Widespread, depth-dependent cortical microstructure alterations in pediatric focal epilepsy.

OBJECTIVE: Tissue abnormalities in focal epilepsy may extend beyond the presumed focus. The underlying pathophysiology of these broader changes is unclear, and it is not known whether they result from ongoing disease processes or treatment-related side effects, or whether they emerge earlier. Few studies have focused on the period of onset for most focal epilepsies, childhood. Fewer still have utilized quantitative magnetic resonance imaging (MRI), which may provide a more sensitive and interpretable measure of tissue microstructural change. Here, we aimed to determine common spatial modes of changes in cortical architecture in children with heterogeneous drug-resistant focal epilepsy and, secondarily, whether changes were related to disease severity. METHODS: To assess cortical microstructure, quantitative T1 and T2 relaxometry (qT1 and qT2) was measured in 43 children with drug-resistant focal epilepsy (age range = 4-18 years) and 46 typically developing children (age range = 2-18 years). We assessed depth-dependent qT1 and qT2 values across the neocortex, as well as their gradient of change across cortical depths. We also determined whether global changes seen in group analyses were driven by focal pathologies in individual patients. Finally, as a proof-of-concept, we trained a classifier using qT1 and qT2 gradient maps from patients with radiologically defined abnormalities (MRI positive) and healthy controls, and tested whether this could classify patients without reported radiological abnormalities (MRI negative). RESULTS: We uncovered depth-dependent qT1 and qT2 increases in widespread cortical areas in patients, likely representing microstructural alterations in myelin or gliosis. Changes did not correlate with disease severity measures, suggesting they may represent antecedent neurobiological alterations. Using a classifier trained with MRI-positive patients and controls, sensitivity was 71.4% at 89.4% specificity on held-out MRI-negative patients. SIGNIFICANCE: These findings suggest the presence of a potential imaging endophenotype of focal epilepsy, detectable irrespective of radiologically identified abnormalities.

Simultaneous Optimization of MP2RAGE T1 -weighted (UNI) and FLuid And White matter Suppression (FLAWS) brain images at 7T using Extended Phase Graph (EPG) Simulations.

PURPOSE: The MP2RAGE sequence is typically optimized for either T1 -weighted uniform image (UNI) or gray matter-dominant fluid and white matter suppression (FLAWS) contrast images. Here, the purpose was to optimize an MP2RAGE protocol at 7 Tesla to provide UNI and FLAWS images simultaneously in a clinically applicable acquisition time at <0.7 mm isotropic resolution. METHODS: Using the extended phase graph formalism, the signal evolution of the MP2RAGE sequence was simulated incorporating T2 relaxation, diffusion, RF spoiling, and B1 + variability. Flip angles and TI were optimized at different TRs (TRMP2RAGE ) to produce an optimal contrast-to-noise ratio for UNI and FLAWS images. Simulation results were validated by comparison to MP2RAGE brain scans of 5 healthy subjects, and a final protocol at TRMP2RAGE  = 4000 ms was applied in 19 subjects aged 8-62 years with and without epilepsy. RESULTS: FLAWS contrast images could be obtained while maintaining >85% of the optimal UNI contrast-to-noise ratio. Using TI1 /TI2 /TRMP2RAGE of 650/2280/4000 ms, 6/8 partial Fourier in the inner phase-encoding direction, and GRAPPA factor = 4 in the other, images with 0.65 mm isotropic resolution were produced in <7.5 min. The contrast-to-noise ratio was around 20% smaller at TRMP2RAGE  = 4000 ms compared to that at TRMP2RAGE  = 5000 ms; however, the 20% shorter duration makes TRMP2RAGE  = 4000 ms a good candidate for clinical applications example, pediatrics. CONCLUSION: FLAWS and UNI images could be obtained in a single scan with 0.65 mm isotropic resolution, providing a set of high-contrast images and full brain coverage in a clinically applicable scan time. Images with excellent anatomical detail were demonstrated over a wide age range using the optimized parameter set.

Towards network-guided neuromodulation for epilepsy.

