Measurement of the Mapping between Intracranial EEG and fMRI Recordings in the Human Brain.

There are considerable gaps in our understanding of the relationship between human brain activity measured at different temporal and spatial scales. Here, electrocorticography (ECoG) measures were used to predict functional MRI changes in the sensorimotor cortex in two brain states: at rest and during motor performance. The specificity of this relationship to spatial co-localisation of the two signals was also investigated. We acquired simultaneous ECoG-fMRI in the sensorimotor cortex of three patients with epilepsy. During motor activity, high gamma power was the only frequency band where the electrophysiological response was co-localised with fMRI measures across all subjects. The best model of fMRI changes across states was its principal components, a parsimonious description of the entire ECoG spectrogram. This model performed much better than any others that were based either on the classical frequency bands or on summary measures of cross-spectral changes. The region-specific fMRI signal is reflected in spatially and spectrally distributed EEG activity.

Normative brain mapping using scalp EEG and potential clinical application.

A normative electrographic activity map could be a powerful resource to understand normal brain function and identify abnormal activity. Here, we present a normative brain map using scalp EEG in terms of relative band power. In this exploratory study we investigate its temporal stability, its similarity to other imaging modalities, and explore a potential clinical application. We constructed scalp EEG normative maps of brain dynamics from 17 healthy controls using source-localised resting-state scalp recordings. We then correlated these maps with those acquired from MEG and intracranial EEG to investigate their similarity. Lastly, we use the normative maps to lateralise abnormal regions in epilepsy. Spatial patterns of band powers were broadly consistent with previous literature and stable across recordings. Scalp EEG normative maps were most similar to other modalities in the alpha band, and relatively similar across most bands. Towards a clinical application in epilepsy, we found abnormal temporal regions ipsilateral to the epileptogenic hemisphere. Scalp EEG relative band power normative maps are spatially stable across time, in keeping with MEG and intracranial EEG results. Normative mapping is feasible and may be potentially clinically useful in epilepsy. Future studies with larger sample sizes and high-density EEG are now required for validation.

Brain Connectivity Correlates of Breathing and Cardiac Irregularities in SUDEP: A Resting-State fMRI Study.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of premature mortality among people with epilepsy. Evidence from witnessed and monitored SUDEP cases indicate seizure-induced cardiovascular and respiratory failures; yet, the underlying mechanisms remain obscure. SUDEP occurs often during the night and early morning hours, suggesting that sleep or circadian rhythm-induced changes in physiology contribute to the fatal event. Resting-state fMRI studies have found altered functional connectivity between brain structures involved in cardiorespiratory regulation in later SUDEP cases and in individuals at high-risk of SUDEP. However, those connectivity findings have not been related to changes in cardiovascular or respiratory patterns. Here, we compared fMRI patterns of brain connectivity associated with regular and irregular cardiorespiratory rhythms in SUDEP cases with those of living epilepsy patients of varying SUDEP risk, and healthy controls. We analysed resting-state fMRI data from 98 patients with epilepsy (9 who subsequently succumbed to SUDEP, 43 categorized as low SUDEP risk (no tonic-clonic seizures (TCS) in the year preceding the fMRI scan), and 46 as high SUDEP risk (>3 TCS in the year preceding the scan)) and 25 healthy controls. The global signal amplitude (GSA), defined as the moving standard deviation of the fMRI global signal, was used to identify periods with regular ('low state') and irregular ('high state') cardiorespiratory rhythms. Correlation maps were derived from seeds in twelve regions with a key role in autonomic or respiratory regulation, for the low and high states. Following principal component analysis, component weights were compared between the groups. We found widespread alterations in connectivity of precuneus/posterior cingulate cortex in epilepsy compared to controls, in the low state (regular cardiorespiratory activity). In the low state, and to a lesser degree in the high state, reduced anterior insula connectivity (mainly with anterior and posterior cingulate cortex) in epilepsy appeared, relative to healthy controls. For SUDEP cases, the insula connectivity differences were inversely related to the interval between the fMRI scan and death. The findings suggest that anterior insula connectivity measures may provide a biomarker of SUDEP risk. The neural correlates of autonomic brain structures associated with different cardiorespiratory rhythms may shed light on the mechanisms underlying terminal apnea observed in SUDEP.

Normative brain mapping using scalp EEG and potential clinical application.

