Distinction between epileptic and non-epileptic arousal by heart rate change.

OBJECTIVE: We investigated the difference in heart rate (HR) change between epileptic and non-epileptic arousals in adult patients with epilepsy (PWE). METHODS: This is a case-control study conducted at the University Hospitals of Cleveland Medical Center. Inclusion criteria are (1) adult (≥18 years old) PWE who had arousal related to a focal aware or impaired awareness automatism seizure with or without focal to bilateral tonic-clonic seizure during an Epilepsy Monitoring Unit (EMU) admission between January 2009 and January 2021 or (2) adult PWE who had a non-epileptic arousal during an EMU admission between July 2020 and January 2021. Outcomes are (1) a percent change in baseline HR within 60 s after arousal and (2) the highest percent change in baseline HR within a 10-s sliding time window within 60 s after arousal. RESULTS: We included 20 non-epileptic arousals from 20 adult PWE and 29 epileptic arousals with seizures from 29 adult PWE. Within 60 s after arousal, HR increased by a median of 86.7% (interquartile range (IQR), 52.7%-121.3%) in the epileptic arousal group compared to a median of 26.1% (12.9%-43.3%) in the non-epileptic arousal group (p < 0.001). The cut-off value was 48.7%. The area under the curve (AUC), sensitivity, and specificity were 0.85, 0.79, and 0.80, respectively. More than 70.1% was only in the epileptic arousals, with 100% specificity. Within 10 s of the greatest change, HR increased by 36.5 (18.7%-48.4%) in the epileptic arousal group compared to 17.7 (10.9%-23.7%) in the non-epileptic arousal group (p < 0.001). The cut-off value was 36.5%. The AUC, sensitivity, and specificity were 0.79, 0.52, and 0.95, respectively. More than 48.1% was only in the epileptic arousals, with 100% specificity. SIGNIFICANCE: Tachycardia during epileptic arousals was significantly higher and more robust compared to tachycardia during non-epileptic arousals.

Machine Learning Interpretability Methods to Characterize Brain Network Dynamics in Epilepsy.

The rapid adoption of machine learning (ML) algorithms in a wide range of biomedical applications has highlighted issues of trust and the lack of understanding regarding the results generated by ML algorithms. Recent studies have focused on developing interpretable ML models and establish guidelines for transparency and ethical use, ensuring the responsible integration of machine learning in healthcare. In this study, we demonstrate the effectiveness of ML interpretability methods to provide important insights into the dynamics of brain network interactions in epilepsy, a serious neurological disorder affecting more than 60 million persons worldwide. Using high-resolution intracranial electroencephalogram (EEG) recordings from a cohort of 16 patients, we developed high accuracy ML models to categorize these brain activity recordings into either seizure or non-seizure classes followed by a more complex task of delineating the different stages of seizure progression to different parts of the brain as a multi-class classification task. We applied three distinct types of interpretability methods to the high-accuracy ML models to gain an understanding of the relative contributions of different categories of brain interaction patterns, including multi-focii interactions, which play an important role in distinguishing between different states of the brain. The results of this study demonstrate for the first time that post-hoc interpretability methods enable us to understand why ML algorithms generate a given set of results and how variations in value of input values affect the accuracy of the ML algorithms. In particular, we show in this study that interpretability methods can be used to identify brain regions and interaction patterns that have a significant impact on seizure events. The results of this study highlight the importance of the integrated implementation of ML algorithms together with interpretability methods in aberrant brain network studies and the wider domain of biomedical research.

Modifying the ICP pulse wave: effects on parenchymal blood flow pulsatility.

