EEG-fMRI in focal epilepsy: local activation and regional networks.

OBJECTIVE: To identify features of BOLD signal change associated with interictal epileptiform discharges (IEDs) in a heterogeneous group of focal epilepsy patients. METHODS: EEG/fMRI studies in 27 focal epilepsy patients were reviewed with attention given to the extent and location of the IED and the resulting pattern of BOLD signal change. Second order group analysis was used to identify common features. RESULTS: fMRI results provided novel clinical information for individual patients. We identified a significant common node within the ipsilateral piriform cortex as well as patterns involving distant cortical or subcortical areas. CONCLUSION: Despite the heterogeneity of IEDs in focal epilepsy, there are important common features underpining IEDs with a highly significant fMRI node in the ipsilateral piriform cortex. SIGNIFICANCE: There are important common features in the networks involved in IEDs in patients with a heterogeneous range of epileptogenic foci. We confirm that the piriform cortex is a common node underlying IEDs in patients with focal epilepsy and so provides a target for further study and potential therapy. We describe important features of BOLD signal change that accompany focal and diffuse IEDs that will help researchers and clinicians navigate the sometimes complex findings revealed by these studies.

Bilateral posterior periventricular nodular heterotopia: a recognizable cortical malformation with a spectrum of associated brain abnormalities.

BACKGROUND AND PURPOSE: Bilateral posterior PNH is a distinctive complex malformation with imaging features distinguishing it from classic bilateral PNH associated with FLNA mutations. The purpose of this study was to define the imaging features of posterior bilateral periventricular nodular heterotopia and to determine whether associated brain malformations suggest specific subcategories. MATERIALS AND METHODS: We identified a cohort of 50 patients (31 females; mean age, 13 years) with bilateral posterior PNH and systematically reviewed and documented associated MR imaging abnormalities. Patients were negative for mutations of FLNA. RESULTS: Nodules were often noncontiguous (n = 28) and asymmetric (n = 31). All except 1 patient showed associated developmental brain abnormalities involving a spectrum of posterior structures. A range of posterior fossa abnormalities affected the cerebellum, including cerebellar malformations and posterior fossa cysts (n = 38). Corpus callosum abnormalities (n = 40) ranged from mild dysplasia to agenesis. Posterior white matter volume was decreased (n = 22), and colpocephaly was frequent (n = 26). Most (n = 40) had associated cortical abnormalities ranging from minor to major (polymicrogyria), typically located in the cortex overlying the PNH. Abnormal Sylvian fissure morphology was common (n = 27), and hippocampal abnormalities were frequent (n = 37). Four family cases were identified-2 with concordant malformation patterns and 2 with discordant malformation patterns. CONCLUSIONS: The associations of bilateral posterior PNH encompass a range of abnormalities involving brain structures inferior to the Sylvian fissures. We were unable to identify specific subgroups and therefore conceptualize bilateral posterior PNH as a continuum of infrasylvian malformations involving the posterior cerebral and hindbrain structures.

The frontal lobe in absence epilepsy: EEG-fMRI findings.

OBJECTIVE: Studies of absence seizures (AS) using EEG with fMRI (EEG-fMRI) show a consistent network with prominent thalamic activation and a variety of cortical changes. Despite evidence suggesting a role of frontal cortex in seizure generation, group studies have not detected consistent AS-related changes in this region. We hypothesized that only a subgroup may show frontal cortical activation. METHOD: We studied 13 subjects with AS during EEG-fMRI to classify the different individual patterns of frontal cortical activation associated with AS. RESULTS: Based upon visual inspection of surface-rendered activation maps we identified 2 subgroups that could be distinguished by the activation in the dorsolateral prefrontal cortex (DLPFC). One group of patients (n = 7) showed a primarily positive signal change (DLPFC-POS), whereas the other group (n = 6) showed a primarily negative signal change (DLFPC-NEG). When the DLPFC-POS group was compared to the DLPFC-NEG group, time-course analysis revealed a larger positive blood oxygenation level-dependent deflection following onset of the AS in cortical and subcortical areas beyond the DLPFC. This suggests a basic biological difference between these groups. CONCLUSION: These observations suggest that there may be at least 2 mechanisms underpinning AS in individuals with absence epilepsy. This may have phenotypic and genetic implications for understanding epilepsy syndromes.

Hippocampal size anomalies in a community-based cohort with childhood-onset epilepsy.