A normative electrographic activity map could be a powerful resource to understand normal brain function and identify abnormal activity. Here, we present a normative brain map using scalp EEG in terms of relative band power. In this exploratory study we investigate its temporal stability, its similarity to other imaging modalities, and explore a potential clinical application. We constructed scalp EEG normative maps of brain dynamics from 17 healthy controls using source-localised resting-state scalp recordings. We then correlated these maps with those acquired from MEG and intracranial EEG to investigate their similarity. Lastly, we use the normative maps to lateralise abnormal regions in epilepsy. Spatial patterns of band powers were broadly consistent with previous literature and stable across recordings. Scalp EEG normative maps were most similar to other modalities in the alpha band, and relatively similar across most bands. Towards a clinical application in epilepsy, we found abnormal temporal regions ipsilateral to the epileptogenic hemisphere. Scalp EEG relative band power normative maps are spatially stable across time, in keeping with MEG and intracranial EEG results. Normative mapping is feasible and may be potentially clinically useful in epilepsy. Future studies with larger sample sizes and high-density EEG are now required for validation.

Volumetric and microstructural abnormalities of the amygdala in focal epilepsy with varied levels of SUDEP risk.

Although the mechanisms of sudden unexpected death in epilepsy (SUDEP) are not yet well understood, generalised- or focal-to-bilateral tonic-clonic seizures (TCS) are a major risk factor. Previous studies highlighted alterations in structures linked to cardio-respiratory regulation; one structure, the amygdala, was enlarged in people at high risk of SUDEP and those who subsequently died. We investigated volume changes and the microstructure of the amygdala in people with epilepsy at varied risk for SUDEP since that structure can play a key role in triggering apnea and mediating blood pressure. The study included 53 healthy subjects and 143 patients with epilepsy, the latter separated into two groups according to whether TCS occur in years before scan. We used amygdala volumetry, derived from structural MRI, and tissue microstructure, derived from diffusion MRI, to identify differences between the groups. The diffusion metrics were obtained by fitting diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) models. The analyses were performed at the whole amygdala level and at the scale of amygdaloid nuclei. Patients with epilepsy showed larger amygdala volumes and lower neurite density indices (NDI) than healthy subjects; the left amygdala volumes were especially enhanced. Microstructural changes, reflected by NDI differences, were more prominent on the left side and localized in the lateral, basal, central, accessory basal and paralaminar amygdala nuclei; basolateral NDI lowering appeared bilaterally. No significant microstructural differences appeared between epilepsy patients with and without current TCS. The central amygdala nuclei, with prominent interactions from surrounding nuclei of that structure, project to cardiovascular regions and respiratory phase switching areas of the parabrachial pons, as well as to the periaqueductal gray. Consequently, they have the potential to modify blood pressure and heart rate, and induce sustained apnea or apneusis. The findings here suggest that lowered NDI, indicative of reduced dendritic density, could reflect an impaired structural organization influencing descending inputs that modulate vital respiratory timing and drive sites and areas critical for blood pressure control.

Volumetric and microstructural abnormalities of the amygdala in focal epilepsy with varied levels of SUDEP risk.

Although the mechanisms of sudden unexpected death in epilepsy (SUDEP) are not yet well understood, generalised- or focal-to-bilateral tonic-clonic seizures (TCS) are a major risk factor. Previous studies highlighted alterations in structures linked to cardio-respiratory regulation; one structure, the amygdala, was enlarged in people at high risk of SUDEP and those who subsequently died. We investigated volume changes and the microstructure of the amygdala in people with epilepsy at varied risk for SUDEP since that structure can play a key role in triggering apnea and mediating blood pressure. The study included 53 healthy subjects and 143 patients with epilepsy, the latter separated into two groups according to whether TCS occur in years before scan. We used amygdala volumetry, derived from structural MRI, and tissue microstructure, derived from diffusion MRI, to identify differences between the groups. The diffusion metrics were obtained by fitting diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) models. The analyses were performed at the whole amygdala level and at the scale of amygdaloid nuclei. Patients with epilepsy showed larger amygdala volumes and lower neurite density indices (NDI) than healthy subjects; the left amygdala volumes were especially enhanced. Microstructural changes, reflected by NDI differences, were more prominent on the left side and localized in the lateral, basal, central, accessory basal and paralaminar amygdala nuclei; basolateral NDI lowering appeared bilaterally. No significant microstructural differences appeared between epilepsy patients with and without current TCS. The central amygdala nuclei, with prominent interactions from surrounding nuclei of that structure, project to cardiovascular regions and respiratory phase switching areas of the parabrachial pons, as well as to the periaqueductal gray. Consequently, they have the potential to modify blood pressure and heart rate, and induce sustained apnea or apneusis. The findings here suggest that lowered NDI, indicative of reduced dendritic density, could reflect an impaired structural organization influencing descending inputs that modulate vital respiratory timing and drive sites and areas critical for blood pressure control.

