Functional Brain Mapping Using Depth Electrodes.

OBJECTIVE: This study investigated the neurologic symptoms and stimulus intensities in the stimulation of deep structures and subcortical fibers with the depth electrodes. METHODS: Seventeen patients with drug-refractory epilepsy who underwent functional brain mapping with the depth electrodes were enrolled. The 50 Hz electrical stimulation was applied, and the diffusion tensor image was used to identify subcortical fibers. The responsible structures and stimulus intensities for the induced neurologic symptoms were evaluated. RESULTS: Neurologic symptoms were induced in 11 of 17 patients. The opercular stimulation elicited the neurologic symptoms in 6 patients at the median threshold of 4.0 mA (visceral/face/hand sensory, hand/throat motor, negative motor and auditory symptoms). The insular stimulation induced the neurologic symptoms in 4 patients at the median threshold of 4.0 mA (auditory, negative motor, and sensory symptoms). The stimulation of subcortical fibers was induced in 5 of 9 patients at the median threshold of 4.5 mA. The thresholds of depth electrodes were significantly lower than those of subdural electrodes in 8 patients who used both subdural and depth electrodes and induced symptoms with both electrodes. CONCLUSIONS: The stimulation of depth electrodes can identify the function of deep structures and subcortical fibers with lower intensities than subdural electrodes.

Intraoperative nerve stimulation during vagal nerve stimulator placement.

Background: Vagal nerve stimulation (VNS) is a palliative treatment for refractory epilepsy and intraoperative nerve stimulation is applied to the vagal and other nerves to prevent electrode misplacement. We evaluated these thresholds to establish intraoperative monitoring procedures for VNS surgery. Methods: Forty-six patients who underwent intraoperative nerve stimulation during VNS placement were enrolled. The vagal nerve and other exposed nerves were electrically stimulated during surgery, and muscle contraction was confirmed by electromyography of the vocal cords and visual recognition of cervical muscle contraction. The nerve thresholds and the most sensitive parts of the vagal nerve were analyzed retrospectively. Results: The stimulation of vagal nerves induced vocal cord responses in all 46 patients; the median thresholds of the most sensitive parts and all parts were 0.2 mA (range: 0.05-0.75 mA) and 0.25 mA (range: 0.15-1.5 mA), respectively. The medial middle region was identified as the most sensitive part of the vagal nerve in the majority of participants (82.5%). In 11 patients, other cervical nerves were stimulated and sternohyoid muscle contraction was induced with a median threshold of 0.35 mA (range: 0.1-0.7 mA) in eight patients, while sternocleidomastoid muscle contraction was induced with a median threshold of 0.2 mA (range: 0.1-0.2 mA) in three. Conclusion: Intraoperative stimulation of vagal nerves induces vocal cord responses with locational variations, and the middle part stimulation could minimize the stimulus intensities. The nerves innervating the sternohyoid and sternocleidomastoid muscles may be exposed during the procedure. Knowledge of these characteristics will enhance the effectiveness of this technique in future applications.

Deep learning for the diagnosis of mesial temporal lobe epilepsy.

OBJECTIVE: This study aimed to enable the automatic detection of the hippocampus and diagnose mesial temporal lobe epilepsy (MTLE) with the hippocampus as the epileptogenic area using artificial intelligence (AI). We compared the diagnostic accuracies of AI and neurosurgical physicians for MTLE with the hippocampus as the epileptogenic area. METHOD: In this study, we used an AI program to diagnose MTLE. The image sets were processed using a code written in Python 3.7.4. and analyzed using Open Computer Vision 4.5.1. The deep learning model, which was a fine-tuned VGG16 model, consisted of several layers. The diagnostic accuracies of AI and board-certified neurosurgeons were compared. RESULTS: AI detected the hippocampi automatically and diagnosed MTLE with the hippocampus as the epileptogenic area on both T2-weighted imaging (T2WI) and fluid-attenuated inversion recovery (FLAIR) images. The diagnostic accuracies of AI based on T2WI and FLAIR data were 99% and 89%, respectively, and those of neurosurgeons based on T2WI and FLAIR data were 94% and 95%, respectively. The diagnostic accuracy of AI was statistically higher than that of board-certified neurosurgeons based on T2WI data (p = 0.00129). CONCLUSION: The deep learning-based AI program is highly accurate and can diagnose MTLE better than some board-certified neurosurgeons. AI can maintain a certain level of output accuracy and can be a reliable assistant to doctors.