Epilepsy is well-recognized as a disorder of brain networks. There is a growing body of research to identify critical nodes within dynamic epileptic networks with the aim to target therapies that halt the onset and propagation of seizures. In parallel, intracranial neuromodulation, including deep brain stimulation and responsive neurostimulation, are well-established and expanding as therapies to reduce seizures in adults with focal-onset epilepsy; and there is emerging evidence for their efficacy in children and generalized-onset seizure disorders. The convergence of these advancing fields is driving an era of 'network-guided neuromodulation' for epilepsy. In this review, we distil the current literature on network mechanisms underlying neurostimulation for epilepsy. We discuss the modulation of key 'propagation points' in the epileptogenic network, focusing primarily on thalamic nuclei targeted in current clinical practice. These include (i) the anterior nucleus of thalamus, now a clinically approved and targeted site for open loop stimulation, and increasingly targeted for responsive neurostimulation; and (ii) the centromedian nucleus of the thalamus, a target for both deep brain stimulation and responsive neurostimulation in generalized-onset epilepsies. We discuss briefly the networks associated with other emerging neuromodulation targets, such as the pulvinar of the thalamus, piriform cortex, septal area, subthalamic nucleus, cerebellum and others. We report synergistic findings garnered from multiple modalities of investigation that have revealed structural and functional networks associated with these propagation points - including scalp and invasive EEG, and diffusion and functional MRI. We also report on intracranial recordings from implanted devices which provide us data on the dynamic networks we are aiming to modulate. Finally, we review the continuing evolution of network-guided neuromodulation for epilepsy to accelerate progress towards two translational goals: (i) to use pre-surgical network analyses to determine patient candidacy for neurostimulation for epilepsy by providing network biomarkers that predict efficacy; and (ii) to deliver precise, personalized and effective antiepileptic stimulation to prevent and arrest seizure propagation through mapping and modulation of each patients' individual epileptogenic networks.

Camera-based Prospective Motion Correction in Paediatric Epilepsy Patients Enables EEG-fMRI Localization Even in High-motion States.

BACKGROUND: EEG-fMRI is a useful additional test to localize the epileptogenic zone (EZ) particularly in MRI negative cases. However subject motion presents a particular challenge owing to its large effects on both MRI and EEG signal. Traditionally it is assumed that prospective motion correction (PMC) of fMRI precludes EEG artifact correction. METHODS: Children undergoing presurgical assessment at Great Ormond Street Hospital were included into the study. PMC of fMRI was done using a commercial system with a Moiré Phase Tracking marker and MR-compatible camera. For retrospective EEG correction both a standard and a motion educated EEG artefact correction (REEGMAS) were compared to each other. RESULTS: Ten children underwent simultaneous EEG-fMRI. Overall head movement was high (mean RMS velocity < 1.5 mm/s) and showed high inter- and intra-individual variability. Comparing motion measured by the PMC camera and the (uncorrected residual) motion detected by realignment of fMRI images, there was a five-fold reduction in motion from its prospective correction. Retrospective EEG correction using both standard approaches and REEGMAS allowed the visualization and identification of physiological noise and epileptiform discharges. Seven of 10 children had significant maps, which were concordant with the clinical EZ hypothesis in 6 of these 7. CONCLUSION: To our knowledge this is the first application of camera-based PMC for MRI in a pediatric clinical setting. Despite large amount of movement PMC in combination with retrospective EEG correction recovered data and obtained clinically meaningful results during high levels of subject motion. Practical limitations may currently limit the widespread use of this technology.

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.

Evaluation of specific absorption rate and heating in children exposed to a 7T MRI head coil.

