, current stereo-EEG trajectory planning methods are agnostic to the spatial recording sensitivity of implanted electrodes. In this study, we used image-based patient-specific computational models to design optimized stereo-EEG electrode configurations. Patient-specific optimized electrode configurations exhibited substantially higher recording sensitivity than clinically implanted configurations, and this may lead to a more accurate delineation of the epileptogenic zone. The optimized configurations also achieved equally good or better recording sensitivity with fewer electrodes compared with clinically implanted configurations, and this may reduce the risk for complications, including intracranial haemorrhage. This approach improves localization of the epileptogenic zone by transforming the clinical use of stereo-EEG from a discrete ad hoc sampling to an intelligent mapping of the regions of interest.

Relative contributions of different neural sources to the EEG.

Dogma dictates that the EEG signal is generated by postsynaptic currents (PSCs) because there are an enormous number of synapses in the brain, and PSCs have relatively long durations. However, PSCs are not the only potential source of electric fields in the brain. Action potentials, afterpolarizations, and presynaptic activity can also generate electric fields. Experimentally it is exceedingly difficult to delineate the contributions of different sources because they are casually linked. However, using computational modeling, we can interrogate the relative contributions of different neural elements to the EEG. We used a library of neuron models with morphologically realistic axonal arbors to quantify the relative contributions of PSCs, action potentials, and presynaptic activity to the EEG signal. Consistent with prior assertions, PSCs were the largest contributor to the EEG, but action potentials and afterpolarizations can also make appreciable contributions. For a population of neurons generating simultaneous PSCs and action potentials, we found that the action potentials accounted for up to 20% of the source strength while PSCs accounted for the other 80% and presynaptic activity negligibly contributed. Additionally, L5 PCs generated the largest PSC and action potential signals indicating that they the dominant EEG signal generator. Further, action potentials and afterpolarizations were sufficient to generate physiological oscillations, indicating that they are valid source contributors to the EEG. The EEG emerges from a combination of multiple different source, and, while PSCs are the largest contributor, other sources are non-negligible and should be included in modeling, analysis and interpretation of the EEG.

Modeling the Impact of Electrode/Tissue Geometry on Electrical Stimulation in Stereo-EEG.

PURPOSE: Electrical stimulation through depth electrodes is used to map function and seizure onset during stereoelectroencephalography in patients undergoing evaluation for epilepsy surgery. Factors such as electrode design, location, and orientation are expected to impact effects of electrical stimulation. METHODS: We developed a steady-state finite element model of brain tissue including five layers (skull through white matter) and an implanted electrode to explore the impact of electrode design and placement on the activation of brain tissue by electrical stimulation. We calculated electric potentials, current densities, and volume of tissue activated ( Volact ) in response to constant current bipolar stimulation. We modeled two depth electrode designs (3.5- and 4.43-mm intercontact spacing) and varied electrode location and orientation. RESULTS: The electrode with greater intercontact spacing produced 8% to 23% larger Volact (1% to 16% considering only gray matter). Vertical displacement of the electrodes by half intercontact space increased Volact for upward displacement (6% to 83% for all brain tissue or -5% to 96% gray matter only) and decreased Volact (1% to 16% or 24% to 49% gray matter only) for downward displacement. Rotating the electrode in the tissue by 30° to 60° with respect to the vertical axis increased Volact by 30% to 90% (20%-48% gray matter only). CONCLUSIONS: Location and orientation of depth electrodes with respect to surrounding brain tissue have a large impact on the amount of tissue activated during electrical stimulation mapping in stereoelectroencephalography. Electrode design has an impact, although modest for commonly used designs. Individualization of stimulation intensity at each location remains critical, especially for avoiding false-negative results.

Ideal current dipoles are appropriate source representations for simulating neurons for intracranial recordings.

OBJECTIVE: To determine whether dipoles are an appropriate simplified representation of neural sources for stereo-EEG (sEEG). METHODS: We compared the distributions of voltages generated by a dipole, biophysically realistic cortical neuron models, and extended regions of cortex to determine how well a dipole represented neural sources at different spatial scales and at electrode to neuron distances relevant for sEEG. We also quantified errors introduced by the dipole approximation of neural sources in sEEG source localization using standardized low-resolution electrotomography (sLORETA). RESULTS: For pyramidal neurons, the coefficient of correlation between voltages generated by a dipole and neuron model were > 0.9 for distances > 1 mm. For small regions of cortex (∼0.1 cm2), the error in voltages between a dipole and region was < 100 µV for all distances. However, larger regions of active cortex (>5 cm2) yielded > 50 µV errors within 1.5 cm of an electrode when compared to single dipoles. Finally, source localization errors were < 5 mm when using dipoles to represent realistic neural sources. CONCLUSIONS: Single dipoles are an appropriate source model to represent both single neurons and small regions of active cortex, while multiple dipoles are required to represent large regions of cortex. SIGNIFICANCE: Dipoles are computationally tractable and valid source models for sEEG.

Excitation properties of computational models of unmyelinated peripheral axons.