Functional MRI Correlates of Carbon Dioxide Chemosensing in Persons With Epilepsy.

Objectives: Sudden unexpected death in epilepsy (SUDEP) is a catastrophic epilepsy outcome for which there are no reliable premortem imaging biomarkers of risk. Percival respiratory depression is seen in monitored SUDEP and near SUDEP cases, and abnormal chemosensing of raised blood carbon dioxide (CO2) is thought to contribute. Damage to brainstem respiratory control and chemosensing structures has been demonstrated in structural imaging and neuropathological studies of SUDEP. We hypothesized that functional MRI (fMRI) correlates of abnormal chemosensing are detectable in brainstems of persons with epilepsy (PWE) and are different from healthy controls (HC). Methods: We analyzed fMRI BOLD activation and brain connectivity in 10 PWE and 10 age- and sex-matched HCs during precisely metered iso-oxic, hypercapnic breathing challenges. Segmented brainstem responses were of particular interest, along with characterization of functional connectivity metrics between these structures. Regional BOLD activations during hypercapnic challenges were convolved with hemodynamic responses, and the resulting activation maps were passed on to group-level analyses. For the functional connectivity analysis, significant clusters from BOLD results were used as seeds. Each individual seed time-series activation map was extracted for bivariate correlation coefficient analyses to study changes in brain connectivity between PWE and HCs. Results: (1) Greater brainstem BOLD activations in PWE were observed compared to HC during hypercapnic challenges in several structures with respiratory/chemosensing properties. Group comparison between PWE vs. HC showed significantly greater activation in the dorsal raphe among PWE (p < 0.05) compared to HCs. (2) PWE had significantly greater seed-seed connectivity and recruited more structures during hypercapnia compared to HC. Significance: The results of this study show that BOLD responses to hypercapnia in human brainstem are detectable and different in PWE compared to HC. Increased dorsal raphe BOLD activation in PWE and increased seed-seed connectivity between brainstem and adjacent subcortical areas may indicate abnormal chemosensing in these individuals. Imaging investigation of brainstem respiratory centers involved in respiratory regulation in PWE is an important step toward identifying suspected dysfunction of brainstem breathing control that culminates in SUDEP and deserve further study as potential imaging SUDEP biomarkers.

Evaluating the Safety of Simultaneous Intracranial Electroencephalography and Functional Magnetic Resonance Imaging Acquisition Using a 3 Tesla Magnetic Resonance Imaging Scanner.

Background: The unsurpassed sensitivity of intracranial electroencephalography (icEEG) and the growing interest in understanding human brain networks and ongoing activities in health and disease have make the simultaneous icEEG and functional magnetic resonance imaging acquisition (icEEG-fMRI) an attractive investigation tool. However, safety remains a crucial consideration, particularly due to the impact of the specific characteristics of icEEG and MRI technologies that were safe when used separately but may risk health when combined. Using a clinical 3-T scanner with body transmit and head-receive coils, we assessed the safety and feasibility of our icEEG-fMRI protocol. Methods: Using platinum and platinum-iridium grid and depth electrodes implanted in a custom-made acrylic-gel phantom, we assessed safety by focusing on three factors. First, we measured radio frequency (RF)-induced heating of the electrodes during fast spin echo (FSE, as a control) and the three sequences in our icEEG-fMRI protocol. Heating was evaluated with electrodes placed orthogonal or parallel to the static magnetic field. Using the configuration with the greatest heating observed, we then measured the total heating induced in our protocol, which is a continuous 70-min icEEG-fMRI session comprising localizer, echo-planar imaging (EPI), and magnetization-prepared rapid gradient-echo sequences. Second, we measured the gradient switching-induced voltage using configurations mimicking electrode implantation in the frontal and temporal lobes. Third, we assessed the gradient switching-induced electrode movement by direct visual detection and image analyses. Results: On average, RF-induced local heating on the icEEG electrode contacts tested were greater in the orthogonal than parallel configuration, with a maximum increase of 0.2°C during EPI and 1.9°C during FSE. The total local heating was below the 1°C safety limit across all contacts tested during the 70-min icEEG-fMRI session. The induced voltage was within the 100-mV safety limit regardless of the configuration. No gradient switching-induced electrode displacement was observed. Conclusion: We provide evidence that the additional health risks associated with heating, neuronal stimulation, or device movement are low when acquiring fMRI at 3 T in the presence of clinical icEEG electrodes under the conditions reported in this study. High specific absorption ratio sequences such as FSE should be avoided to prevent potential inadvertent tissue heating.