Pulsation of the cerebral blood flow (CBF) produces intercranial pressure (ICP) waves. The aim of this study is to determine whether externally modifying ICP pulsatility alters parenchymal blood flow pulsatility. A cardiac-gated inflatable device was inserted in the lateral epidural space of 12 anesthetized canines (canis familiaris) and used to cause reduction, inversion, and augmentation of the ICP pulse. CBF in each hemisphere was measured using laser Doppler velocimetry. A significant increase in both mean CBF and its amplitude was observed for reduction as well as inversion of the ICP pulse, with larger changes observed for the inversion protocol. Significant increases in the mean CBF were also observed ipsilaterally for the augmentation protocol together with indications of reduced CBF amplitude contralaterally. External alteration of the ICP pulse thus caused significant changes in parenchymal blood flow pulsatility. The inverse relationship between the ICP and CBF amplitude suggests that the changes did not occur via modification of the intracranial Windkessel mechanism. Thus, the effects likely occurred in the low-pressure vessels, i.e., capillaries and/or venules, rather than the high-pressure arteries. Future MRI studies are however required to map and quantify the effects on global cerebral blood flow.NEW & NOTEWORTHY This study demonstrated that external modification of ICP pulsatility, using a cardiac-gated inflatable device implanted epidurally in canines, alters brain tissue blood flow pulsatility. Specifically, decreasing systolic ICP increased blood flow pulsatility in brain tissue. The results suggest that the altered CBF pulsatility is unlikely to depend on modification of the Windkessel effect on the feeding arterial system but was rather an effect directly on tissue and the lower pressure distal vessels.

Epileptic negative myoclonus in herpes simplex virus encephalitis.

Epileptic negative myoclonus (ENM) is a rarely reported clinical seizure semiology. It is defined as a brief interruption of tonic muscle activity in association with an epileptiform discharge on the EEG (spike or sharp wave) without preceding myoclonia. The diagnosis of ENM requires a polygraphic recording with EEG and surface EMG electrodes covering the affected body part(s), while the muscles have tonic activity. Historically, ENM has been reported in a variety of chronic epilepsy syndromes such as benign epilepsy with centrotemporal spikes, progressive myoclonic epilepsy syndromes, symptomatic partial epilepsy syndromes due to structural pathologies, cryptogenic epilepsies, etc. In this paper, we report a patient with herpes simplex virus encephalitis who presented with multiple different seizure types including ENM. The patient showed significant improvement after treatment with acyclovir.

Stereotactic-EEG-guided radiofrequency multiple hippocampal transection (SEEG-guided-RF-MHT) for the treatment of mesial temporal lobe epilepsy: a minimally invasive method for diagnosis and treatment.

For the treatment of mesial temporal lobe epilepsy on the language-dominant side in patients at high risk of memory decline, we propose a minimally invasive diagnostic and treatment technique, adopting the principles of multiple hippocampal transections (MHT) using stereo-electroencephalography-guided radiofrequency (SEEG-guided-RF-MHT). This new technique allows targeting of the longitudinal fibers in the hippocampus critical for seizure spreading, while sparing the transverse circuits which are considered important for memory processing and avoiding discomfort and longer post-operatory recovery time associated with craniotomies. We report the efficacy and safety of this procedure in a preliminary observational study of cases. Five patients at high risk of memory decline, including three with non-lesional hippocampi on MRI, had temporal lobe epilepsy (TLE) necessitating depth electrode implantation. A new strategy of SEEG electrode placement was used to mimic MHT. After confirming hippocampal seizure onset, all the patients had three linear ablations perpendicular to the amigdalohippocampal complex. The procedure was performed at the patient's bedside with the patient awake during the full length of the procedure. Four out of five patients were seizure-free (average follow up: 14-18 months). There were no associated complications. Visual inspection of brain MRI of patients at six months following SEEG-guided RF-MHT showed significant hippocampal volume preservation. Subjects who received the procedure in the dominant side reported no subjective memory complaints in the follow-up clinic assessments at six months. Our preliminary seizure outcome seems very promising since the majority of our patients (four out of five patients) were seizure-free. Since no lesions are made outside the amygdalo-hippocampal complex using this technique and the temporal stem remains intact, more favorable memory and language outcome is expected in patients at high risk of memory decline.