Steady-State Cortico-Cortical Evoked Potential.

PURPOSE: The present study evaluated the utility of the steady-state responses of cortico-cortical evoked potentials (SSCCEPs) and compared them with the responses of conventional CCEPs. METHODS: Eleven patients with medically intractable focal epilepsy who underwent the implantation of subdural electrodes or stereoelectroencephalography were enrolled. Conventional CCEPs were obtained by averaging responses to alternating 1-Hz electrical stimuli, and 5-Hz stimuli were delivered for recording SSCCEPs. The distribution of SSCCEPs was assessed by a frequency analysis of fast Fourier transform and compared with conventional CCEPs. RESULTS: Steady-state responses of cortico-cortical evoked potentials were successfully recorded in areas consistent with conventional CCEPs in all patients. However, SSCCEPs were more easily disturbed by the 5-Hz stimulation, and small responses had difficulty generating SSCCEPs. CONCLUSIONS: Steady-state responses of cortico-cortical evoked potentials may be a useful alternative to conventional CCEPs.

Effect of Early Surgical Intervention for Brain Tumors Associated with Epilepsy on the Improvement in Memory Performance.

We evaluated the effect of early surgical intervention on the change in memory performance of patients with low-grade brain tumors associated with epilepsy. Twenty-three adult patients with low-grade brain tumors and epilepsy who underwent surgery at our institution between 2010 and 2019 were included. The Wechsler Memory Scale-Revised (WMS-R) was used to assess cognitive memory performance. Memory performance before and after surgery was retrospectively evaluated. In addition, the relationships among preoperative memory function, postoperative seizure outcome, preoperative seizure control, temporal lobe lesion, and change in memory function were examined. There were statistically significant improvements from median preoperative to postoperative WMS-R subscale scores for verbal memory, general memory, and delayed recall (p<0.001, p<0.001, and p=0.0055, respectively) regardless of preoperative sores and tumor location. Good postsurgical seizure control was associated with significant improvements in postoperative WMS-R performance. Our results indicated that early surgical intervention might improve postoperative memory function in patients with low-grade brain tumors and epilepsy.

Motor Mapping with Functional Magnetic Resonance Imaging: Comparison with Electrical Cortical Stimulation.

The aim of the present study was to evaluate motor area mapping using functional magnetic resonance imaging (fMRI) compared with electrical cortical stimulation (ECS). Motor mapping with fMRI and ECS were retrospectively compared in seven patients with refractory epilepsy in which the primary motor (M1) areas were identified by fMRI and ECS mapping between 2012 and 2019. A right finger tapping task was used for fMRI motor mapping. Blood oxygen level-dependent activation was detected in the left precentral gyrus (PreCG)/postcentral gyrus (PostCG) along the "hand knob" of the central sulcus in all seven patients. Bilateral supplementary motor areas (SMAs) were also activated (n = 6), and the cerebellar hemisphere showed activation on the right side (n = 3) and bilateral side (n = 4). Furthermore, the premotor area (PM) and posterior parietal cortex (PPC) were also activated on the left side (n = 1) and bilateral sides (n = 2). The M1 and sensory area (S1) detected by ECS included fMRI-activated PreCG/PostCG areas with broader extent. This study showed that fMRI motor mapping was locationally well correlated to the activation of M1/S1 by ECS, but the spatial extent was not concordant. In addition, the involvement of SMA, PM/PPC, and the cerebellum in simple voluntary movement was also suggested. Combination analysis of fMRI and ECS motor mapping contributes to precise localization of M1/S1.

Cortical regions and networks of hyperkinetic seizures: Electrocorticography and diffusion tensor imaging study.