Safety of intracranial electroencephalography during functional electromagnetic resonance imaging in humans at 1.5 tesla using a head transmit RF coil: Histopathological and heat-shock immunohistochemistry observations.

OBJECTIVES: Simultaneous intracranial EEG and functional MRI (icEEG-fMRI) recordings in humans, whereby EEG is recorded from electrodes implanted inside the cranium during fMRI scanning, were made possible following safety studies on test phantoms and our specification of a rigorous data acquisition protocol. In parallel with this work, other investigations in our laboratory revealed the damage caused by the EEG electrode implantation procedure at the cellular level. The purpose of this report is to further explore the safety of performing MRI, including simultaneous icEEG-fMRI data acquisitions, in the presence of implanted intra-cranial EEG electrodes, by presenting some histopathological and heat-shock immunopositive labeling observations in surgical tissue samples from patients who underwent the scanning procedure. METHODS: We performed histopathology and heat shock protein expression analyses on surgical tissue samples from nine patients who had been implanted with icEEG electrodes. Three patients underwent icEEG-fMRI and structural MRI (sMRI); three underwent sMRI only, all at similar time points after icEEG implantation; and three who did not undergo functional or sMRI with icEEG electrodes. RESULTS: The histopathological findings from the three patients who underwent icEEG-fMRI were similar to those who did not, in that they showed no evidence of additional damage in the vicinity of the electrodes, compared to cases who had no MRI with implanted icEEG electrodes. This finding was similar to our observations in patients who only underwent sMRI with implanted icEEG electrodes. CONCLUSION: This work provides unique evidence on the safety of functional MRI in the presence of implanted EEG electrodes. In the cases studied, icEEG-fMRI performed in accordance with our protocol based on low-SAR (≤0.1 W/kg) sequences at 1.5T using a head-transmit RF coil, did not result in measurable additional damage to the brain tissue in the vicinity of implanted electrodes. Furthermore, while one cannot generalize the results of this study beyond the specific electrode implantation and scanning conditions described herein, we submit that our approach is a useful framework for the post-hoc safety assessment of MR scanning with brain implants.

Mapping Epileptic Networks Using Simultaneous Intracranial EEG-fMRI.

Background: Potentially curative epilepsy surgery can be offered if a single, discrete epileptogenic zone (EZ) can be identified. For individuals in whom there is no clear concordance between clinical localization, scalp EEG, and imaging data, intracranial EEG (icEEG) may be needed to confirm a predefined hypothesis regarding irritative zone (IZ), seizure onset zone (SOZ), and EZ prior to surgery. However, icEEG has limited spatial sampling and may fail to reveal the full extent of epileptogenic network if predefined hypothesis is not correct. Simultaneous icEEG-fMRI has been safely acquired in humans and allows exploration of neuronal activity at the whole-brain level related to interictal epileptiform discharges (IED) captured intracranially. Methods: We report icEEG-fMRI in eight patients with refractory focal epilepsy who had resective surgery and good postsurgical outcome. Surgical resection volume in seizure-free patients post-surgically reflects confirmed identification of the EZ. IEDs on icEEG were classified according to their topographic distribution and localization (Focal, Regional, Widespread, and Non-contiguous). We also divided IEDs by their location within the surgical resection volume [primary IZ (IZ1) IED] or outside [secondary IZ (IZ2) IED]. The distribution of fMRI blood oxygen level-dependent (BOLD) changes associated with individual IED classes were assessed over the whole brain using a general linear model. The concordance of resulting BOLD map was evaluated by comparing localization of BOLD clusters with surgical resection volume. Additionally, we compared the concordance of BOLD maps and presence of BOLD clusters in remote brain areas: precuneus, cuneus, cingulate, medial frontal, and thalamus for different IED classes. Results: A total of 38 different topographic IED classes were identified across the 8 patients: Focal (22) and non-focal (16, Regional = 9, Widespread = 2, Non-contiguous = 5). Twenty-nine IEDs originated from IZ1 and 9 from IZ2. All IED classes were associated with BOLD changes. BOLD maps were concordant with the surgical resection volume for 27/38 (71%) IED classes, showing statistical global maximum BOLD cluster or another cluster in the surgical resection volume. The concordance of BOLD maps with surgical resection volume was greater (p < 0.05) for non-focal (87.5%, 14/16) as compared to Focal (59%, 13/22) IED classes. Additionally, BOLD clusters in remote cortical and deep brain areas were present in 84% (32/38) of BOLD maps, more commonly (15/16; 93%) for non-focal IED-related BOLD maps. Conclusions: Simultaneous icEEG-fMRI can reveal BOLD changes at the whole-brain level for a wide range of IEDs on icEEG. BOLD clusters within surgical resection volume and remote brain areas were more commonly seen for non-focal IED classes, suggesting that a wider hemodynamic network is at play.