OBJECTIVES: Epidemiologic evidence suggests the natural history of refractory mesial temporal lobe epilepsy is complicated, yet little is known about the hippocampus from the nontertiary center perspective. METHODS: In a community-based cohort, individuals with nonsyndromic focal epilepsy with onset <16 years and controls had research MRI scans. Hippocampal (HC) volumes were manually measured, corrected for total brain volume, and converted to Z scores (Z(HC)) based on the controls' values. Volumes in cases and controls were compared. RESULTS: Average volumes were not significantly different in cases with unknown cause (n = 117) relative to controls (n = 63). The group with structural and other conditions (n = 23) had significantly smaller volumes. Asymmetry (larger/smaller HC) did not vary among the 3 groups. Hippocampal variances were significantly larger in each epilepsy group relative to controls. In the unknown cause group, 25 (21%) had extreme() values: 15 (13%) with Z(HC) >1.96; 10 (9%) with Z(HC) <-1.96. By contrast, 2/63 (3%) controls had extreme values (p = 0.001). Within the unknown cause group, temporal lobe epilepsy (TLE) cases were more likely to have extreme hippocampal volumes than non-TLE (31% vs 15%, p = 0.03). Extreme volumes were generally interpreted as normal visually. These anomalies were not associated with seizure remission or pharmacoresistance. CONCLUSIONS: Classic mesial TLE with hippocampal sclerosis is an uncommon finding in the general population. Volume anomalies, both large and small, are often bilateral. The significance of these findings is unclear; however, speculations regarding preexisting hippocampal pathology (e.g., dysplasia) as a factor in TLE and other neocortical epilepsies have been made by others.

Changes in brain morphology in patients with obstructive sleep apnoea.

BACKGROUND: Obstructive sleep apnoea (OSA) is a common disease that leads to daytime sleepiness and cognitive impairment. Attempts to investigate changes in brain morphology that may underlie these impairments have led to conflicting conclusions. This study was undertaken to aim to resolve this confusion, and determine whether OSA is associated with changes in brain morphology in a large group of patients with OSA, using improved voxel-based morphometry analysis, an automated unbiased method of detecting local changes in brain structure. METHODS: 60 patients with OSA (mean apnoea hypopnoea index 55 (95% CI 48 to 62) events/h, 3 women) and 60 non-apnoeic controls (mean apnoea hypopnoea index 4 (95% CI 3 to 5) events/h, 5 women) were studied. Subjects were imaged using T1-weighted 3-D structural MRI (69 subjects at 1.5 T, 51 subjects at 3 T). Differences in grey matter were investigated in the two groups, controlling for age, sex, site and intracranial volume. Dedicated cerebellar analysis was performed on a subset of 108 scans using a spatially unbiased infratentorial template. RESULTS: Patients with OSA had a reduction in grey matter volume in the right middle temporal gyrus compared with non-apnoeic controls (p<0.05, corrected for topological false discovery rate across the entire brain). A reduction in grey matter was also seen within the cerebellum, maximal in the left lobe VIIIb close to XI, extending across the midline into the right lobe. CONCLUSION: These data show that OSA is associated with focal loss of grey matter that could contribute to cognitive decline. Specifically, lesions in the cerebellum may result in both motor dysfunction and working memory deficits, with downstream negative consequences on tasks such as driving.

The core network in absence epilepsy. Differences in cortical and thalamic BOLD response.

OBJECTIVES: We used EEG-fMRI to study epileptiform activity in a cohort of untreated children with typical absence seizures (AS). Our aim was to identify cortical and subcortical regions involved in spike and wave events and to explore the timing of activity in these regions. METHODS: Eleven children with AS confirmed on video-EEG underwent EEG-fMRI. An event-related analysis of epileptiform activity was performed. Regions of interest (ROIs), identified in the event-related analysis, were used to study the time course of the blood oxygen level-dependent (BOLD) signal prior to and immediately following events of interest in these ROIs. RESULTS: Group analysis confirmed positive BOLD in the thalamus and negative BOLD in the lateral and mesial parietal lobe, caudate nuclei, and additionally the brainstem reticular formation. The event-related time course differed between the thalamus, the parietal cortex, and the pons and caudate nuclei. In the subcortical structures, BOLD signal change occurred at, or immediately after, electrographic onset. Importantly, in the parietal cortex, but not in other cortical regions, there was a subtle BOLD signal increase for 10 seconds prior to the onset of epileptiform activity. CONCLUSIONS: In children with typical AS, we have confirmed a core network of structures involved in generalized epileptiform activity that includes the reticular structures of the brainstem. Furthermore, we have identified changes in parietal BOLD signal which precede the onset of epileptiform activity, suggesting the parietal cortex has a role in the initiation of epileptiform activity.