PURPOSE: To evaluate specific absorption rate (SAR) and temperature distributions resulting from pediatric exposure to a 7T head coil. METHODS: Exposure from a 297-MHz birdcage head transmit coil (CP mode single-channel transmission) was simulated in several child models (ages 3-14, mass 13.9-50.4 kg) and one adult, using time-domain electromagnetic and thermal solvers. Position variability, age-related changes in dielectric properties, and differences in thermoregulation were also considered. RESULTS: Age-adjusted dielectric properties had little effect in this population. Head average SAR (hdSAR) was the limiting factor for all models centered in the coil. The value of hdSAR (normalized to net power) was found to decrease linearly with increasing mass (R2  = 0.86); no equivalent relationship for peak-spatial 10g averaged SAR (psSAR10g ) was identified. Relatively small (< 10%) variability was observed in hdSAR for position shifts of ±25 mm in each orthogonal direction when normalized to net power; accounting for B1+$$ {\mathrm{B}}_1^{+} $$ efficiency can lead to much larger variability. Position sensitivity of psSAR10g was greater, but in most cases hdSAR remained the limiting quantity. For thermal simulations, if blood temperature is fixed (i.e., asserting good thermoregulation), maximum temperatures are compliant with International Electrotechnical Commission limits during 60-min exposure at the SAR limit. Introducing variable blood temperature leads to core temperature changes proportional to whole-body averaged SAR, exceeding guideline limits for all child models. CONCLUSIONS: Children experienced higher SAR than adults for the 297-MHz head transmit coil examined in this work. Thermal simulations suggest that core temperature changes could occur in smaller subjects, although experimental data are needed for validation.

Quantitative MRI susceptibility mapping reveals cortical signatures of changes in iron, calcium and zinc in malformations of cortical development in children with drug-resistant epilepsy.

OBJECTIVE: Malformations of cortical development (MCD), including focal cortical dysplasia (FCD), are the most common cause of drug-resistant focal epilepsy in children. Histopathological lesion characterisation demonstrates abnormal cell types and lamination, alterations in myelin (typically co-localised with iron), and sometimes calcification. Quantitative susceptibility mapping (QSM) is an emerging MRI technique that measures tissue magnetic susceptibility (χ) reflecting it's mineral composition. We used QSM to investigate abnormal tissue composition in a group of children with focal epilepsy with comparison to effective transverse relaxation rate (R2*) and Synchrotron radiation X-ray fluorescence (SRXRF) elemental maps. Our primary hypothesis was that reductions in χ would be found in FCD lesions, resulting from alterations in their iron and calcium content. We also evaluated deep grey matter nuclei for changes in χ with age. METHODS: QSM and R2* maps were calculated for 40 paediatric patients with suspected MCD (18 histologically confirmed) and 17 age-matched controls. Patients' sub-groups were defined based on concordant electro-clinical or histopathology data. Quantitative investigation of QSM and R2* was performed within lesions, using a surface-based approach with comparison to homologous regions, and within deep brain regions using a voxel-based approach with regional values modelled with age and epilepsy as covariates. Synchrotron radiation X-ray fluorescence (SRXRF) was performed on brain tissue resected from 4 patients to map changes in iron, calcium and zinc and relate them to MRI parameters. RESULTS: Compared to fluid-attenuated inversion recovery (FLAIR) or T1-weighted imaging, QSM improved lesion conspicuity in 5% of patients. In patients with well-localised lesions, quantitative profiling demonstrated decreased χ, but not R2*, across cortical depth with respect to the homologous regions. Contra-lateral homologous regions additionally exhibited increased χ at 2-3 mm cortical depth that was absent in lesions. The iron decrease measured by the SRXRF in FCDIIb lesions was in agreement with myelin reduction observed by Luxol Fast Blue histochemical staining. SRXRF analysis in two FCDIIb tissue samples showed increased zinc and calcium in one patient, and decreased iron in the brain region exhibiting low χ and high R2* in both patients. QSM revealed expected age-related changes in the striatum nuclei, substantia nigra, sub-thalamic and red nucleus. CONCLUSION: QSM non-invasively revealed cortical/sub-cortical tissue alterations in MCD lesions and in particular that χ changes in FCDIIb lesions were consistent with reduced iron, co-localised with low myelin and increased calcium and zinc content. These findings suggest that measurements of cortical χ could be used to characterise tissue properties non-invasively in epilepsy lesions.

Neural diffusivity and pre-emptive epileptic seizure intervention.

