Aging-associated inflammation and fibrosis in arachnoid membrane.

BACKGROUND: The physiological and pathological significance of the arachnoid membrane (AM) is still unknown. In this study, we investigated various characteristics of the AM, focusing on the influence of inflammation and fibrosis. METHODS: Small pieces of AM sample were obtained during neurosurgical procedures from 74 cases. The clinical and pathological characteristics of the hyperplastic AM group (≥ 50 µm) and the non-hyperplastic AM group (< 50 µm) were compared. Then, potential correlations between AM thickness and clinical characteristics were analyzed. Moreover, VEGFα, TGFß, and TGFα levels were quantitated by real time PCR. Then, the potential correlations between AM thickness and these inflammatory or anti-inflammatory markers, and the influence of the original disease were calculated. RESULTS: The median age of the patients in hyperplastic AM group was significantly older than that of the non-hyperplastic AM group. Moreover, the number of fibroblasts, CD68+ cells, CD86+ cells, and CD206+ cells in the hyperplastic AM group was significantly higher than that in the non-hyperplastic AM group. The AM thickness was significantly correlated to age and number of fibroblasts, CD68+ cells, CD86+ cells, and CD206+ cells. The thickness of the AM was significantly correlated to the messenger RNA expression levels of VEGFα (ρ = 0.337), and the VEGFα expression levels were significantly correlated with TGFß and TNFα. CONCLUSIONS: The AM hyperplasia was influenced by aging and could be a result of inflammation and fibrosis through cytokine secretion from the inflammatory cells and fibroblasts in the AM.

[Bone Flap Resorption after Cranioplasty in Pediatric Patients:Report of 2 Cases].

Aseptic bone flap resorption, a rare complication after cranioplasty following decompressive craniectomy, is more likely to develop in children. We experienced two cases of aseptic bone flap resorption and identified potential pathophysiological mechanisms through histological findings. In the first case, an 11-year-old girl underwent decompressive craniectomy due to brain swelling with contusion. An autologous bone flap was cryopreserved for four months. Twenty-five months after cranioplasty with autologous bone flap, aseptic bone flap resorption was observed, and cranioplasty was performed with ceramic bone. Most of the histological findings in this case showed mature osseous tissue, while some showed osteoclasts and new bone formation due to endochondral ossification. In the second case, a 10-year-old girl underwent frontal craniectomy and removal of contusional hematoma. Fourteen months after cranioplasty with autologous bone flap, aseptic bone flap resorption was observed, and cranioplasty was performed with ceramic bone paste. The progression of bone flap resorption was not recognized for 12 months. In these cases, new bone formation was not necessarily linked to pathological bone flap resorption. It is supposed that the balance between bone destruction and new bone formation was disrupted by unknown factors.

[Pediatric Iatrogenic Vertebral Arteriovenous Fistula Successfully Treated with Endovascular Treatment:A Case Report].

OBJECT: We report a relatively rare case of pediatric iatrogenic extradural vertebral arteriovenous fistula. CASE: A five-year-old boy with a history of multiple surgeries for Total Anomalous Pulmonary Venous Return(TAPVR)exhibited vascular engorgement of his right neck from about 4 years old. We thought that this was caused by his past operations. He demonstrated swollen blood vessels in the right neck and pulmonary hypertension with increased right heart load. A right extradural vertebral arteriovenous fistula was seen on angiography. A high flow shunt was present at the V1 segment, at the level of the sixth cervical vertebra, and a 12 mm venous pouch was present anterior to the vertebral artery. We recognized the outlet passages of the cranial tract were the vertebral venous plexus, internal jugular vein, and right atrium. We performed endovascular transarterial embolization using a hydrogel coil. As a result, we treated with a high volume embolization ratio. Following treatment, the arteriovenous fistula disappeared while anterograde blood flow of the vertebral artery was preserved. The patient demonstrated no neurological deficits, improved right heart load, and his venous pouch of the neck. He has had no recurrence in the two years after treatment. CONCLUSION: Endovascular surgery is effective and safe for the treatment of iatrogenic vertebral arteriovenous fistula.

Mechanical Thrombectomy Using a Large Dual-Layer Stent Retriever for Near-Occlusion of the Common Carotid Bifurcation Caused by a Giant Free-Floating Thrombus.

Objective: We report a case of near-occlusion of the common carotid bifurcation caused by a giant free-floating thrombus (FFT) successfully treated with mechanical thrombectomy using a large dual-layer stent retriever. Case Presentation: A 51-year-old man presented to our hospital with dysarthria, right hemiparalysis, and paresthesia. MRI revealed an acute infarction of the left cortical watershed zone, and MRA revealed decreased signals in the left common carotid bifurcation. Carotid ultrasonography demonstrated a giant FFT in the left common carotid bifurcation. Angiography revealed a giant thrombus extending from the left common carotid artery (CCA) to the internal carotid artery (ICA) and the external carotid artery. As direct aspiration from both a balloon-guided catheter (BGC) and an aspiration catheter (AC) was ineffective, we deployed a large dual-layer stent retriever from the ICA to the CCA with an AC-connected aspiration pump and retrieved it under manual aspiration through the BGC. The giant thrombus was successfully removed, and complete recanalization was achieved without distal embolisms. Conclusion: Although there is no established treatment for giant thrombi in the carotid artery, mechanical thrombectomy using a large dual-layer stent retriever may be an effective treatment option.