Altered Relationship Between Heart Rate Variability and fMRI-Based Functional Connectivity in People With Epilepsy.

Background: Disruptions in central autonomic processes in people with epilepsy have been studied through evaluation of heart rate variability (HRV). Decreased HRV appears in epilepsy compared to healthy controls, suggesting a shift in autonomic balance toward sympathetic dominance; recent studies have associated HRV changes with seizure severity and outcome of interventions. However, the processes underlying these autonomic changes remain unclear. We examined the nature of these changes by assessing alterations in whole-brain functional connectivity, and relating those alterations to HRV. Methods: We examined regional brain activity and functional organization in 28 drug-resistant epilepsy patients and 16 healthy controls using resting-state functional magnetic resonance imaging (fMRI). We employed an HRV state-dependent functional connectivity (FC) framework with low and high HRV states derived from the following four cardiac-related variables: 1. RR interval, 2. root mean square of successive differences (RMSSD), 4. low-frequency HRV (0.04-0.15 Hz; LF-HRV) and high-frequency HRV (0.15-0.40 Hz; HF-HRV). The effect of group (epilepsy vs. controls), HRV state (low vs. high) and the interactions of group and state were assessed using a mixed analysis of variance (ANOVA). We assessed FC within and between 7 large-scale functional networks consisting of cortical regions and 4 subcortical networks, the amygdala, hippocampus, basal ganglia and thalamus networks. Results: Consistent with previous studies, decreased RR interval (increased heart rate) and decreased HF-HRV appeared in people with epilepsy compared to healthy controls. For both groups, fluctuations in heart rate were positively correlated with BOLD activity in bilateral thalamus and regions of the cerebellum, and negatively correlated with BOLD activity in the insula, putamen, superior temporal gyrus and inferior frontal gyrus. Connectivity strength in patients between right thalamus and ventral attention network (mainly insula) increased in the high LF-HRV state compared to low LF-HRV; the opposite trend appeared in healthy controls. A similar pattern emerged for connectivity between the thalamus and basal ganglia. Conclusion: The findings suggest that resting connectivity patterns between the thalamus and other structures underlying HRV expression are modified in people with drug-resistant epilepsy compared to healthy controls.

Source analyses of axial and vestibular evoked potentials associated with brainstem-spinal reflexes show cerebellar and cortical contributions.

In this work we examine the possible neural basis for two brainstem-spinal reflexes using source analyses of brain activity recorded over the cortex and posterior fossa. In a sample of 5 healthy adult subjects, using axial and vestibular stimulation by means of applied impulsive forces, evoked potentials were recorded with 63 channels using a 10 % cerebellar extension montage. In parallel, EMG was recorded from soleus and tibialis anterior muscles and accelerometry from the lower leg. Recordings over the cerebellum (ECeG) confirmed the presence of short latency (SL) potentials and these were associated with changes in high-frequency power. The SL responses to the two stimulus modalities differed in that the axial stimulation produced an initial pause and then a burst in the high-frequency ECeG, followed by excitation/inhibition in soleus while vestibular stimulation produced an initial burst then a pause, followed by inhibition/excitation in soleus. These short latency responses were followed by longer latency N1/P2/N2 responses in the averaged EEG, which were maximal at FCz. Brain Electrical Source Analysis (BESA) demonstrated both cerebellar and cerebral cortical contributions to the short-latency responses and primarily frontal cortex contributions to the long-latency EPs. The latency and polarity of the SL EPs, in conjunction with changes in high-frequency spontaneous activity, are consistent with cerebellar involvement in the control of brainstem-spinal reflexes. The early involvement of frontal cortex and subsequent later activity may be an indicator of the activation of the cortical motor-related system for rapid responses which may follow the reflexive components. These findings provide evidence of the feasibility of non-invasive electrophysiology of the human cerebellum and have demonstrated cerebellar and frontal activations associated with postural-related stimuli.