The propagation of epileptic seizure activity in the brain is a widespread pathophysiology that, in principle, should yield to intervention techniques guided by mathematical models of neuronal ensemble dynamics. During a seizure, neural activity will deviate from its current dynamical regime to one in which there are significant signal fluctuations. In silico treatments of neural activity are an important tool for the understanding of how the healthy brain can maintain stability, as well as of how pathology can lead to seizures. The hope is that, contained within the mathematical foundations of such treatments, there lie potential strategies for mitigating instabilities, e.g. via external stimulation. Here, we demonstrate that the dynamic causal modelling neuronal state equation generalises to a Fokker-Planck formalism if one extends the framework to model the ways in which activity propagates along the structural connections of neural systems. Using the Jacobian of this generalised state equation, we show that an initially unstable system can be rendered stable via a reduction in diffusivity-i.e., by lowering the rate at which neuronal fluctuations disperse to neighbouring regions. We show, for neural systems prone to epileptic seizures, that such a reduction in diffusivity can be achieved via external stimulation. Specifically, we show that this stimulation should be applied in such a way as to temporarily mirror the activity profile of a pathological region in its functionally connected areas. This counter-intuitive method is intended to be used pre-emptively-i.e., in order to mitigate the effects of the seizure, or ideally even prevent it from occurring in the first place. We offer proof of principle using simulations based on functional neuroimaging data collected from patients with idiopathic generalised epilepsy, in which we successfully suppress pathological activity in a distinct sub-network prior to seizure onset. Our hope is that this technique can form the basis for future real-time monitoring and intervention devices that are capable of treating epilepsy in a non-invasive manner.

Unified Retrospective EEG Motion Educated Artefact Suppression for EEG-fMRI to Suppress Magnetic Field Gradient Artefacts During Motion.

The data quality of simultaneously acquired electroencephalography and functional magnetic resonance imaging (EEG-fMRI) can be strongly affected by motion. Recent work has shown that the quality of fMRI data can be improved by using a Moiré-Phase-Tracker (MPT)-camera system for prospective motion correction. The use of the head position acquired by the MPT-camera-system has also been shown to correct motion-induced voltages, ballistocardiogram (BCG) and gradient artefact residuals separately. In this work we show the concept of an integrated framework based on the general linear model to provide a unified motion informed model of in-MRI artefacts. This model (retrospective EEG motion educated gradient artefact suppression, REEG-MEGAS) is capable of correcting voltage-induced, BCG and gradient artefact residuals of EEG data acquired simultaneously with prospective motion corrected fMRI. In our results, we have verified that applying REEG-MEGAS correction to EEG data acquired during subject motion improves the data quality in terms of motion induced voltages and also GA residuals in comparison to standard Artefact Averaging Subtraction and Retrospective EEG Motion Artefact Suppression. Besides that, we provide preliminary evidence that although adding more regressors to a model may slightly affect the power of physiological signals such as the alpha-rhythm, its application may increase the overall quality of a dataset, particularly when strongly affected by motion. This was verified by analysing the EEG traces, power spectra density and the topographic distribution from two healthy subjects. We also have verified that the correction by REEG-MEGAS improves higher frequency artefact correction by decreasing the power of Gradient Artefact harmonics. Our method showed promising results for decreasing the power of artefacts for frequencies up to 250 Hz. Additionally, REEG-MEGAS is a hybrid framework that can be implemented for real time prospective motion correction of EEG and fMRI data. Among other EEG-fMRI applications, the approach described here may benefit applications such as EEG-fMRI neurofeedback and brain computer interface, which strongly rely on the prospective acquisition and application of motion artefact removal.

MRI profiling of focal cortical dysplasia using multi-compartment diffusion models.

