Quantitative Approaches to Functional MRI: Applications in Epilepsy

Summary:  The application of functional magnetic resonance imaging (fMRI) to elucidation of seizures and epilepsy has been built primarily upon a framework derived from cortical responses to periodic sensory (and cognitive) stimuli. This analytical approach relies upon assumptions that may be less applicable to the problem of seizure origination. Because of the heterogeneous and complex nature of seizures, a number of quantitative methodologies have been derived to understand fMRI changes that are associated with epileptiform neural activity. Separated broadly, these can be divided into those making some set of assumptions about the form of the MRI signal response to neural activation (the general linear model), and those that are data driven. It is likely that a combination of methodologies, where data driven methods are "informed" by knowledge of the underlying neurobiological process will provide the greatest insight into the underlying neurobiological basis of seizure origination.     

ICA decomposition of EEG signal for fMRI processing in epilepsy

In this study, we introduce a new approach to process simultaneous Electroencephalography and functional Magnetic Resonance Imaging (EEG‐fMRI) data in epilepsy. The method is based on the decomposition of the EEG signal using independent component analysis (ICA) and the usage of the relevant components' time courses to define the event related model necessary to find the regions exhibiting fMRI signal changes related to interictal activity. This approach achieves a natural data‐driven differentiation of the role of distinct types of interictal activity with different amplitudes and durations in the epileptogenic process. Agreement between the conventional method and this new approach was obtained in 6 out of 9 patients that had interictal activity inside the scanner. In all cases, the maximum Z‐score was greater in the fMRI studies based on ICA component method and the extent of activation was increased in 5 out of the 6 cases in which overlap was found. Furthermore, the three cases where an agreement was not found were those in which no significant activation was found at all using the conventional approach. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.     

Intracranial EEG-fMRI analysis of focal epileptiform discharges in humans

Purpose: Combining intracranial electroencephalography (iEEG) with functional magnetic resonance imaging (fMRI) is of interest in epilepsy studies as it would allow the detection of much smaller interictal epileptiform discharges than can be recorded using scalp EEG‐fMRI. This may help elucidate the spatiotemporal mechanisms underlying the generation of interictal discharges. To our knowledge, iEEG‐fMRI has never been performed at 3 Tesla (3T) in humans. We report our findings relating to spike‐associated blood oxygen level–dependent (BOLD) signal changes in two subjects. Methods: iEEG‐fMRI at 3T was performed in two subjects. Twelve channels of iEEG were recorded from subdural strips implanted on the left posterior temporal and middle frontal lobes in a 20‐year‐old female with bilateral periventricular gray matter heterotopia. Twenty channels of iEEG were recorded bilaterally from two subdural strips laid anterior–posterior along mesial temporal surfaces in a 29‐year‐old woman with bilateral temporal seizures and mild left amygdalar enlargement on MRI. Functional MRI (fMRI) statistical maps were generated and thresholded at p = 0.01. Key Findings: No adverse events were noted. A total of 105 interictal discharges were recorded in the posterior middle temporal gyrus of Subject 1. In Subject 2, 478 discharges were recorded from both mesial temporal surfaces (n = 194 left, 284 right). The right and left discharges were modeled separately, as they were independent. Subject 1 showed spike‐associated BOLD signal increases in the left superior temporal region, left middle frontal gyrus, and right parietal lobe. BOLD decreases were seen in the right frontal and parietal lobes. In Subject 2, BOLD signal increases were seen in both mesial temporal lobes, which when left and right spikes were modeled independently, were greater on the side of the discharge. In addition, striking BOLD signal decreases were observed in the thalamus and posterior cingulate gyrus. Significance: iEEG‐fMRI can be performed at 3T with low risk. Notably, runs of only 5 or 10 min of EEG‐fMRI were performed as part of our implementation protocol, yet a significant number of epileptiform discharges were recorded, allowing meaningful analyses. With these studies, we have shown that deactivation can be seen in individual subjects with focal epileptiform discharges. These preliminary observations suggest a novel mechanism through which focal interictal discharges may have widespread cortical and subcortical influences.     