OBJECTIVE: The present study investigated the cortical areas and networks responsible for hyperkinetic seizures by analyzing invasive recordings and diffusion tensor imaging (DTI) tractography. METHODS: Seven patients with intractable focal epilepsy in whom hyperkinetic seizures were recorded during an invasive evaluation at Sapporo Medical University between January 2012 and March 2020 were enrolled in the present study. Intracranial recordings were analyzed to localize seizure-onset zones (SOZs) and symptomatogenic zones (spread areas at clinical onset). DTI was used to identify the subcortical fibers originating from SOZs. RESULTS: Ten SOZs were located in four areas: (1) the inferior parietal lobule (two SOZs in two patients), (2) temporo-occipital junction (three SOZs in two patients), (3) medial temporal area (three SOZs in three patients) and (4) medial/lateral frontal lobe (two SOZs in two patients). Symptomatogenic zones appeared to be the premotor area, basal temporal area, temporo-occipital junction, and the postcentral gyrus/supramarginal gyrus. The tractographic analysis revealed that the inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), middle longitudinal fasciculus (MLF), arcuate fasciculus (AF)/superior longitudinal fasciculus (SLF) II, III, and cingulum bundle may be associated with hyperkinetic seizures. CONCLUSION: The present results suggest the cortical areas (the inferior parietal lobule, temporo-occipital junction, medial temporal area, and medial/lateral frontal lobe) and subcortical fibers (IFOF, ILF, MLF, AF/SLFII, III, and the cingulum bundle) responsible for generating hyperkinetic seizures.

Effects of polarity of bipolar sensorimotor direct cortical stimulation on intraoperative motor evoked potentials.

OBJECTIVE: The present study investigated the effects of the stimulus polarity and location of motor evoked potential (MEP) to establish a stimulation protocol. METHODS: Nineteen patients who intraoperatively underwent MEP in bipolar direct cortical stimulation were enrolled in the present study. Somatosensory evoked potentials (SEP) of the contralateral median nerve stimulation were recorded to determine stimulation sites. MEP was performed under two settings in all patients: 1. Anodal bipolar stimulation: an anode on the precentral gyrus and a cathode on the postcentral gyrus, 2. Cathodal bipolar stimulation: a cathode on the precentral gyrus and an anode on the postcentral gyrus. MEP amplitudes and the coefficient of variation (CV) at a stimulation intensity of 25 mA and the thresholds of induced MEP were compared between the two settings. RESULTS: An electrical stimulation at 25 mA induced a significantly higher amplitude in cathodal bipolar stimulation than in anodal bipolar stimulation. Cathodal bipolar stimulation also showed significantly lower thresholds than anodal stimulation. CV did not significantly differ between the two groups. CONCLUSIONS: These results indicate that cathodal bipolar stimulation is superior to anodal bipolar stimulation for intraoperative MEP monitoring. SIGNIFICANCE: MEP in cathodal bipolar cortical stimulation may be used in a safe and useful evaluation method of motor fiber damage that combines sensitivity and specificity.

A case of paroxysmal kinesigenic dyskinesia suspected to be reflex epilepsy.

An 11-year-old male patient developed weakness or right arm elevation after sudden movement at the age of eight. Reflex epilepsy was initially suspected; however, magnetic resonance imaging and electroencephalography (EEG) revealed no abnormality. Video-EEG monitoring was performed, but no change was noted during attacks of weakness. He was diagnosed with paroxysmal kinesigenic dyskinesia (PKD) and carbamazepine has stopped his attacks. PKD is a rare neurological disorder characterized by brief attacks of involuntary movement triggered by sudden voluntary movements, which may be confused with reflex epilepsy. PKD should be considered as a differential diagnosis of reflex epilepsy.

Eye Movement Network Originating from Frontal Eye Field: Electric Cortical Stimulation and Diffusion Tensor Imaging.

This study investigated the networks originating from frontal eye fields (FEFs) using electric cortical stimulation and diffusion tensor imaging (DTI). Seven patients with intractable focal epilepsy, in which FEFs were identified by electrical cortical stimulation, were enrolled in this study. Electric stimulation at 50 Hz was applied to the electrodes for functional mapping. DTI was used to identify the subcortical fibers originating from the FEFs with two regions of interests (ROIs) in the FEF and contralateral paramedian pontine reticular formation (PPRF). FEFs were found in the superior precentral sulcus (pre-CS) in six patients and superior frontal gyrus (SFG) in three patients. DTI detected fibers connecting FEFs and contralateral PPRFs, passing within the internal capsule. The fibers were located close to the lateral antero-superior border of the subthalamic nucleus (STN) and medial posterior border of the globus pallidus internus (GPi). This study found the characteristic subcortical networks of the FEF. These tracts should be noted to prevent complications of deep brain stimulation (DBS) of the STN or GPi.