OBJECTIVE: Focal cortical dysplasia (FCD) lesion detection and subtyping remain challenging on conventional MRI. New diffusion models such as the spherical mean technique (SMT) and neurite orientation dispersion and density imaging (NODDI) provide measurements that potentially produce more specific maps of abnormal tissue microstructure. This study aims to assess the SMT and NODDI maps for computational and radiological lesion characterization compared to standard fractional anisotropy (FA) and mean diffusivity (MD). METHODS: SMT, NODDI, FA, and MD maps were calculated for 33 pediatric patients with suspected FCD (18 histologically confirmed). Two neuroradiologists scored lesion visibility on clinical images and diffusion maps. Signal profile changes within lesions and homologous regions were quantified using a surface-based approach. Diffusion parameter changes at multiple cortical depths were statistically compared between FCD type IIa and type IIb. RESULTS: Compared to fluid-attenuated inversion recovery (FLAIR) or T1-weighted imaging, lesions conspicuity on NODDI intracellular volume fraction (ICVF) maps was better/equal/worse in 5/14/14 patients, respectively, while on SMT intra-neurite volume fraction (INVF) in 3/3/27. Compared to FA or MD, lesion conspicuity on the ICVF was better/equal/worse in 27/4/2, while on the INVF in 20/7/6. Quantitative signal profiling demonstrated significant ICVF and INVF reductions in the lesions, whereas SMT microscopic mean, radial, and axial diffusivities were significantly increased. FCD type IIb exhibited greater changes than FCD type IIa. No changes were detected on FA or MD profiles. SIGNIFICANCE: FCD lesion-specific signal changes were found in ICVF and INVF but not in FA and MD maps. ICVF and INVF showed greater contrast than FLAIR in some cases and had consistent signal changes specific to FCD, suggesting that they could improve current presurgical pediatric epilepsy imaging protocols and can provide features useful for automated lesion detection.

Traumatic axonal injury influences the cognitive effect of non-invasive brain stimulation.

Non-invasive brain stimulation has been widely investigated as a potential treatment for a range of neurological and psychiatric conditions, including brain injury. However, the behavioural effects of brain stimulation are variable, for reasons that are poorly understood. This is a particular challenge for traumatic brain injury, where patterns of damage and their clinical effects are heterogeneous. Here we test the hypothesis that the response to transcranial direct current stimulation following traumatic brain injury is dependent on white matter damage within the stimulated network. We used a novel simultaneous stimulation-MRI protocol applying anodal, cathodal and sham stimulation to 24 healthy control subjects and 35 patients with moderate/severe traumatic brain injury. Stimulation was applied to the right inferior frontal gyrus/anterior insula node of the salience network, which was targeted because our previous work had shown its importance to executive function. Stimulation was applied during performance of the Stop Signal Task, which assesses response inhibition, a key component of executive function. Structural MRI was used to assess the extent of brain injury, including diffusion MRI assessment of post-traumatic axonal injury. Functional MRI, which was simultaneously acquired to delivery of stimulation, assessed the effects of stimulation on cognitive network function. Anodal stimulation improved response inhibition in control participants, an effect that was not observed in the patient group. The extent of traumatic axonal injury within the salience network strongly influenced the behavioural response to stimulation. Increasing damage to the tract connecting the stimulated right inferior frontal gyrus/anterior insula to the rest of the salience network was associated with reduced beneficial effects of stimulation. In addition, anodal stimulation normalized default mode network activation in patients with poor response inhibition, suggesting that stimulation modulates communication between the networks involved in supporting cognitive control. These results demonstrate an important principle: that white matter structure of the connections within a stimulated brain network influences the behavioural response to stimulation. This suggests that a personalized approach to non-invasive brain stimulation is likely to be necessary, with structural integrity of the targeted brain networks an important criterion for patient selection and an individualized approach to the selection of stimulation parameters.

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.

Cognitive enhancement with Salience Network electrical stimulation is influenced by network structural connectivity.

The Salience Network (SN) and its interactions are important for cognitive control. We have previously shown that structural damage to the SN is associated with abnormal functional connectivity between the SN and Default Mode Network (DMN), abnormal DMN deactivation, and impaired response inhibition, which is an important aspect of cognitive control. This suggests that stimulating the SN might enhance cognitive control. Here, we tested whether non-invasive transcranial direct current stimulation (TDCS) could be used to modulate activity within the SN and enhance cognitive control. TDCS was applied to the right inferior frontal gyrus/anterior insula cortex during performance of the Stop Signal Task (SST) and concurrent functional (f)MRI. Anodal TDCS improved response inhibition. Furthermore, stratification of participants based on SN structural connectivity showed that it was an important influence on both behavioural and physiological responses to anodal TDCS. Participants with high fractional anisotropy within the SN showed improved SST performance and increased activation of the SN with anodal TDCS, whilst those with low fractional anisotropy within the SN did not. Cathodal stimulation of the SN produced activation of the right caudate, an effect which was not modulated by SN structural connectivity. Our results show that stimulation targeted to the SN can improve response inhibition, supporting the causal influence of this network on cognitive control and confirming it as a target to produce cognitive enhancement. Our results also highlight the importance of structural connectivity as a modulator of network to TDCS, which should guide the design and interpretation of future stimulation studies.