Functional imaging in the work-up of childhood epilepsy

In children with medically intractable lesional epilepsy, surgery is deemed successful if the epileptogenic focus can be removed while major neurological functions are spared. Current techniques rely on invasive intracranial recordings. The new developments in functional imaging offer the possibility of localizing the epileptogenic focus noninvasively (PET/SPECT) and mapping cognitive functions (fMRI). Ictal SPECT shows hyperperfusion in the focus and has proved to have better localizing value than interictal PET or SPECT, which show focal hypometabolism or hypoperfusion. Ictal SPECT is useful for deciding on the placement of intracranial electrodes in extratemporal epilepsies, particularly in young children. Functional MRI has proved highly accurate for localizing motor and language networks, thus offering the possibilities of replacing the Wada test (language hemispheric lateralization) and studying postlesional brain plasticity. Despite the difficulties of functional imaging in children owing to the limited cooperation that can be expected, ethical constraints, and poor normative data, SPECT/PET and fMRI provide clinically useful information for presurgical work-up of childhood epilepsies. Received: 30 March 2000     

Minimally resective epilepsy surgery in MRI‐negative children

Aim. Performing epilepsy surgery on children with non‐lesional brain MRI often results in large lobar or multilobar resections. The aim of this study was to determine if smaller resections result in a comparable rate of seizure freedom. Methods. We reviewed 25 children who had undergone focal corticectomies restricted to one aspect of a single lobe or the insula at our institution within a 5.5‐year period. Data collected in the comprehensive non‐invasive pre‐surgical evaluation (including scalp video‐EEG, volumetric MRI, functional MRI, EEG source localization, and SPECT and PET), as well as from invasive recordings performed in each patient, was reviewed. Data from each functional modality was identified as convergent or divergent with the epileptogenic zone using image coregistration. Specific biomarkers (from extra‐operative and invasive testing) previously indicated to be indicative of focal epileptogenicity were used to further tailor each resection to an epileptogenic epicentre. Tissue pathology and postoperative outcomes were obtained from all 25 patients. Results. Two years postoperatively, 15/25 (60%) children were seizure‐free, three (12%) experienced >90% reduction in seizure frequency, two (8%) had a 50–90% reduction in seizure frequency, and the remaining five (20%) had no change in seizure burden. There was no significant difference in outcome based on numerous pre‐ and postoperative factors including location of resection, the number of preoperative functional tests providing convergent data, and tissue pathology. Conclusion. In MRI‐negative children with focal epilepsy, an epileptogenic epicentre within a larger epileptogenic zone can be identified when specific biomarkers are recognized on non‐invasive and invasive testing. When such children undergo resection of a small, well‐defined epileptogenic epicentre, favourable outcomes can be achieved.     

Complex discharge‐affecting networks in juvenile myoclonic epilepsy: A simultaneous EEG‐fMRI study

Juvenile myoclonic epilepsy (JME) is a common subtype of idiopathic generalized epilepsies (IGEs) and is characterized by myoclonic jerks, tonic‐clonic seizures and infrequent absence seizures. The network notion has been proposed to better characterize epilepsy. However, many issues remain not fully understood in JME, such as the associations between discharge‐affecting networks and the relationships among resting‐state networks. In this project, eigenspace maximal information canonical correlation analysis (emiCCA) and functional network connectivity (FNC) analysis were applied to simultaneous EEG‐fMRI data from JME patients. The main findings of our study are as follows: discharge‐affecting networks comprising the default model (DMN), self‐reference (SRN), basal ganglia (BGN) and frontal networks have linear and nonlinear relationships with epileptic discharge information in JME patients; the DMN, SRN and BGN have dense/specific associations with discharge‐affecting networks as well as resting‐state networks; and compared with controls, significantly increased FNCs between the salience network (SN) and resting‐state networks are found in JME patients. These findings suggest that the BGN, DMN and SRN may play intermediary roles in the modulation and propagation of epileptic discharges. These roles further tend to disturb the switching function of the SN in JME patients. We also postulate that emiCCA and FNC analysis may provide a potential analysis platform to provide insights into our understanding of the pathophysiological mechanism of epilepsy subtypes such as JME. Hum Brain Mapp 37:3515–3529, 2016. © 2016 Wiley Periodicals, Inc.     

Sex/gender differences in brain function and structure in alcohol use: A narrative review of neuroimaging findings over the last 10 years

Over the last 10 years, rates of alcohol use disorder (AUD) have increased in women by 84% relative to a 35% increase in men. Rates of alcohol use and high‐risk drinking have also increased in women by 16% and 58% relative to a 7% and 16% increase in men, respectively, over the last decade. This robust increase in drinking among women highlights the critical need to identify the underlying neural mechanisms that may contribute to problematic alcohol consumption across sex/gender (SG), especially given that many neuroimaging studies are underpowered to detect main or interactive effects of SG on imaging outcomes. This narrative review aims to explore the recent neuroimaging literature on SG differences in brain function and structure as it pertains to alcohol across positron emission tomography, magnetic resonance imaging, and functional magnetic resonance imaging modalities in humans. Additional work using magnetic resonance spectroscopy, diffusion tensor imaging, and event‐related potentials to examine SG differences in AUD will be covered. Overall, current research on the neuroimaging of AUD, alcohol consumption, or risk of AUD is limited, and findings are mixed regarding the effect of SG on neurochemical, structural, and functional mechanisms associated with AUD. We address SG disparities in the neuroimaging of AUD and propose a call to action to include women in brain imaging research. Future studies are crucial to our understanding of the neurobiological underpinnings of AUD across neural systems and the vulnerability for AUD among women and men.     