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.

Accumulation of Macromolecules in Idiopathic Normal Pressure Hydrocephalus.

The clearance system in the brain is not completely understood. The aim of this study was to prove the presence of the "glymphatic system" in the human brain using magnetic resonance spectroscopy (MRS).Spectral data of the brain white matter were obtained from healthy volunteers and patients with hydrocephalic dementia and used to measure intracerebral metabolites, including macromolecules (MMs) and lipids. Data were transferred from the MRS scanners to a workstation, and metabolites were quantified with the spectrogram-based eddy current method and water scaling.MM levels were significantly higher in patients with a slow gait and executive dysfunction due to normal pressure hydrocephalus (NPH) than in asymptomatic volunteers (p <0.01). In contrast, the N-acetyl aspartate (NAA) level was significantly lower in patients with executive dysfunction than in asymptomatic volunteers (p <0.01). There were no statistically significant differences in metabolites, including alanine, aspartate, creatine, γ-amino butyric acid, D-glucose, glutamine, glutamate, glycerophosphorylcholine, phosphorylcholine, lactate, myoinositol, N-acetyl-aspartyl-glutamate, scyllo-inositol, taurine, creatine methylene, and guanine, in the centrum semiovale between patients with NPH and asymptomatic volunteers.We quantitatively evaluated cerebral metabolites, particularly in the centrum semiovale, with MRS. In the brain of patients with a slow gait and executive dysfunction due to NPH, MRS revealed significantly higher MM levels and lower NAA levels compared to healthy volunteers. Therefore, it may be concluded that the patients have a dysfunctional glymphatic system in the brain.

Diagnosis of a Rare Intraventricular Schwannoma.

BACKGROUND: Intraventricular schwannoma is extremely rare, with only 35 cases reported to date in the literature. Consequently, its etiology and pathogenesis are still unclear, and therefore require further investigations. Here, we report on and discuss a rare case of intraventricular schwannoma to elucidate on this matter. CASE DESCRIPTION: A 26-year-old man was admitted to our institution with a 1-month history of headaches and left hemianopsia. At diagnosis, magnetic resonance imaging of the brain revealed a well-demarcated mass with surrounding edema in the right lateral ventricle. Total resection of the tumor was performed by a transsulcal approach through the right parietal lobe. In surgery, it was observed that the tumor was attached to the choroid plexus without invading the wall of the right lateral ventricle. The respective histologic examination confirmed the diagnosis of intraventricular schwannoma. Six months after the surgery, there was no recurrence. Additionally, during this follow-up period, the patient did not develop any neurologic deficit, including visual field narrowing or parietal symptoms, such as acalculia and right-left, finger, and space agnosias. CONCLUSIONS: Although intraventricular schwannomas are rare, 35 cases have already been reported to date. We emphasize the importance of diagnosing such cases correctly to increase knowledge on the origin and pathogenesis of intraventricular tumors, which would facilitate disease management.

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.

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.

Neuroimaging and neurophysiological evaluation of severity of Parkinson's disease.

OBJECTIVES: Parkinson's disease (PD) is a neurodegenerative disease presenting characteristic motor features. Severity is usually assessed by clinical symptoms; however, few objective indicators are available. In this study, we evaluated the utility of dopamine transporter (DAT) imaging and subthalamic nucleus (STN) activities as indicators of PD severity. MATERIALS AND METHODS: Twelve hemispheres of ten patients with PD who underwent deep brain stimulation (DBS) were included in this study. Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part 3 scores were used to evaluate clinical severity. The relationship between specific binding ratio (SBR) of DAT imaging and the root mean square (RMS) of STN micro-electrode recording (MER) was evaluated. RESULTS: A negative correlation was detected between the MDS-UPDRS part 3 scores and SBR (N = 20, R2 = 0.418; P = 0.002). With respect to subscores, rigidity (R2 = 0.582; P < 0.001) and bradykinesia (R2 = 0.378; P = 0.004) showed negative correlation with SBR, whereas tremor showed no correlation (R2 = 0.054; P = 0.324) (N = 20). On the other hand, no correlation was found between MER and the MDS-UPDRS part 3 scores in ten hemispheres of six patients. CONCLUSION: DAT findings may be useful in evaluating PD severity, especially rigidity and bradykinesia.

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.

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.

Molecular Aberrations Associated with Seizure Control in Diffuse Astrocytic and Oligodendroglial Tumors.