Flexible proton density (PD) mapping using multi-contrast variable flip angle (VFA) data.

Quantitative proton density (PD) maps measure the amount of free water, which is important for non-invasive tissue characterization in pathology and across lifespan. PD mapping requires the estimation and subsequent removal of factors influencing the signal intensity other than PD. These factors include the T1, T2* relaxation effects, transmit field inhomogeneities, receiver coil sensitivity profile (RP) and the spatially invariant factor that is required to scale the data. While the transmit field can be reliably measured, the RP estimation is usually based on image post-processing techniques due to limitations of its measurement at magnetic fields higher than 1.5 T. The post-processing methods are based on unified bias-field/tissue segmentation, fitting the sensitivity profile from images obtained with different coils, or on the linear relationship between T1 and PD. The scaling factor is derived from the signal within a specific tissue compartment or reference object. However, these approaches for calculating the RP and scaling factor have limitations particularly in severe pathology or over a wide age range, restricting their application. We propose a new approach for PD mapping based on a multi-contrast variable flip angle acquisition protocol and a data-driven estimation method for the RP correction and map scaling. By combining all the multi-contrast data acquired at different echo times, we are able to fully correct the MRI signal for T2* relaxation effects and to decrease the variance and the entropy of PD values within tissue class of the final map. The RP is determined from the corrected data applying a non-parametric bias estimation, and the scaling factor is based on the median intensity of an external calibration object. Finally, we compare the signal intensity and homogeneity of the multi-contrast PD map with the well-established effective PD (PD*) mapping, for which the RP is based on concurrent bias field estimation and tissue classification, and the scaling factor is estimated from the mean white matter signal. The multi-contrast PD values homogeneity and accuracy within the cerebrospinal fluid (CSF) and deep brain structures are increased beyond that obtained using PD* maps. We demonstrate that the multi-contrast RP approach is insensitive to anatomical or a priori tissue information by applying it in a patient with extensive brain abnormalities and for whole body PD mapping in post-mortem foetal imaging.

Brain state and polarity dependent modulation of brain networks by transcranial direct current stimulation.

Despite its widespread use in cognitive studies, there is still limited understanding of whether and how transcranial direct current stimulation (tDCS) modulates brain network function. To clarify its physiological effects, we assessed brain network function using functional magnetic resonance imaging (fMRI) simultaneously acquired during tDCS stimulation. Cognitive state was manipulated by having subjects perform a Choice Reaction Task or being at "rest." A novel factorial design was used to assess the effects of brain state and polarity. Anodal and cathodal tDCS were applied to the right inferior frontal gyrus (rIFG), a region involved in controlling activity large-scale intrinsic connectivity networks during switches of cognitive state. tDCS produced widespread modulation of brain activity in a polarity and brain state dependent manner. In the absence of task, the main effect of tDCS was to accentuate default mode network (DMN) activation and salience network (SN) deactivation. In contrast, during task performance, tDCS increased SN activation. In the absence of task, the main effect of anodal tDCS was more pronounced, whereas cathodal tDCS had a greater effect during task performance. Cathodal tDCS also accentuated the within-DMN connectivity associated with task performance. There were minimal main effects of stimulation on network connectivity. These results demonstrate that rIFG tDCS can modulate the activity and functional connectivity of large-scale brain networks involved in cognitive function, in a brain state and polarity dependent manner. This study provides an important insight into mechanisms by which tDCS may modulate cognitive function, and also has implications for the design of future stimulation studies.

Optimal repetition time reduction for single subject event-related functional magnetic resonance imaging.