The neural architecture of discourse compression.

Re-telling a story is thought to produce a progressive refinement in the mental representation of the discourse. A neuroanatomical substrate for this compression effect, however, has yet to be identified. We used a discourse re-listening task and functional magnetic resonance imaging (fMRI) to identify brain regions responsive to repeated discourse in twenty healthy volunteers. We found a striking difference in the pattern of activation associated with the first and subsequent presentations of the same story relative to rest. The first presentation was associated with a highly significant increase in blood oxygen level dependent (BOLD) signal in a bilateral perisylvian distribution, including auditory cortex. Listening to the same story on subsequent occasions revealed a wider network with activation extending into frontal, parietal, and subcortical structures. When the first and final presentations of the same story were directly compared, significant increments in activation were found in the middle frontal gyrus bilaterally, and the right inferior parietal lobule, suggesting that the spread of activation with re-listening reflected an active neural process over and above that required for comprehension of the text. Within the right inferior parietal region the change in BOLD signal was highly correlated with a behavioural index of discourse compression based in re-telling, providing converging evidence for the role of the right inferior parietal region in the representation of discourse. Our findings demonstrate, for the first time, the existence of a neural network underlying discourse compression, showing that parts of this network are common to re-telling and re-listening effects.

Why do seizures in generalized epilepsy often occur in the morning?

OBJECTIVE: We used transcranial magnetic stimulation to investigate the effect of diurnal variability on cortical excitability in patients with epilepsy. METHODS: Thirty drug-naive patients with epilepsy (20 idiopathic generalized epilepsy [IGE], including 10 juvenile myoclonic epilepsy [JME], and 10 focal epilepsy) and 10 control subjects without epilepsy were studied both early in the morning and late in the afternoon. We measured the mean motor thresholds and constructed recovery curves at short (2-15 msec) and long (50-400 msec) interstimulus intervals. RESULTS: An increase in cortical excitability indicated by decreased short and long intracortical inhibition was observed early in the morning compared to the afternoon in patients with JME. In other IGE syndromes, there was decreased long intracortical inhibition only. No effect was found in subjects with focal epilepsy or controls without epilepsy. CONCLUSION: Cortical excitability measured by transcranial magnetic stimulation increases early in the morning in patients with idiopathic generalized epilepsy, particularly in juvenile myoclonic epilepsy, but not in subjects with focal epilepsy or controls without epilepsy. This may explain the increased seizure susceptibility in this cohort at this time of day.

Asymmetry of language activation relates to regional callosal morphology following early cerebral injury.

The anatomical factors underlying reorganization of language representation are yet to be elucidated, although correlations between asymmetric structures and language lateralization have been identified. Previous research has implicated the corpus callosum in the development of language lateralization. This study examined the relationship between callosal morphology and language asymmetry, using letter fluency functional magnetic resonance imaging, in 13 patients with focal epilepsy and 8 healthy controls. Regional callosal thickness was determined without relying on a priori delineation of callosal segments. We predicted that language asymmetry measured by fMRI activation laterality scores would be correlated with regional callosal thickness in both groups. However, only the degree of language activation asymmetry was significantly correlated with callosal thickness in the isthmus and the midbody of patients, and there was a significant interaction between the groups with respect to callosal thickness and language activation asymmetry. These data suggest that callosal pathways may be important for language reorganization in the context of early cerebral injury.

Interstitial deletion of chromosome 4p associated with mild mental retardation, epilepsy and polymicrogyria of the left temporal lobe.

In this study, we present a 38-year-old woman with an interstitial deletion of 4p15.1-15.3, mild mental retardation, epilepsy and polymicrogyria adjacent to an arachnoid cyst of the left temporal lobe. The deletion was ascertained through array-comparative genome hybridization screening of patients with epilepsy and brain malformations. To date, about 35 patients with cytogenetically visible deletions involving 4p15 and without Wolf-Hirschhorn syndrome have been described, but the extent of the deletions has not been determined in the majority of these cases. The clinical manifestations of the patient described in this study were similar but not identical to the previously reported cases with 4p15 interstitial deletions. This finding indicates the presence of one or more genes involved in brain development and epilepsy in this chromosome region.