In vitro evaluation of cerebrospinal fluid velocity measurement in type I Chiari malformation: repeatability, reproducibility, and agreement using 2D phase contrast and 4D flow MRI.

BACKGROUND: Phase contrast magnetic resonance imaging, PC MRI, is a valuable tool allowing for non-invasive quantification of CSF dynamics, but has lacked adoption in clinical practice for Chiari malformation diagnostics. To improve these diagnostic practices, a better understanding of PC MRI based measurement agreement, repeatability, and reproducibility of CSF dynamics is needed. METHODS: An anatomically realistic in vitro subject specific model of a Chiari malformation patient was scanned three times at five different scanning centers using 2D PC MRI and 4D Flow techniques to quantify intra-scanner repeatability, inter-scanner reproducibility, and agreement between imaging modalities. Peak systolic CSF velocities were measured at nine axial planes using 2D PC MRI, which were then compared to 4D Flow peak systolic velocity measurements extracted at those exact axial positions along the model. RESULTS: Comparison of measurement results showed good overall agreement of CSF velocity detection between 2D PC MRI and 4D Flow (p = 0.86), fair intra-scanner repeatability (confidence intervals ± 1.5 cm/s), and poor inter-scanner reproducibility. On average, 4D Flow measurements had a larger variability than 2D PC MRI measurements (standard deviations 1.83 and 1.04 cm/s, respectively). CONCLUSION: Agreement, repeatability, and reproducibility of 2D PC MRI and 4D Flow detection of peak CSF velocities was quantified using a patient-specific in vitro model of Chiari malformation. In combination, the greatest factor leading to measurement inconsistency was determined to be a lack of reproducibility between different MRI centers. Overall, these findings may help lead to better understanding for application of 2D PC MRI and 4D Flow techniques as diagnostic tools for CSF dynamics quantification in Chiari malformation and related diseases.

Epidural Oscillating Cardiac-Gated Intracranial Implant Modulates Cerebral Blood Flow.

BACKGROUND: We have previously reported a method and device capable of manipulating ICP pulsatility while minimally effecting mean ICP. OBJECTIVE: To test the hypothesis that different modulations of the intracranial pressure (ICP) pulse waveform will have a differential effect on cerebral blood flow (CBF). METHODS: Using an epidural balloon catheter attached to a cardiac-gated oscillating pump, 13 canine subjects underwent ICP waveform manipulation comparing different sequences of oscillation in successive animals. The epidural balloon was implanted unilaterally superior to the Sylvian sulcus. Subjects underwent ICP pulse augmentation, reduction and inversion protocols, directly comparing time segments of system activation and deactivation. ICP and CBF were measured bilaterally along with systemic pressure and heart rate. CBF was measured using both thermal diffusion, and laser doppler probes. RESULTS: The activation of the cardiac-gate balloon implant resulted in an ipsilateral/contralateral ICP pulse amplitude increase with augmentation (217%/202% respectively, P < .0005) and inversion (139%/120%, P < .0005). The observed changes associated with the ICP mean values were smaller, increasing with augmentation (23%/31%, P < .0001) while decreasing with inversion (7%/11%, P = .006/.0003) and reduction (4%/5%, P < .0005). CBF increase was observed for both inversion and reduction protocols (28%/7.4%, P < .0001/P = .006 and 2.4%/1.3%, P < .0001/P = .003), but not the augmentation protocol. The change in CBF was correlated with ICP pulse amplitude and systolic peak changes and not with change in mean ICP or systemic variables (heart rate, arterial blood pressure). CONCLUSION: Cardiac-gated manipulation of ICP pulsatility allows the study of intracranial pulsatile dynamics and provides a potential means of altering CBF.

Connectivity-based identification of a potential neurosurgical target for mood disorders.