Visual evoked potentials may be recorded simultaneously with fMRI scanning: A validation study

Integrating electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data may help to optimize anatomical and temporal resolution in the investigation of cortical function. Successful removal of fMRI scanning artifacts from continuous EEG in simultaneous recordings has been reported. We assessed the feasibility of recording reliable visual evoked potentials (VEPs) during fMRI scanning using available artifact removing procedures. EEG during administration of visual stimuli was recorded using MRI-compatible 32-channel equipment in nine normal subjects (mean age, 23.9 +/- 2.5 years), with and without fMRI acquisition. fMRI scanning and cardioballistographic artifacts were removed after subtraction of averaged artifact waveforms. Consistency between VEPs waveforms and of P1 and N1 peak latencies and amplitudes in the two conditions was assessed. Good correlation was found between VEP waveforms (Pearson's correlation coefficient: r(P) between 0.76-0.94 across subjects; P < 0.0001) and between latency or amplitude of P1 and N1 peaks (latencies: r = 0.7, P < 0.035; amplitudes: r > 0.65, P < 0.05; Spearman rank correlation coefficient) in the two recording conditions. No significant differences were found between P1 and N1 parameters in the two conditions (Wilcoxon signed rank test). Consistent VEP waveforms, latencies, and amplitudes with and without fMRI scanning indicate that reliable VEPs may be obtained simultaneously with fMRI recording. This possibility might be helpful by shortening recording times and reducing variability from learning, habituation, and fatigue phenomena from separate recordings for the integration of event-related EEG and fMRI data.     

The value of EEG-fMRI and EEG source analysis in the presurgical setup of children with refractory focal epilepsy

Purpose: In the presurgical evaluation of children and juvenile patients with refractory focal epilepsy, the main challenge is to localize the point of seizure onset as precisely as possible. We compared results of the conventional electroencephalography–functional magnetic resonance imaging (EEG‐fMRI) analysis with those obtained with a newly developed method using voltage maps of average interictal epileptiform discharges (IEDs) recorded during clinical long‐term monitoring and with the results of the electric source imaging (ESI). Methods: Simultaneous EEG‐fMRI was recorded in nine patients (ages 1.5–17.5 years) undergoing presurgical evaluation. The postoperative outcome and resected area were compared with the following: the localizations of blood oxygen–level dependent (BOLD) signal changes associated with IEDs, which were identified by visual inspection changes using SPM5 software (Analysis I); BOLD signal changes related to IED topography, which was characterized using spike‐specific voltage maps of average IED recorded outside the MR scanner during clinical long‐term monitoring (Analysis II); as well as results of EEG source analysis based on the distributed linear local autoregressive average (LAURA) algorithm using the Cartool software by Denis Brunet (Analysis III). Key Findings: All nine patients had postoperative outcome Engel class I–IIb (postoperative time 6–26 months). The analysis I revealed an IED‐related area of activation within the resection area in 3 (33%) of 9 patients, analysis II was able to reliably localize the source of epileptic activity in 4 (44%) of 9 patients, and analysis III rendered results concordant with the postoperative resection site in all nine patients. Conclusions: The localization of seizure onset based on EEG‐fMRI may be a useful adjunct in the preoperative evaluation but also has some deficits that impair the reliability of results. In contrast, EEG source analysis is clearly a more credible method for epileptic focus localization in children with refractory epilepsies. It seems likely that the analysis based on IED topography (Analysis II) may increase sensitivity and reliability of EEG‐fMRI in some patients. However, the benefit from this innovative method in children is rather limited compared with adults.     