Relationship between language lateralization and handedness in left-hemispheric partial epilepsy.

OBJECTIVE: To investigate the relationship between language lateralization and handedness in patients with epilepsy and a left-sided seizure focus and in healthy control subjects. METHODS: We recruited a consecutive series of 74 patients and 70 control subjects. Functional MRI, using a noun-verb generation task, was performed to establish the language laterality index (LI). Handedness was quantified using the Edinburgh Handedness Inventory. RESULTS: Patients showed a shift toward atypical language lateralization (0.43 +/- 0.47; controls 0.57 +/- 034; p < or = 0.05) and left-handedness (55 +/- 57; controls 74 +/- 39; p < or = 0.05). The LI and handedness were correlated in patients (r = 0.54; F = 25.9; p < 0.001) but not in control subjects (r = 0.1; F = 0.64; NS). A combination of left-handedness and atypical LI was more frequent in patients (12%) than control subjects (0%; p < or = 0.05). Crossed hemispheric specialization (e.g., right-handedness associated with atypical LI) was equally frequent in patients (20%) and control subjects (16%; NS). CONCLUSION: In epilepsy patients with a left-sided seizure focus, language lateralization is correlated to handedness. The increased frequency of left-handedness and associated atypical language lateralization is most likely related to the left-hemispheric seizure focus, influencing hemispheric specialization for both domains.

Pathologic and physiologic function in the subcortical band of double cortex.

Double cortex is a neuronal migration disorder, associated with impaired cognitive function and seizures, and characterized by a subcortical band of neurons. Using functional MRI, we assessed the involvement of the subcortical band in language function and with interictal discharges. In both girls assessed, language-associated activation was in typical cortical areas, as well as in parts of the subcortical band. Interictal discharges were associated with deactivation in the subcortical band. This suggests involvement of the subcortical neurons in physiologic and pathologic functions.

A developmental and genetic classification for malformations of cortical development.

Increasing recognition of malformations of cortical development and continuing improvements in imaging techniques, molecular biologic techniques, and knowledge of mechanisms of brain development have resulted in continual improvement of the understanding of these disorders. The authors propose a revised classification based on the stage of development (cell proliferation, neuronal migration, cortical organization) at which cortical development was first affected. The categories are based on known developmental steps, known pathologic features, known genetics (when possible), and, when necessary, neuroimaging features. In those cases in which the precise developmental and genetic features are uncertain, classification is based on known relationships among the genetics, pathologic features, and neuroimaging features. The major change since the prior classification has been a shift to using genotype, rather than phenotype, as the basis for classifying disorders wherever the genotype-phenotype relationship is adequately understood. Other substantial changes include more detailed classification of congenital microcephalies, particularly those in which the genes have been mapped or identified, and revised classification of congenital muscular dystrophies and polymicrogyrias. Information on genetic testing is also included. This classification allows a better conceptual understanding of the disorders, and the use of neuroimaging characteristics allows it to be applied to all patients without necessitating brain biopsy, as in pathology-based classifications.

Structural abnormalities remote from the seizure focus: a study using T2 relaxometry at 3 T.

OBJECTIVE: To determine the extent and severity of mesial temporal and subcortical signal abnormalities in patients with partial epilepsy. METHODS: T2 relaxation time maps were acquired in 50 consecutive patients and 55 control subjects on a 3 T MRI scanner. Twenty-two patients had hippocampal sclerosis (HS), 16 had malformations of cortical development (MCD), and 12 had no obvious MR abnormalities (normal MR). The following eight regions were measured bilaterally: hippocampus, anterior temporal lobe (ATL) white matter, amygdala, frontal lobe white matter, caudate, putamen, pallidum, and thalamus. RESULTS: In patients with HS, increased T2 relaxation times were found in the ipsilateral hippocampus and ATL but not in subcortical nuclei. In patients with MCD, increased T2 relaxation times were found in the temporal lobe (hippocampus, ATL) and in subcortical areas (caudate, putamen, and pallidum); in patients with normal MR, increased T2 relaxation times were found in the hippocampus and putamen. The degree of abnormality did not correlate with the duration of epilepsy or the estimated seizure load. CONCLUSIONS: Mesial temporal structures show increased T2 relaxation times not only in patients with hippocampal sclerosis but also in patients with a seizure focus remote from the hippocampus. Patients with normal MR and focal malformations of cortical development have increased T2 relaxation times in subcortical structures. Therefore, abnormalities in T2 relaxation time can be found remote from the seizure focus. They cannot be simply attributed to secondary seizure effects.