Peri-ictal hypoxia is related to extent of regional brain volume loss accompanying generalized tonic-clonic seizures.

OBJECTIVES: Hypoxia, or abnormally low blood-oxygen levels, often accompanies seizures and may elicit brain structural changes in people with epilepsy which contribute to central processes underlying sudden unexpected death in epilepsy (SUDEP). The extent to which hypoxia may be related to brain structural alterations in this patient group remains unexplored. METHODS: We analyzed high-resolution T1-weighted magnetic resonance imaging (MRI) to determine brain morphometric and volumetric alterations in people with generalized tonic-clonic seizures (GTCS) recorded during long-term video-electroencephalography (VEEG), recruited from two sites (n = 22), together with data from age- and sex-matched healthy controls (n = 43). Subjects were sub-divided into those with mild/moderate (GTCS-hypox-mild/moderate, n = 12) and severe (GTCS-hypox-severe, n = 10) hypoxia, measured by peripheral oxygen saturation (SpO2 ) during VEEG. Whole-brain voxel-based morphometry (VBM) and regional volumetry were used to assess group comparisons and correlations between brain structural measurements as well as the duration and extent of hypoxia during GTCS. RESULTS: Morphometric and volumetric alterations appeared in association with peri-GTCS hypoxia, including volume loss in the periaqueductal gray (PAG), thalamus, hypothalamus, vermis, cerebellum, parabrachial pons, and medulla. Thalamic and PAG volume was significantly reduced in GTCS patients with severe hypoxia compared with GTCS patients with mild/moderate hypoxia. Brainstem volume loss appeared in both hypoxia groups, although it was more extensive in those with severe hypoxia. Significant negative partial correlations emerged between thalamic and hippocampal volume and extent of hypoxia, whereas vermis and accumbens volumes declined with increasing hypoxia duration. SIGNIFICANCE: Brain structural alterations in patients with GTCS are related to the extent of hypoxia in brain sites that serve vital functions. Although the changes are associative only, they provide evidence of injury to regulatory brain sites related to respiratory manifestations of seizures.

Temperature Measurements in the Vicinity of Human Intracranial EEG Electrodes Exposed to Body-Coil RF for MRI at 1.5T.

The application of intracranial electroencephalography (icEEG) recording during functional magnetic resonance imaging (icEEG-fMRI) has allowed the study of the hemodynamic correlates of epileptic activity and of the neurophysiological basis of the blood oxygen level-dependent (BOLD) signal. However, the applicability of this technique is affected by data quality issues such as signal drop out in the vicinity of the implanted electrodes. In our center we have limited the technique to a quadrature head transmit and receive RF coil following the results of a safety evaluation. The purpose of this study is to gather further safety-related evidence for performing icEEG-fMRI using a body RF-transmit coil, to allow the greater flexibility afforded by the use of modern, high-density receive arrays, and therefore parallel imaging with benefits such as reduced signal drop-out and distortion artifact. Specifically, we performed a set of empirical temperature measurements on a 1.5T Siemens Avanto MRI scanner with the body RF-transmit coil in a range of electrode and connector cable configurations. The observed RF-induced heating during a high-SAR sequence was maximum in the immediate vicinity of a depth electrode located along the scanner's central axis (range: 0.2-2.4°C) and below 0.5°C at the other electrodes. Also for the high-SAR sequence, we observed excessive RF-related heating in connection cable configurations that deviate from our recommended setup. For the low-SAR sequence, the maximum observed temperature increase across all configurations was 0.3°C. This provides good evidence to allow simultaneous icEEG-fMRI to be performed utilizing the body transmit coil on the 1.5T Siemens Avanto MRI scanner at our center with acceptable additional risk by following a well-defined protocol.

Neuroimaging of Sudden Unexpected Death in Epilepsy (SUDEP): Insights From Structural and Resting-State Functional MRI Studies.

The elusive nature of sudden unexpected death in epilepsy (SUDEP) has led to investigations of mechanisms and identification of biomarkers of this fatal scenario that constitutes the leading cause of premature death in epilepsy. In this short review, we compile evidence from structural and functional neuroimaging that demonstrates alterations to brain structures and networks involved in central autonomic and respiratory control in SUDEP and those at elevated risk. These findings suggest that compromised central control of vital regulatory processes may contribute to SUDEP. Both structural changes and dysfunctional interactions indicate potential mechanisms underlying the fatal event; contributions to individual risk prediction will require further study. The nature and sites of functional disruptions suggest potential non-invasive interventions to overcome failing processes.