OBJECTIVE: Stereotactic ablation (cingulotomy) and subcallosal cingulate deep brain stimulation (SCC DBS) of different regions of the cingulum bundle (CB) have been successfully used to treat psychiatric disorders, such as depression and bipolar disorder. They are hypothesized to work by disrupting white matter pathways involved in the clinical manifestation of these disorders. This study aims to compare the connectivity of different CB subregions using tractography to evaluate stereotactic targets for the treatment of mood disorders. METHODS: Fourteen healthy volunteers underwent 3T-MR imaging followed by connectivity analysis using probabilistic tractography. Twenty-one anatomic regions of interest were defined for each subject: 10 CB subregions (including the classical cingulotomy and SCC DBS targets) and 11 cortical/subcortical structures implicated in mood disorders. Connectivity results were compared using Friedman and Bonferroni-corrected post-hoc Wilcoxon tests. RESULTS: CB connectivity showed a high degree of regional specificity. Both of the traditional stereotactic targets had widespread connectivity with discrete topology. The cingulotomy target connected primarily to the dorsomedial frontal, dorsal anterior cingulate, and posterior cingulate cortices, whereas the SCC DBS target connected mostly to the subgenual anterior cingulate and medial/central orbitofrontal cortices. However, a region of the rostral dorsal CB, lying between these surgical targets, encompassed statistically equivalent connections to all five cortical regions. CONCLUSIONS: The CB is associated with brain structures involved in affective disorders, and the rostral dorsal CB demonstrates connectivity that is comparable to the combined connectivity of cingulotomy and SCC DBS neurosurgical interventions. The rostral dorsal CB represents a surgical target worthy of clinical exploration for mood disorders.

Clinical Evaluation of Cingulum Bundle Connectivity for Neurosurgical Hypothesis Development.

BACKGROUND: The cingulum bundle (CB) has long been a target for psychiatric neurosurgical procedures, but with limited understanding of the brain networks being impacted. Recent advances in human tractography could provide a foundation to better understand the effects of neurosurgical interventions on the CB; however, the reliability of tractography remains in question. OBJECTIVE: To evaluate the ability of different tractography techniques, derived from typical, human diffusion-weighted imaging (DWI) data, to characterize CB connectivity described in animal models. This will help validate the clinical applicability of tractography, and generate insight on current and future neurosurgical targets for psychiatric disorders. METHODS: Connectivity of the CB in 15 healthy human subjects was evaluated using DWI-based tractography, and compared to tract-tracing findings from nonhuman primates. Brain regions of interest were defined to coincide with the animal model. Tractography was performed using 3 techniques (FSL probabilistic, Camino probabilistic, and Camino deterministic). Differences in connectivity were assessed, and the CB segment with the greatest connectivity was determined. RESULTS: Each tractography technique successfully reproduced the animal tracing model with a mean accuracy of 72% (68-75%, P < .05). Additionally, one region of the CB, the rostral dorsal segment, had significantly greater connectivity to associated brain structures than all other CB segments (P < .05). CONCLUSION: Noninvasive, in vivo human analysis of the CB, using clinically available DWI for tractography, consistently reproduced the results of an animal tract-tracing model. This suggests that tractography of the CB can be used for clinical applications, which may aid in neurosurgical targeting for psychiatric disorders.

An MRI-Compatible Hydrodynamic Simulator of Cerebrospinal Fluid Motion in the Cervical Spine.