癫癎患者脑电图癎样放电起源区域与头颅MRI病变部位的相关性研究

目的：探讨脑电图（EEG）样放电起源区域与头颅MRI病变部位的关系.方法：回顾性总结221例因癫癎症状就诊患者的病史和EEG特点,分析其影像学改变,利用描述性分析及Logistic回归分析等统计学方法进行分析.结果：221例癫患者EEG出现样放电波127例（57.47%）,局灶懒波51例（23.07%）,背景节律改变39例（17.65%）,前额部高波幅δ节律44例（19.91%）,局部高波幅慢活动13例（5.88%）.头颅EEG癎样放电波出现区域与头颅MRI发现病变部位相吻合者101/127例（79.53%）,与头颅MRI发现病变部位异侧的为8/127例（6.30%）.Logistic回归分析结果显示大部分EEG癎样放电波起源区域与头颅MRI病变部位有着较好的对应关系.结论：癎样放电波形起源区域与头颅MRI病变部位有着较好的吻合程度.     

难治性癫痫致病灶术前定位EEG联合fMRI检查的临床研究

目的探讨对难治性癫痫患者术前进行EEG联合fMRI检查确定癫痫致病灶的准确性。方法选取行外科手术的难治性癫痫患者23例为研究对象,患者佩戴能在高场强MR室中使用的EEG高级电极帽,在MR扫描的同时采集EEG数据,记录棘波发生时间,并根据棘波的发放时间输入信号曲线,找出fMRI数据,求fMRI数据体与该曲线的相应关系,将相应程度高的区域(激活区)叠加在MRI的三维图像上,从而对癫痫致病灶进行定位。将该致病灶的位置、范围与手术中脑皮质电极及深部电极中显示的致痫灶进行比较。结果 13例(56.52%)EEG联合fMRI检查显示的癫痫致病灶与术中通过皮质电极及深部电极EEG所描记、确定的致病灶位置和范围完全相同。另外10例(43.48%)EEG联合fMRI检查显示的癫痫致病灶与术中通过皮质电极及深部电极EEG所描记、确定的致病灶位置相同,但是范围明显大于术中所确定的致病灶范围;对患者出院后进行随访6个月以上,其中15例(65.22%)癫痫未再发作,5例(14.29%)术后3周内出现癫痫发作1~4次,给予抗癫痫药物治疗后得到控制,3例(13.04%)仍有发作,给予药物控制后仍无法控制,但发作频率为每月(3.1±1.4)次,较术前发作次数明显降低。结论对难治性癫痫患者术前进行EEG联合fMRI检查定位致病灶,其定位准确,时间及空间分辨率均较高且是无创性的。     

Comparison of various imaging modalities in localization of epileptogenic lesion using epilepsy surgery outcome in pediatric patients

PurposeWe employed the results of imaging modalities from pediatric patients who received successful epilepsy surgery to determine the accuracy of each imaging tool in identifying epileptic zones in youngsters.MethodsAll Engel class I pediatric patients who received epilepsy surgery between October 2003 and April 2008 were selected. Their pathology, EEG, MRI, PET, and subtraction ictal SPECT coregistered to MRI (SISCOM) results were compared for accuracy in locating the epileptic foci, defined as “area that resulted in seizure ablation after resection”.ResultsForty-two patients were enrolled (23 temporal lobectomy, 19 extratemporal resections). MRI showed concordance in 84.2% of extratemporal cases, all of which had precise localization of lesions. In temporal cases, lateralization was 91.3% and localization was 82.6%. PET showed a concordance rate of 95.5% and localization was 72.7% for temporal lesions. For extratemporal lesions, concordance was only 68.4%. SISCOM showed concordance in 100% of temporal and 92.3% of extratemporal cases, with localization in 66.7% of temporal and 84.6% of extratemporal cases. Most temporal lobe cases had hippocampal sclerosis, and cortical dysplasia was observed in extratemporal cases.DiscussionMRI was invariably reliable in all cases. PET results were as reliable in lateralizing the temporal epileptic area, while its efficacy was lower for extratemporal cases. SISCOM effectively localized lesions in extratemporal cases, but its efficacy was lower in temporal lesions. In cases of conflicting pre-surgical results, MRI, with supplementary data from PET, helped to establish correct decisions in temporal epilepsies, while utilization of SISCOM and MRI data is advised for extratemporal cases.     

Intrinsic brain activity as a diagnostic biomarker in children with benign epilepsy with centrotemporal spikes