PURPOSE: Short TRs are increasingly used for fMRI as fast sequences such as simultaneous multislice excitation become available. These have been associated with apparent sensitivity improvements, although greater temporal autocorrelation at shorter TRs can inflate sensitivity measurements leading to uncertainty regarding the optimal approach. METHODS: In volunteers (n = 10), the optimal TR was assessed at the single subject level for event-related designs (visual stimulation) with 4 frequencies of presentation at 4 TR values (412-2550 ms). T-values in the visual cortex localized in each individual were obtained and receiver operating characteristics (ROC) analysis was performed by counting voxels within and outside expected task active regions at different thresholds. This analysis was repeated using 4 different autoregressive (AR) models; SPM AR(1) and SPM AR(fast) which globally estimate autocorrelation, and fMRIstat AR(1) and AR(5) that use a local estimate. RESULTS: The use of modest multiband factors of 2 or 3 with a reduction in TR to 1000 ± 200 ms had greater sensitivity and specificity as shown by higher T-values in visual cortex and ROC analysis. At these TRs, the ROC analysis demonstrated that a local AR model fit improved performance while high order AR models were unnecessary. CONCLUSIONS: Modest TR reductions (to 1000 ± 200 ms) optimally improved event-related fMRI performance independent of design frequency. Autoregressive models with a local as opposed to global fit performed better, while low order autoregressive models were sufficient at the optimal TR.

Sensorimotor network hypersynchrony as an endophenotype in families with genetic generalized epilepsy: A resting-state functional magnetic resonance imaging study.

Recent evidence suggests that three specific brain networks show state-dependent levels of synchronization before, during, and after episodes of generalized spike-wave discharges (GSW) in patients with genetic generalized epilepsy (GGE). Here, we investigate whether synchronization in these networks differs between patients with GGE (n = 13), their unaffected first-degree relatives (n = 17), and healthy controls (n = 18). All subjects underwent two 10-minute simultaneous electroencephalographic-functional magnetic resonance imaging (fMRI) recordings without GSW. Whole-brain data were divided into 90 regions, and blood oxygen level-dependent (BOLD) phase synchrony in a 0.04-0.07-Hz band was estimated between all pairs of regions. Three networks were defined: (1) the network with highest synchrony during GSW events, (2) a sensorimotor network, and (3) an occipital network. Average synchrony (mean node degree) was inferred across each network over time. Notably, synchrony was significantly higher in the sensorimotor network in patients and in unaffected relatives, compared to controls. There was a trend toward higher synchrony in the GSW network in patients and in unaffected relatives. There was no difference between groups for the occipital network. Our findings provide evidence that elevated fMRI BOLD synchrony in a sensorimotor network is a state-independent endophenotype of GGE, present in patients in the absence of GSW, and present in unaffected relatives.

Dynamic brain network states in human generalized spike-wave discharges.

Generalized spike-wave discharges in idiopathic generalized epilepsy are conventionally assumed to have abrupt onset and offset. However, in rodent models, discharges emerge during a dynamic evolution of brain network states, extending several seconds before and after the discharge. In human idiopathic generalized epilepsy, simultaneous EEG and functional MRI shows cortical regions may be active before discharges, and network connectivity around discharges may not be normal. Here, in human idiopathic generalized epilepsy, we investigated whether generalized spike-wave discharges emerge during a dynamic evolution of brain network states. Using EEG-functional MRI, we studied 43 patients and 34 healthy control subjects. We obtained 95 discharges from 20 patients. We compared data from patients with discharges with data from patients without discharges and healthy controls. Changes in MRI (blood oxygenation level-dependent) signal amplitude in discharge epochs were observed only at and after EEG onset, involving a sequence of parietal and frontal cortical regions then thalamus (P < 0.01, across all regions and measurement time points). Examining MRI signal phase synchrony as a measure of functional connectivity between each pair of 90 brain regions, we found significant connections (P < 0.01, across all connections and measurement time points) involving frontal, parietal and occipital cortex during discharges, and for 20 s after EEG offset. This network prominent during discharges showed significantly low synchrony (below 99% confidence interval for synchrony in this network in non-discharge epochs in patients) from 16 s to 10 s before discharges, then ramped up steeply to a significantly high level of synchrony 2 s before discharge onset. Significant connections were seen in a sensorimotor network in the minute before discharge onset. This network also showed elevated synchrony in patients without discharges compared to healthy controls (P = 0.004). During 6 s prior to discharges, additional significant connections to this sensorimotor network were observed, involving prefrontal and precuneus regions. In healthy subjects, significant connections involved a posterior cortical network. In patients with discharges, this posterior network showed significantly low synchrony during the minute prior to discharge onset. In patients without discharges, this network showed the same level of synchrony as in healthy controls. Our findings suggest persistently high sensorimotor network synchrony, coupled with transiently (at least 1 min) low posterior network synchrony, may be a state predisposing to generalized spike-wave discharge onset. Our findings also show that EEG onset and associated MRI signal amplitude change is embedded in a considerably longer period of evolving brain network states before and after discharge events.