GOAL: Develop and test an MRI-compatible hydrodynamic simulator of cerebrospinal fluid (CSF) motion in the cervical spinal subarachnoid space. Four anatomically realistic subject-specific models were created based on a 22-year-old healthy volunteer and a five-year-old patient diagnosed with Chiari I malformation. METHODS: The in vitro models were based on manual segmentation of high-resolution T2-weighted MRI of the cervical spine. Anatomically realistic dorsal and ventral spinal cord nerve rootlets (NR) were added. Models were three dimensional (3-D) printed by stereolithography with 50-µm layer thickness. A computer controlled pump system was used to replicate the shape of the subject specific in vivo CSF flow measured by phase-contrast MRI. Each model was then scanned by T2-weighted and 4-D phase contrast MRI (4D flow). RESULTS: Cross-sectional area, wetted perimeter, and hydraulic diameter were quantified for each model. The oscillatory CSF velocity field (flow jets near NR, velocity profile shape, and magnitude) had similar characteristics to previously reported studies in the literature measured by in vivo MRI. CONCLUSION: This study describes the first MRI-compatible hydrodynamic simulator of CSF motion in the cervical spine with anatomically realistic NR. NR were found to impact CSF velocity profiles to a great degree. SIGNIFICANCE: CSF hydrodynamics are thought to be altered in craniospinal disorders such as Chiari I malformation. MRI scanning techniques and protocols can be used to quantify CSF flow alterations in disease states. The provided in vitro models can be used to test the reliability of these protocols across MRI scanner manufacturers and machines.

Quantifying the influence of respiration and cardiac pulsations on cerebrospinal fluid dynamics using real-time phase-contrast MRI.

PURPOSE: To validate a real-time phase contrast magnetic resonance imaging (RT-PCMRI) sequence in a controlled phantom model, and to quantify the relative contributions of respiration and cardiac pulsations on cerebrospinal fluid (CSF) velocity at the level of the foramen magnum (FM). MATERIALS AND METHODS: To validate the 3T MRI techniques, in vitro studies used a realistic model of the spinal subarachnoid space driven by pulsatile flow waveforms mimicking the respiratory and cardiac components of CSF flow. Subsequently, CSF flow was measured continuously during 1-minute RT-PCMRI acquisitions at the FM while healthy subjects (N = 20) performed natural breathing, deep breathing, breath-holding, and coughing. Conventional cardiac-gated PCMRI was obtained for comparison. A frequency domain power ratio analysis determined the relative contribution of respiration versus cardiac ([r/c]) components of CSF velocity. RESULTS: In vitro studies demonstrating the accuracy of RT-PCMRI within 5% of input values showed that conventional PCMRI measures only the cardiac component of CSF velocity (0.42 ± 0.02 cm/s), averages out respiratory effects, and underestimates the magnitude of CSF velocity (0.96 ± 0.07 cm/s). In vivo RT-PCMRI measurements indicated the ratio of respiratory to cardiac velocity pulsations averaged over all subjects as [r/c = 0.14 ± 0.27] and [r/c = 0.40 ± 0.47] for natural and deep breathing, respectively. During coughing, the peak CSF velocity increased by a factor of 2.27 ± 1.40. CONCLUSION: RT-PCMRI can noninvasively measure instantaneous CSF velocity driven by cardiac pulsations, respiration, and coughing in real time. A comparable contribution of respiration and cardiac pulsations on CSF velocity was found during deep breathing but not during natural breathing. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:431-439.

Novel method for dynamic control of intracranial pressure.