Forgetting to take antiseizure medications is associated with focal to bilateral tonic-clonic seizures, as revealed by a cross-sectional study.

OBJECTIVES: To evaluate the effects of nonadherence to antiseizure medications (ASMs) and clinical characteristics on seizure control, we employed a prospective cohort cross-sectional study using self-reports and medical records of patients with epilepsy (PWEs). METHODS: Eight hundred and fifty-five PWEs taking ASMs were enrolled from fourteen collaborative outpatient clinics from January 2018 to March 2019. Questions from the Morisky Medication Adherence Scale were used as adherence self-reports. If a PWE's questionnaire indicated that they had missed doses of their ASMs, outpatient physicians asked them directly about the details of their compliance, including the timing of intentionally or unintentionally missed doses. The association between lack of seizure control and utilization outcomes, such as missed doses, demographics, and clinical characteristics of the PWEs, were assessed by univariate and multivariate analyses. RESULTS: Multivariate analysis revealed that forgetting to take ASMs was associated with lack of seizure control and the existence of focal to bilateral tonic-clonic seizures. Dementia, younger age, use of three or more antiepileptic agents, and living in a one-person household were associated with the risk of forgetting to take ASMs. SIGNIFICANCE: For PWEs with poor drug management or a high incidence of missed doses of ASMs, efforts to improve adherence could facilitate better seizure control and decrease focal to bilateral tonic-clonic propagation.

Anatomical and functional distribution of functional MRI language mapping.

OBJECTIVE: The aim of the present study was to compare localization of the language cortex using electrical cortical stimulation (ECS) and functional magnetic resonance imaging (fMRI) to establish the relevance of fMRI language mapping. METHODS: Language mapping with fMRI and functional ECS mapping were retrospectively compared in ten patients with refractory epilepsy who underwent fMRI language mapping and functional ECS mapping between June 2012 and April 2019. A shiritori task, a popular Japanese word chain game, was used for fMRI language mapping. RESULTS: BOLD signal activation was observed in the left inferior frontal gyrus (including the pars opecularis and the pars triangularis), and superior temporal gyrus, which is a language-related area, as well as in the left superior and middle frontal gyri, the intraparietal sulcus, and fusiform gyrus. These results were compared with ECS to elucidate the functional role of the activated areas during fMRI language tasks. These activated areas included language areas, negative motor areas, supplementary motor areas (SMAs), and non-functional areas. CONCLUSION: The activated areas of fMRI language mapping include language-related areas, the negative motor area, and SMAs. These findings suggest the involvement of language and higher order motor networks in verbal expression.

The Immediate Effects of Vagus Nerve Stimulation in Intractable Epilepsy: An Intra-operative Electrocorticographic Analysis.

The purpose of this study was to investigate whether and how vagus nerve stimulation (VNS) reduces the epileptogenic activity in the bilateral cerebral cortex in patients with intractable epilepsy. We analyzed the electrocorticograms (ECoGs) of five patients who underwent callosotomy due to intractable epilepsy even after VNS implantation. We recorded ECoGs and analyzed power spectrum in both VNS OFF and ON phases. We counted the number of spikes and electrodes with epileptic spikes, distinguishing unilaterally and bilaterally hemispherically spread spikes as synchronousness of the epileptic spikes in both VNS OFF and ON phases. There were 24.80 ± 35.55 and 7.20 ± 9.93 unilaterally spread spikes in the VNS OFF and ON phases, respectively (P = 0.157), and 35.8 ± 29.21 and 10.6 ± 13.50 bilaterally spread spikes in the VNS OFF and ON phases, respectively (P = 0.027). The number of electrodes with unilaterally and bilaterally spread spikes in the VNS OFF and ON phases was 3.84 ± 2.13 and 3.59 ± 1.82 (P = 0.415), and 8.20 ± 3.56 and 6.89 ± 2.89 (P = 0.026), respectively. The ECoG background power spectra recordings in the VNS OFF and ON phases were also analyzed. The spectral power tended to be greater in the high-frequency band at VNS ON phase than OFF phase. This study showed the reduction of epileptogenic spikes and spread areas of the spikes by VNS as immediate effects, electrophysiologically.

Misleading non-epileptic epileptiform activities on intracranial recordings.