Language cortex activation in normal children.

OBJECTIVE: To describe a protocol for use in young children and adolescents for determining language representation. METHODS: We performed 130 fMRI studies in 48 children and 17 adults. Verb generation (VG) and orthographic lexical retrieval (OLR) were used. The localization and lateralization of activation was rated visually. Regional voxel counts measured asymmetry and extent of activation. RESULTS: Activation was predominantly left-lateralized (children 85%, adults 94%), and there was no difference in the localization of activation for either paradigm. Children's typical sites of activation included mesial (96%), inferior (94%) and middle frontal (92%) gyri, the inferior (85%) and superior (65%) temporal cortex, and the cerebellum (67%). Less frequently activated sites were insular (50%) and posterior parietal (48%) cortices. Quantitative asymmetry index scores and visual inspection of laterality were concordant. Greater quantitative asymmetry for VG than OLR occurred in children. Laterality was not related to age, sex, task proficiency, or handedness. Frontal region voxel counts lower in children than adults and left sided counts correlated with task proficiency. CONCLUSIONS: Language fMRI can be performed in young children using resources available to clinical centers. The similarity in frequency of left language lateralization between children and adults suggests that language representation establishes early in development. The reduced amount of frontal region of interest activation in task-specific regions in children may reflect different levels of ability. However, the left-right distribution of activation does not appear to depend on task performance or age. These normative data provide a basis for decisions about language laterality in pediatric patients.

Longitudinal study of MRS metabolites in Rasmussen encephalitis.

This study analyses the evolution of metabolite changes in an 8-year-old boy with focal Rasmussen encephalitis. Five MRI examinations, including magnetic resonance spectroscopy (MRS) were performed over 9 months. Following complex partial status, T2-weighted imaging showed transient dramatic signal increase in the left superior temporal gyrus and mesial temporal structures. Subsequent scans showed resolution of the swelling and signal normalization, with development of slight focal atrophy. MRS after status showed a reduction in N-acetylaspartate, total creatine and trimethylamines. Subsequent scans showed complete resolution of these metabolite abnormalities, followed later by development of further abnormal metabolite values. Lactate and glutamine/glutamate were elevated after status. After surgery, ex vivo high-field (1)H and (31)P MRS confirmed metabolite abnormalities (elevated choline and decreased aspartate, N-acetylaspartate, [(1)H]glutamate together with altered [(31)P]phospholipid ratios. These findings suggested active disease process in the anterior region of the excised superior temporal gyrus. We conclude that Rasmussen encephalitis is a combination of progressive encephalitic damage and fluctuating seizure effects, in which neuronal injury and recovery can occur. MRS measurements at a single time point should consider the fluctuating metabolite profile related to seizure activity.

Spike-triggered fMRI in reading epilepsy: involvement of left frontal cortex working memory area.

OBJECTIVE: To determine the origin of epileptiform activity in reading epilepsy (RE) and the association between these regions and regions activated by reading, and to assess brain morphometry in these areas. METHODS: In two subjects with RE, EEG was recorded inside the three tesla MRI while subjects read silently. Spike-triggered fMRI images were compared to baseline. In a second fMRI study, 30 seconds of silent reading was compared to visual fixation. Morphometry of these areas was assessed using curvilinear surface reconstruction. Left central sulcal patterns in three subjects with RE were compared to three subjects with idiopathic generalized epilepsy (IGE) and 12 normal controls. RESULTS: One subject with RE showed spike-related activity (17 spikes) in the left precentral gyrus, and bilaterally in the central sulcus and globus pallidus. The other showed no definite activation owing to low spike numbers (4 spikes). In both subjects, the block reading task recruited normal visual and language areas including the left posterior middle frontal gyrus. Two subjects with RE showed an unusual gyrus branching anteriorly off the left central sulcus. A similar sulcal pattern was seen in none of the subjects with IGE and only 1 of 12 controls. CONCLUSION: Spike activity overlapped with reading activity in the left middle frontal gyrus, a structure recruited during working memory cognitive tasks. The authors postulate that, because of a local structural anomaly, the spikes of reading epilepsy spread from working memory areas into adjacent motor cortex, activating a cortical subcortical circuit.