OBJECT Intracranial pressure (ICP) pulsations are generally considered a passive result of the pulsatility of blood flow. Active experimental modification of ICP pulsations would allow investigation of potential active effects on blood and CSF flow and potentially create a new platform for the treatment of acute and chronic low blood flow states as well as a method of CSF substance clearance and delivery. This study presents a novel method and device for altering the ICP waveform via cardiac-gated volume changes. METHODS The novel device used in this experiment (named Cadence) consists of a small air-filled inelastic balloon (approximately 1.0 ml) implanted into the intracranial space and connected to an external programmable pump, triggered by an R-wave detector. Balloons were implanted into the epidural space above 1 of the hemispheres of 19 canines for up to 10 hours. When activated, the balloons were programed to cyclically inflate with the cardiac cycle with variable delay, phase, and volume. The ICP response was measured in both hemispheres. Additionally, cerebral blood flow (heat diffusion and laser Doppler) was studied in 16 canines. RESULTS This system, depending on the inflation pattern of the balloon, allowed a flattening of the ICP waveform, increase in the ICP waveform amplitude, or phase shift of the wave. This occurred with small mean ICP changes, typically around ± 2 mm Hg (15%). Bilateral ICP effects were observed with activation of the device: balloon inflation at each systole increased the systolic ICP pulse (up to 16 mm Hg, 1200%) and deflation at systole decreased or even inverted the systolic ICP pulse (-0.5 to -19 mm Hg, -5% to -1600%) in a dose-(balloon volume) dependent fashion. No aphysiological or deleterious effects on systemic pressure (≤ ±10 mm Hg; 13% change in mean pressure) or cardiac rate (≤ ± 17 beats per minute; 16% change) were observed during up to 4 hours of balloon activity. CONCLUSIONS The results of these initial studies using an intracranially implanted, cardiac-gated, volume-oscillating balloon suggest the Cadence device can be used to modify ICP pulsations, without physiologically deleterious effects on mean ICP, systemic vascular effects, or brain injury. This device and technique may be used to study the role of ICP pulsatility in intracranial hemo- and hydrodynamic processes and introduces the creation of a potential platform of a cardiac-gated system for treatment of acute and chronic low blood flow states, and diseases requiring augmentation of CSF substance clearance or delivery.

Accuracy of 4D Flow Measurement of Cerebrospinal Fluid Dynamics in the Cervical Spine: An In Vitro Verification Against Numerical Simulation.

Abnormal alterations in cerebrospinal fluid (CSF) flow are thought to play an important role in pathophysiology of various craniospinal disorders such as hydrocephalus and Chiari malformation. Three directional phase contrast MRI (4D Flow) has been proposed as one method for quantification of the CSF dynamics in healthy and disease states, but prior to further implementation of this technique, its accuracy in measuring CSF velocity magnitude and distribution must be evaluated. In this study, an MR-compatible experimental platform was developed based on an anatomically detailed 3D printed model of the cervical subarachnoid space and subject specific flow boundary conditions. Accuracy of 4D Flow measurements was assessed by comparison of CSF velocities obtained within the in vitro model with the numerically predicted velocities calculated from a spatially averaged computational fluid dynamics (CFD) model based on the same geometry and flow boundary conditions. Good agreement was observed between CFD and 4D Flow in terms of spatial distribution and peak magnitude of through-plane velocities with an average difference of 7.5 and 10.6% for peak systolic and diastolic velocities, respectively. Regression analysis showed lower accuracy of 4D Flow measurement at the timeframes corresponding to low CSF flow rate and poor correlation between CFD and 4D Flow in-plane velocities.

Inter-operator Reliability of Magnetic Resonance Image-Based Computational Fluid Dynamics Prediction of Cerebrospinal Fluid Motion in the Cervical Spine.

For the first time, inter-operator dependence of MRI based computational fluid dynamics (CFD) modeling of cerebrospinal fluid (CSF) in the cervical spinal subarachnoid space (SSS) is evaluated. In vivo MRI flow measurements and anatomy MRI images were obtained at the cervico-medullary junction of a healthy subject and a Chiari I malformation patient. 3D anatomies of the SSS were reconstructed by manual segmentation by four independent operators for both cases. CFD results were compared at nine axial locations along the SSS in terms of hydrodynamic and geometric parameters. Intraclass correlation (ICC) assessed the inter-operator agreement for each parameter over the axial locations and coefficient of variance (CV) compared the percentage of variance for each parameter between the operators. Greater operator dependence was found for the patient (0.19 < ICC < 0.99) near the craniovertebral junction compared to the healthy subject (ICC > 0.78). For the healthy subject, hydraulic diameter and Womersley number had the least variance (CV = ~2%). For the patient, peak diastolic velocity and Reynolds number had the smallest variance (CV = ~3%). These results show a high degree of inter-operator reliability for MRI-based CFD simulations of CSF flow in the cervical spine for healthy subjects and a lower degree of reliability for patients with Type I Chiari malformation.