Numerous non-epileptic physiological electroencephalographic (EEG) patterns morphologically mimic epileptiform activity. However, misleading non-epileptic findings of electrocorticography (ECoG) have not yet been examined in detail. The aim of the present study was to identify non-epileptic epileptiform ECoG findings. We retrospectively reviewed the intracranial recordings of 21 patients with intractable focal epilepsy who became seizure-free after a presurgical evaluation with subdural electrodes following resective surgeries at Sapporo Medical University between January 2014 and December 2018. Morphological epileptiform findings outside epileptogenic areas were judged as non-epileptic and analyzed. Seventeen areas in nine patients exhibited non-epileptic epileptiform activities. These areas were identified in the lateral temporal cortices, basal temporal areas, rolandic areas, and frontal lobe. Morphological patterns were classified into three types: 1) spiky oscillations, 2) isolated spiky activity, and 3) isolated fast activity. The normal cortex may exhibit non-epileptic epileptiform activities. These activities need to be carefully differentiated from real epileptic abnormalities to prevent the mislocalization of epileptogenic areas.

Intraoperative Monitoring for Vagus Nerve Stimulation.

BACKGROUND: Vagus nerve stimulation is a palliative treatment for patients with refractory epilepsy; however, the misplacement of electrodes may cause complications and thus needs to be avoided. METHODS: We herein report an intraoperative monitoring technique to prevent the misplacement of electrodes. Endotracheal tube electrodes were inserted to record electromyographic activity from the vocal cords and identify the vagus nerve. Electromyography electrodes were placed on the sternomastoid muscle, sternohyoid muscle, geniohyoid muscle, and trapezius muscle to record muscle activities innervated by the ansa cervicalis. The vagus nerve and ansa cervicalis were electrically stimulated during surgery, and electromyography of the vocal cords and muscles innervated by the ansa cervicalis was recorded. The threshold of vagus nerve activation ranged between 0.05 and 0.75 mA. RESULTS: The vagus nerve was successfully identified and differentiated from the nerve root of the ansa cervicalis using this technique. CONCLUSIONS: Intraoperative monitoring of the vagus nerve and ansa cervicalis is useful for safe and effective vagus nerve stimulation.

Psychogenic Pseudo-responses in an Electrical Cortical Stimulation.

An electrical cortical stimulation provides important information for functional brain mapping. However, subjective responses (i.e. sensory, visual, and auditory symptoms) are purely detected by patients' descriptions, and may be affected by patients' awareness and intelligence levels. We experienced psychogenic responses in the electrical cortical stimulation of two patients with intractable epilepsy. A sham stimulation was useful for differentiating pseudo-responses from real responses in the electrical cortical stimulation. Inductive questions, long testing durations, and clear cues of stimulation onsets need to be avoided to prevent psychogenic pseudo-responses in the electrical cortical stimulation. Furthermore, a sham stimulation is applicable for detecting pseudo-responses the moment patients show atypical or inexplicable symptoms.

The Influence of Anesthesia on Corticocortical Evoked Potential Monitoring Network Between Frontal and Temporoparietal Cortices.

BACKGROUND: Previous studies have reported the usefulness of intraoperative corticocortical evoked potentials (CCEPs) for preserving language function during brain surgery. OBJECTIVE: This study aimed to assess the influence of depth of anesthesia on CCEP to establish its clinical utility. METHODS: Twenty patients with brain tumors or epilepsy who underwent awake craniotomy were included in this study. Before resection, the electrode plates were placed on the frontal and temporoparietal cortices, and 1-Hz alternating electrical stimuli were delivered to the pars opercularis/pars triangularis in a bipolar fashion. Electrocorticograms from the temporoparietal cortices time-locked to stimuli were averaged to obtain CCEP responses from a state of deep anesthesia until the awake state. The correlation between CCEP waveforms and bispectral index (BIS) was evaluated. RESULTS: CCEP amplitude increased with the increase in the BIS level. CCEP latency decreased in 5 patients and increased in 15 patients under anesthesia compared with the awake state. CCEP amplitudes decreased by 11.3% to 75.2% (median 31.3%) under anesthesia with <65 BIS level. These differences were statistically significant (P < 0.01, Wilcoxon signed-rank test). With respect to CCEP latencies, there was no significant difference between the awake and anesthetic states. CONCLUSIONS: CCEP amplitudes were correlated with depth of anesthesia, whereas CCEP latencies were not affected by anesthesia. The influence of anesthesia should be considered when applying this technique to intraoperative monitoring.