Combined electroencephalography-functional magnetic resonance imaging and electrical source imaging improves localization of pediatric focal epilepsy.

OBJECTIVE: Surgical treatment in epilepsy is effective if the epileptogenic zone (EZ) can be correctly localized and characterized. Here we use simultaneous electroencephalography-functional magnetic resonance imaging (EEG-fMRI) data to derive EEG-fMRI and electrical source imaging (ESI) maps. Their yield and their individual and combined ability to (1) localize the EZ and (2) predict seizure outcome were then evaluated. METHODS: Fifty-three children with drug-resistant epilepsy underwent EEG-fMRI. Interictal discharges were mapped using both EEG-fMRI hemodynamic responses and ESI. A single localization was derived from each individual test (EEG-fMRI global maxima [GM]/ESI maximum) and from the combination of both maps (EEG-fMRI/ESI spatial intersection). To determine the localization accuracy and its predictive performance, the individual and combined test localizations were compared to the presumed EZ and to the postsurgical outcome. RESULTS: Fifty-two of 53 patients had significant maps: 47 of 53 for EEG-fMRI, 44 of 53 for ESI, and 34 of 53 for both. The EZ was well characterized in 29 patients; 26 had an EEG-fMRI GM localization that was correct in 11, 22 patients had ESI localization that was correct in 17, and 12 patients had combined EEG-fMRI and ESI that was correct in 11. Seizure outcome following resection was correctly predicted by EEG-fMRI GM in 8 of 20 patients, and by the ESI maximum in 13 of 16. The combined EEG-fMRI/ESI region entirely predicted outcome in 9 of 9 patients, including 3 with no lesion visible on MRI. INTERPRETATION: EEG-fMRI combined with ESI provides a simple unbiased localization that may predict surgery better than each individual test, including in MRI-negative patients. Ann Neurol 2017;82:278-287.

Thalamic volume reduction in drug-naive patients with new-onset genetic generalized epilepsy.

OBJECTIVE: Patients with genetic generalized epilepsy (GGE) have subtle morphologic abnormalities of the brain revealed with magnetic resonance imaging (MRI), particularly in the thalamus. However, it is unclear whether morphologic abnormalities of the brain in GGE are a consequence of repeated seizures over the duration of the disease, or are a consequence of treatment with antiepileptic drugs (AEDs), or are independent of these factors. Therefore, we measured brain morphometry in a cohort of AED-naive patients with GGE at disease onset. We hypothesize that drug-naive patients at disease onset have gray matter changes compared to age-matched healthy controls. METHODS: We performed quantitative measures of gray matter volume in the thalamus, putamen, caudate, pallidum, hippocampus, precuneus, prefrontal cortex, precentral cortex, and cingulate in 29 AED-naive patients with new-onset GGE and compared them to 32 age-matched healthy controls. We subsequently compared the shape of any brain structures found to differ in gray matter volume between the groups. RESULTS: The thalamus was the only structure to show reduced gray matter volume in AED-naive patients with new-onset GGE compared to healthy controls. Shape analysis revealed that the thalamus showed deflation, which was not uniformly distributed, but particularly affected a circumferential strip involving anterior, superior, posterior, and inferior regions with sparing of medial and lateral regions. SIGNIFICANCE: Structural abnormalities in the thalamus are present at the initial onset of GGE in AED-naive patients, suggesting that thalamic structural abnormality is an intrinsic feature of GGE and not a consequence of AEDs or disease duration.