Diffuse astrocytic and oligodendroglial tumors are frequently associated with symptomatic epilepsy, and predictive seizure control is important for the improvement of patient quality of life. To elucidate the factors related to drug resistance of brain tumor-associated epilepsy from a pathological perspective. From January 2012 to October 2017, 36 patients diagnosed with diffuse astrocytic or oligodendroglial tumors were included. Assessment for seizure control was performed according to the Engel classification of seizures. Patient clinical, radiological, and pathological data were stratified based on the following 16 variables: age, sex, location of tumor, existence of the preoperative seizure, extent of resection, administration of temozolomide, radiation therapy, recurrence, Karnofsky performance scale, isocitrate dehydrogenase 1, 1p/19q co-deletion, Olig2, platelet-derived growth factor receptor alpha, p53, ATRX, and Ki67. These factors were compared between the well-controlled group and drug-resistant seizure group. Twenty-seven patients experienced seizures; of these, 14 cases were well-controlled, and 13 cases were drug-resistant. Neither clinical nor radiological characteristics were significantly different between these two groups, though p53 immunodetection levels were significantly higher, and the frequency of 1p/19q co-deletion was significantly lower in the group with drug-resistant seizures than in the well-controlled group. In the multivariate analysis, only one item was selected according to stepwise methods, and a significant difference was observed for p53 (OR, 21.600; 95% CI, 2.135-218.579; P = 0.009). Upregulation of p53 may be a molecular mechanism underlying drug resistant epilepsy associated with diffuse astrocytic and oligodendroglial tumors.

Far-anterior Interhemispheric Transcallosal Approach for a Central Neurocytoma in the Lateral Ventricle.

To describe the far-anterior interhemispheric transcallosal approach for the treatment of a central neurocytoma at the roof of the lateral ventricle. In comparison to the view obtained during the usual anterior transcallosal approach, the far-anterior approach allowed for a higher view of the lateral ventricle to be obtained without further injury or retraction of the corpus callous. Two patients with central neurocytoma in the lateral ventricle were treated with the far-anterior interhemispheric transcallosal approach. Gross-total resections were achieved in both the patients without any postoperative neurological impairments by only 2-3 cm incisions of the corpus callosum. With the anterior transcallosal approach, which was usually used for the intraventricular tumors, the surgical view was relatively downward into the lateral ventricle and suitable for the resection of the tumors located at the base of the lateral ventricle or even in the third ventricle through the foramen of Monro. However, it was relatively difficult to reach the roof of the lateral ventricle using this approach. In contrast, the surgical corridor of the far-anterior transcallosal approach reaches upward to the roof of the lateral ventricle. The far-anterior transcallosal approach provides an alternative to reach the lesions, especially those located in the upper region of the lateral ventricle near important structures, such as the pyramidal tracts.

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.

Total Resection of Unilateral Adult-onset Xanthogranuloma of the Orbit via a Transcranial Orbital Approach.

Adult orbital xanthogranuloma is rare and usually associated with systemic disease. There are several options available to treat this disorder. Periorbital lesions are treated with steroids, chemotherapy, radiotherapy, or local excision; however, there is still no consensus regarding optimal treatment. Here, we report a rare case of orbital xanthogranuloma that was not associated with systemic disease and was treated by transcranial surgery. The patient was a 52-year-old man who presented with a 2-year history of unilateral eye symptoms. A computed tomography scan revealed a well-defined mass in the right orbit. The mass was completely removed via a transcranial orbital approach. The histopathologic diagnosis was xanthogranuloma. No recurrence was observed during 15 months of postoperative follow-up. Complete surgical resection might be an effective treatment option for locally growing sporadic adult xanthogranulomatous disease of the orbit, and allows systemic steroids, chemotherapy, and irradiation to be avoided.

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.

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.

Transdural Propagation of Glioblastoma Through Foramen Rotundum.

BACKGROUND: Glioblastoma, also known as glioblastoma multiforme, is the most common primary malignant cerebral tumor in adults. Although glioblastoma multiforme is one of the most aggressive tumors in the brain, propagation through the dura mater is rare. CASE DESCRIPTION: A 59-year-old man presented with progressive headache and aphasia. Magnetic resonance imaging identified an abnormal mass extending transcranially through the widened foramen rotundum into the infratemporal fossa and cavernous sinus. Emergency surgery was performed because of the patient's disturbed consciousness and uncal herniation. The pathologic diagnosis was glioblastoma with isocitrate dehydrogenase 1 (IDH-1) wild type arising in the left temporal region of the brain, penetrating the dura mater and propagating to the middle fossa with enlargement of the foramen rotundum. The tumor was resected, and radiochemotherapy with temozolomide was administered. CONCLUSION: Although the mechanism of tumor spread is unknown, we hypothesized that originally there may have been spontaneous dural defects or thinning, such as a meningoencephalocele in the middle fossa, and the tumor coincidentally occurred there.

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.