The auditory cortex network in the posterior superior temporal area.

OBJECTIVE: This study investigated the function and networks of the auditory cortices in the posterior lateral superior temporal area (PLST) using a combination of electrical cortical stimulation and diffusion tensor imaging (DTI). METHODS: Seven patients with intractable focal epilepsy in which the PLST auditory cortices were identified during the electrical cortical stimulation were enrolled in this study (left side: four patients, right side: three patients). Electrical stimulation at 50 Hz was applied to the chronically implanted subdural electrodes to identify the PLST auditory cortices. DTI was used to identify the subcortical fibers originating from the PLST auditory cortices found by electrical stimulation. RESULTS: Electrical stimulation of the right PLST auditory cortices induced hearing impairment in three patients and left side stimulation elicited hearing illusory sounds in four patients. DTI detected the middle longitudinal fasciculus (MLF) in all patients, the superior longitudinal fasciculus (SLF) in six patients and the inferior fronto-occipital fasciculus (IFOF) in three patients, originating from the PLST auditory cortices. CONCLUSION: This study suggests different functional roles between the right and left PLST auditory cortices, and the networks originating from these areas. SIGNIFICANCE: MLF, SLF and IFOF might be associated with the auditory processing.

Interhemispheric Asymmetry of Network Connecting Between Frontal and Temporoparietal Cortices: A Corticocortical-Evoked Potential Study.

BACKGROUND: The connection between the ventrolateral frontal and temporoparietal cortices has an important role in language function on the language-dominant side and spatial awareness on the nondominant side. However, the laterality of these pathways remains controversial. We investigated the laterality of this connection using corticocortical-evoked potentials (CCEPs). METHODS: From April 2014 to March 2016, 27 patients who had undergone frontotemporal craniotomy were enrolled. With the patients under general anesthesia, subdural electrodes were placed on both frontal and temporoparietal areas intraoperatively. Alternating 1-Hz electrical stimuli were delivered to the pars opercularis and pars triangularis with a stimulus intensity of 10 mA. CCEPs were obtained from temporoparietal areas by averaging the electrocorticogram time-locked to the stimulus onset. The amplitudes and latencies of the CCEP N1 components were compared between the dominant and nondominant sides. RESULTS: The median amplitudes of the CCEPs were 335.1 µV (range, 60.2-750) and 125.65 µV (range, 55.1-634) on the dominant and nondominant sides, respectively. The CCEP amplitudes were significantly larger on the dominant side than on the nondominant side (P = 0.013). In contrast, the median latency was 27.8 ms (range, 19.3-36.6) on the language-dominant side and 28.9 ms (range, 8.9-38.5) on the nondominant side. The latencies were not significantly different between the 2 sides (P = 0.604). CONCLUSIONS: The CCEP amplitudes were significantly larger in the dominant hemisphere. These findings can lead to better hypotheses regarding the relationship between language functions and the development of the network connecting the frontal and temporoparietal cortices.

Threshold and distribution of afterdischarges with electrical cortical stimulation.

OBJECTIVE: The present study aimed to investigate the threshold and distribution of afterdischarges (ADs) with cortical electrical stimulation for functional brain mapping. METHOD: We retrospectively analyzed data from 11 patients with medically intractable epilepsy who underwent 50-Hz cortical electrical stimulation for functional mapping followed by resection. These patients became seizure free for more than six months. The threshold and distribution of ADs induced by the stimulation were evaluated. RESULTS: The median threshold was 6 mA (range: 2-15 mA) for the frontal lobe, 8 mA (3-15 mA) for the temporal lobe, 6 mA (2-15 mA) for the parietal lobe, and 6 mA (4-12 mA) for the occipital lobe. No significant interlobar differences were observed in AD thresholds. No significant differences were noted between within and outside epileptogenic zones. The distribution of ADs, remote spread was observed in all patients, reflecting fronto-parieto-temporal connections, as well as contiguous spread. The stimulation of premotor areas, the inferior parietal lobule, supplementary motor area, and basal temporal areas appeared to induce ADs in remote cortices. CONCLUSION: While no locational differences were observed in AD thresholds, each brain region showed a characteristic pattern for AD spread. Remote AD spread needs to be considered for safe functional mapping.