Benign epilepsy with centrotemporal spikes (BECTS) is often associated with neural circuit dysfunction, particularly during the transient active state characterized by interictal epileptiform discharges (IEDs). Little is known, however, about the functional neural circuit abnormalities in BECTS without IEDs, or if such abnormalities could be used to differentiate BECTS patients without IEDs from healthy controls (HCs) for early diagnosis. To this end, we conducted resting‐state functional magnetic resonance imaging (RS‐fMRI) and simultaneous Electroencephalogram (EEG) in children with BECTS (n = 43) and age‐matched HC (n = 28). The simultaneous EEG recordings distinguished BECTS with IEDs (n = 20) from without IEDs (n = 23). Intrinsic brain activity was measured in all three groups using the amplitude of low frequency fluctuation at rest. Compared to HC, BECTS patients with IEDs exhibited an intrinsic activity abnormality in the thalamus, suggesting that thalamic dysfunction could contribute to IED emergence while patients without IEDs exhibited intrinsic activity abnormalities in middle frontal gyrus and superior parietal gyrus. Using multivariate pattern classification analysis, we were able to differentiate BECTS without IEDs from HCs with 88.23% accuracy. BECTS without epileptic transients can be distinguished from HC and BECTS with IEDs by unique regional abnormalities in resting brain activity. Both transient abnormalities as reflected by IEDs and chronic abnormalities as reflected by RS‐fMRI may contribute to BECTS development and expression. Intrinsic brain activity and multivariate pattern classification techniques are promising tools to diagnose and differentiate BECTS syndromes. Hum Brain Mapp 36:3878–3889, 2015. © 2015 Wiley Periodicals, Inc.     

Role of Neuroimaging in the Presurgical Evaluation of Epilepsy

A significant minority of patients with focal epilepsy are candidates for resective epilepsy surgery. Structural and functional neuroimaging plays an important role in the presurgical evaluation of theses patients. The most frequent etiologies of pharmacoresistant epilepsy in the adult population are mesial temporal sclerosis, malformations of cortical development, cavernous angiomas, and low-grade neoplasms. High-resolution multiplanar magnetic resonance imaging (MRI) with sequences providing T1 and T2 contrast is the initial imaging study of choice to detect these epileptogenic lesions. The epilepsy MRI protocol can be individually tailored when considering the patient''s clinical and electrophysiological data. Metabolic imaging techniques such as positron emission tomography (PET) and single photon emission tomography (SPECT) visualize metabolic alterations of the brain in the ictal and interictal states. These techniques may have localizing value in patients with a normal MRI scan. Functional MRI is helpful in non-invasively identifying areas of eloquent cortex.Developments in imaging technology and digital postprocessing may increase the yield for imaging studies to detect the epileptogenic lesion and to characterize its connectivity within the epileptic brain.     

Investigation of the electrophysiological correlates of negative BOLD response during intermittent photic stimulation: An EEG‐fMRI study

Although the occurrence of concomitant positive BOLD responses (PBRs) and negative BOLD responses (NBRs) to visual stimuli is increasingly investigated in neuroscience, it still lacks a definite explanation. Multimodal imaging represents a powerful tool to study the determinants of negative BOLD responses: the integration of functional Magnetic Resonance Imaging (fMRI) and electroencephalographic (EEG) recordings is especially useful, since it can give information on the neurovascular coupling underlying this complex phenomenon. In the present study, the brain response to intermittent photic stimulation (IPS) was investigated in a group of healthy subjects using simultaneous EEG‐fMRI, with the main objective to study the electrophysiological mechanisms associated with the intense NBRs elicited by IPS in extra‐striate visual cortex. The EEG analysis showed that IPS induced a desynchronization of the basal rhythm, followed by the instauration of a novel rhythm driven by the visual stimulation. The most interesting results emerged from the EEG‐informed fMRI analysis, which suggested a relationship between the neuronal rhythms at 10 and 12 Hz and the BOLD dynamics in extra‐striate visual cortex. These findings support the hypothesis that NBRs to visual stimuli may be neuronal in origin rather than reflecting pure vascular phenomena. Hum Brain Mapp 37:2247–2262, 2016. © 2016 Wiley Periodicals, Inc.     

癫(痫)患者脑磁共振表现与脑电图异常的相关性

目的:探讨癫(痫)患者脑电图(EEG)异常部位与脑磁共振(MRI)异常部位的相关性.方法:收集2015年1月～2016年8月在南京脑科医院住院的290例癫(痫)患者的EEG及MRI结果进行回顾性分析.结果:EEG癫(痫)波检出率在MRI异常组为98.5％,显著高于MRI正常组(79.5％)(P＜0.05).耐药性癫(痫)的发生率在MRI异常组(26.1％)显著高于MRI正常组(10.3％)(P＜0.05).MRI异常部位与EEG异常部位的重合率在海马硬化组(95％)和脑发育不良组(84.6％)显著高于其它各组.耐药性癫(痫)的发生率在脑发育不良组(50％)及海马硬化组(30％)高于其他各组.结论:癫(痫)患者在MRI上显示海马硬化及脑发育不良时,其作为癫(痫)病灶存在的可能性极大,且耐药性癫(痫)的发生率高.