BOLD mapping of human epileptic spikes recorded during simultaneous intracranial EEG-fMRI: The impact of automated spike classification.

OBJECTIVES: Simultaneous intracranial EEG and functional MRI (icEEG-fMRI) can be used to map the haemodynamic (BOLD) changes associated with the generation of IEDs. Unlike scalp EEG-fMRI, in most patients who undergo icEEG-fMRI, IEDs recorded intracranially are numerous and show variability in terms of field amplitude and morphology. Therefore, visual marking can be highly subjective and time consuming. In this study, we applied an automated spike classification algorithm, Wave_clus (WC), to IEDs marked visually on icEEG data acquired during simultaneous fMRI acquisition. The motivation of this work is to determine whether using a potentially more consistent and unbiased automated approach can produce more biologically meaningful BOLD patterns compared to the BOLD patterns obtained based on the conventional, visual classification. METHODS: We analysed simultaneous icEEG-fMRI data from eight patients with severe drug resistant epilepsy, and who subsequently underwent resective surgery that resulted in a good outcome: confirmed epileptogenic zone (EZ). For each patient two fMRI analyses were performed: one based on the conventional visual IED classification and the other based on the automated classification. We used the concordance of the IED-related BOLD maps with the confirmed EZ as an indication of their biological meaning, which we compared for the automated and visual classifications for all IED originating in the EZ. RESULTS: Across the group, the visual and automated classifications resulted in 32 and 24 EZ IED classes respectively, for which 75% vs 83% of the corresponding BOLD maps were concordant. At the single-subject level, the BOLD maps for the automated approach had greater concordance in four patients, and less concordance in one patient, compared to those obtained using the conventional visual classification, and equal concordance for three remaining patients. These differences did not reach statistical significance. CONCLUSION: We found automated IED classification on icEEG data recorded during fMRI to be feasible and to result in IED-related BOLD maps that may contain similar or greater biological meaning compared to the conventional approach in the majority of the cases studied. We anticipate that this approach will help to gain significant new insights into the brain networks associated with IEDs and in relation to postsurgical outcome.

A hemodynamic network involving the insula, the cingulate, and the basal forebrain correlates with EEG synchronization phases of sleep instability.

The cyclic alternating pattern (CAP) encompasses the pseudoperiodic appearance of synchronized brain waves and rhythms and is considered a regulator of the nonrapid eye movement (NREM) sleep vigilance level, reflecting sleep instability. To determine the brain regions responsible for this phenomenon, we scored and analyzed sleep functional magnetic resonance imaging data acquired with simultaneous electroencephalography (EEG-fMRI). Group analysis revealed a set of brain areas showing statistically significant blood oxygen-level dependent signal correlated positively with the synchronization phase of the CAP, most prominent being the insula, the middle cingulate gyrus, and the basal forebrain. These areas may form a network acting as a synchronization pacemaker, controlling the level of NREM sleep vigilance and the sleeper's arousability.

The impact of mapping interictal discharges using EEG-fMRI on the epilepsy presurgical clinical decision making process: A prospective study.

PURPOSE: We set out to establish the clinical utility of EEG-correlated fMRI as part of the presurgical evaluation, by measuring prospectively its effects on the clinical decision. METHODS: Patients with refractory extra-temporal focal epilepsy, referred for presurgical evaluation were recruited in a period of 18 months. The EEG-fMRI based localization was presented during a multi-disciplinary meeting after the team had defined the presumed RESULTS: Sixteen patients (six women), with a median age of 28 years, were recruited. Interpretable EEG-fMRI results were available in 13: interictal epileptic discharges (IEDs) were recorded in eleven patients and seizures were recorded in two patients. In three patients, no epileptic activity was captured during EEG-fMRI acquisition and in two of those an IED topographic map correlation was performed (between EEG recorded inside the scanner and long-term video EEG monitoring). EEG-fMRI results presentation had no impact on the initial clinical decision in three patients (23%) of the thirteen and resulted in a modification of the initial surgical plan in ten patients (77%) of the thirteen finally presented in MDT; in eight patients the impact was on the planned placement of invasive electrodes and in two patients the EEG-fMRI led to additional non-invasive tests before proceeding further with surgery. CONCLUSION: The study is a prospective observational cohort study specifically designed to assess the impact of EEG-fMRI on the clinical decision making process, suggesting a significant influence of EEG-fMRI on epilepsy surgery planning.

Epileptic Seizures are Reduced by Autonomic Biofeedback Therapy Through Enhancement of Fronto-limbic Connectivity: A Controlled Trial and Neuroimaging Study.