Biophysically based computational models of nerve fibers are important tools for designing electrical stimulation therapies, investigating drugs that affect ion channels, and studying diseases that affect neurons. Although peripheral nerves are primarily composed of unmyelinated axons (i.e., C-fibers), most modeling efforts focused on myelinated axons. We implemented the single-compartment model of vagal afferents from Schild et al. (1994) (Schild JH, Clark JW, Hay M, Mendelowitz D, Andresen MC, Kunze DL. J Neurophysiol 71: 2338-2358, 1994) and extended the model into a multicompartment axon, presenting the first cable model of a C-fiber vagal afferent. We also implemented the updated parameters from the Schild and Kunze (1997) model (Schild JH, Kunze DL. J Neurophysiol 78: 3198-3209, 1997). We compared the responses of these novel models with those of three published models of unmyelinated axons (Rattay F, Aberham M. IEEE Trans Biomed Eng 40: 1201-1209, 1993; Sundt D, Gamper N, Jaffe DB. J Neurophysiol 114: 3140-3153, 2015; Tigerholm J, Petersson ME, Obreja O, Lampert A, Carr R, Schmelz M, Fransén E. J Neurophysiol 111: 1721-1735, 2014) and with experimental data from single-fiber recordings. Comparing the two models by Schild et al. (1994, 1997) revealed that differences in rest potential and action potential shape were driven by changes in maximum conductances rather than changes in sodium channel dynamics. Comparing the five model axons, the conduction speeds and strength-duration responses were largely within expected ranges, but none of the models captured the experimental threshold recovery cycle-including a complete absence of late subnormality in the models-and their action potential shapes varied dramatically. The Tigerholm et al. (2014) model best reproduced the experimental data, but these modeling efforts make clear that additional data are needed to parameterize and validate future models of autonomic C-fibers.NEW & NOTEWORTHY Peripheral nerves are primarily composed of unmyelinated axons, and there is growing interest in electrical stimulation of the autonomic nervous system to treat various diseases. We present the first cable model of an unmyelinated vagal nerve fiber and compare its ion channel isoforms and conduction responses with other published models of unmyelinated axons, establishing important tools for advancing modeling of autonomic nerves.

Multimodal characterization of the human nucleus accumbens.

Dysregulation of the nucleus accumbens (NAc) is implicated in numerous neuropsychiatric disorders. Treatments targeting this area directly (e.g. deep brain stimulation) demonstrate variable efficacy, perhaps owing to non-specific targeting of a functionally heterogeneous nucleus. Here we provide support for this notion, first observing disparate behavioral effects in response to direct simulation of different locations within the NAc in a human patient. These observations motivate a segmentation of the NAc into subregions, which we produce from a diffusion-tractography based analysis of 245 young, unrelated healthy subjects. We further explore the mechanism of these stimulation-induced behavioral responses by identifying the most probable subset of axons activated using a patient-specific computational model. We validate our diffusion-based segmentation using evidence from several modalities, including MRI-based measures of function and microstructure, human post-mortem immunohistochemical staining, and cross-species comparison of cortical-NAc projections that are known to be conserved. Finally, we visualize the passage of individual axon bundles through one NAc subregion in a post-mortem human sample using CLARITY 3D histology corroborated by 7T tractography. Collectively, these findings extensively characterize human NAc subregions and provide insight into their structural and functional distinctions with implications for stereotactic treatments targeting this region.

Modeling Current Sources for Neural Stimulation in COMSOL.

Background: Computational modeling provides an important toolset for designing and analyzing neural stimulation devices to treat neurological disorders and diseases. Modeling enables efficient exploration of large parameter spaces, where preclinical and clinical studies would be infeasible. Current commercial finite element method software packages enable straightforward calculation of the potential distributions, but it is not always clear how to implement boundary conditions to appropriately represent metal stimulating electrodes. By quantifying the effects of different electrode representations on activation thresholds for model axons, we provide recommendations for accurate and efficient modeling of neural stimulating electrodes. Methods: We quantified the effects of different representations of current sources for neural stimulation in COMSOL Multiphysics for monopolar, bipolar, and multipolar electrode designs. Results: We recommend modeling each electrode contact as a thin platinum domain, modeling the electrode substrate with the conductivity of silicone, and either using a point current source in the center of each electrode contact or using a boundary current source. Alternatively, to avoid possible numerical instabilities associated with a large range of conductivity values (i.e., platinum and silicone) and to eliminate the small mesh elements required for thin electrode contacts, the electrode substrate can be assigned the conductivity of platinum by using insulating boundaries between the substrate and surrounding medium, and within the substrate to isolate the contacts from each other. When modeling more than one contact, we recommend using superposition by solving the model once for each contact, leaving inactive contacts floating, and superposing the resulting potentials. We computed comparable errors in activation thresholds across the different implementations in a simplified model (electrode in a homogeneous, isotropic medium), and in realistic models of rat spinal cord stimulation (SCS) and human deep brain stimulation, indicating that the recommended approaches are applicable to different stimulation targets.