BACKGROUND: Thirty-percent of patients with epilepsy are drug-resistant, and might benefit from effective noninvasive therapeutic interventions. Evidence is accumulating on the efficacy of autonomic biofeedback therapy using galvanic skin response (GSR; an index of sympathetic arousal) in treating epileptic seizures. This study aimed to extend previous controlled clinical trials of autonomic biofeedback therapy with a larger homogeneous sample of patients with temporal lobe epilepsy. In addition, we used neuroimaging to characterize neural mechanisms of change in seizure frequency following the therapy. METHODS: Forty patients with drug-resistant temporal lobe epilepsy (TLE) (age: 18 to 70years old), on stable doses of anti-epileptic medication, were recruited into a controlled and parallel-group trial from three screening centers in the UK. Patients were allocated to either an active intervention group, who received therapy with GSR biofeedback, or a control group, who received treatment as usual. Allocation to the group was informed, in part, by whether patients could travel to attend repeated therapy sessions (non-randomized). Measurement of outcomes was undertaken by an assessor blinded to the patients' group membership. Resting-state functional and structural MRI data were acquired before and after one month of therapy in the therapy group, and before and after a one-month interval in the control group. The percentage change of seizure frequency was the primary outcome measure. The analysis employed an intention-to-treat principle. The secondary outcome was the change in default mode network (DMN) and limbic network functional connectivity tested for effects of therapy. The trial was registered with the National Institute for Health Research (NIHR) portfolio (ID 15967). FINDINGS: Data were acquired between May 2014 and October 2016. Twenty participants were assigned to each group. Two patients in the control group dropped out before the second scan, leaving 18 control participants. There was a significant difference in reduction of seizure frequency between the therapy and control groups (p<0.001: Mann Whitney U Test). The seizure frequency in the therapy group was significantly reduced (p<0.001: Wilcoxon Signed Rank Test) following GSR biofeedback, with a mean seizure reduction of 43% (SD=± 32.12, median=-37.26, 95% CI -58.02% to -27.96%). No significant seizure reduction was observed in the control group, with a mean increase in seizure frequency of 31% (SD=±88.27, median=0, 95% CI -12.83% to 74.96%). The effect size of group comparison was 1.14 (95% CI 0.44 to 1.82). 45% of patients in the therapy group showed a seizure reduction of >50%. Neuroimaging analysis revealed that post-therapy seizure reduction was linearly correlated with enhanced functional connectivity between right amygdala and both the orbitofrontal cortex (OFC) and frontal pole (FP). INTERPRETATION: Our clinical study provides evidence for autonomic biofeedback therapy as an effective and potent behavioral intervention for patients with drug-resistant epilepsy. This approach is non-pharmacological, non-invasive and seemingly side-effect free.

Fractal and Multifractal Properties of Electrographic Recordings of Human Brain Activity: Toward Its Use as a Signal Feature for Machine Learning in Clinical Applications.

The quantification of brain dynamics is essential to its understanding. However, the brain is a system operating on multiple time scales, and characterization of dynamics across time scales remains a challenge. One framework to study such dynamics is that of fractal geometry; and currently there exist several methods for the study of brain dynamics using fractal geometry. We aim to highlight some of the practical challenges of applying fractal geometry to brain dynamics-and as a putative feature for machine learning applications, and propose solutions to enable its wider use in neuroscience. Using intracranially recorded electroencephalogram (EEG) and simulated data, we compared monofractal and multifractal methods with regards to their sensitivity to signal variance. We found that both monofractal and multifractal properties correlate closely with signal variance, thus not being a useful feature of the signal. However, after applying an epoch-wise standardization procedure to the signal, we found that multifractal measures could offer non-redundant information compared to signal variance, power (in different frequency bands) and other established EEG signal measures. We also compared different multifractal estimation methods to each other in terms of reliability, and we found that the Chhabra-Jensen algorithm performed best. Finally, we investigated the impact of sampling frequency and epoch length on the estimation of multifractal properties. Using epileptic seizures as an example event in the EEG, we show that there may be an optimal time scale (i.e., combination of sampling frequency and epoch length) for detecting temporal changes in multifractal properties around seizures. The practical issues we highlighted and our suggested solutions should help in developing robust methods for the application of fractal geometry in EEG signals. Our analyses and observations also aid the theoretical understanding of the multifractal properties of the brain and might provide grounds for new discoveries in the study of brain signals. These could be crucial for the understanding of neurological function and for the developments of new treatments.