Children with Rolandic epilepsy have micro- and macrostructural abnormalities in white matter constituting networks necessary for language function.

INTRODUCTION: Self-limited epilepsy with centrotemporal spikes is a transient developmental epilepsy with a seizure onset zone localized to the centrotemporal cortex that commonly impacts aspects of language function. To better understand the relationship between these anatomical findings and symptoms, we characterized the language profile and white matter microstructural and macrostructural features in a cohort of children with SeLECTS. METHODS: Children with active SeLECTS (n = 13), resolved SeLECTS (n = 12), and controls (n = 17) underwent high-resolution MRIs including diffusion tensor imaging sequences and multiple standardized neuropsychological measures of language function. We identified the superficial white matter abutting the inferior rolandic cortex and superior temporal gyrus using a cortical parcellation atlas and derived the arcuate fasciculus connecting them using probabilistic tractography. We compared white matter microstructural characteristics (axial, radial and mean diffusivity, and fractional anisotropy) between groups in each region, and tested for linear relationships between diffusivity metrics in these regions and language scores on neuropsychological testing. RESULTS: We found significant differences in several language modalities in children with SeLECTS compared to controls. Children with SeLECTS performed worse on assessments of phonological awareness (p = 0.045) and verbal comprehension (p = 0.050). Reduced performance was more pronounced in children with active SeLECTS compared to controls, namely, phonological awareness (p = 0.028), verbal comprehension (p = 0.028), and verbal category fluency (p = 0.031), with trends toward worse performance also observed in verbal letter fluency (p = 0.052), and the expressive one-word picture vocabulary test (p = 0.068). Children with active SeLECTS perform worse than children with SeLECTS in remission on tests of verbal category fluency (p = 0.009), verbal letter fluency (p = 0.006), and the expressive one-word picture vocabulary test (p = 0.045). We also found abnormal superficial white matter microstructure in centrotemporal ROIs in children with SeLECTS, characterized by increased diffusivity and fractional anisotropy compared to controls (AD p = 0.014, RD p = 0.028, MD p = 0.020, and FA p = 0.024). Structural connectivity of the arcuate fasciculus connecting perisylvian cortical regions was lower in children with SeLECTS (p = 0.045), and in the arcuate fasciculus children with SeLECTS had increased diffusivity (AD p = 0.007, RD p = 0.006, MD p = 0.016), with no difference in fractional anisotropy (p = 0.22). However, linear tests comparing white matter microstructure in areas constituting language networks and language performance did not withstand correction for multiple comparisons in this sample, although a trend was seen between FA in the arcuate fasciculus and verbal category fluency (p = 0.047) and the expressive one-word picture vocabulary test (p = 0.036). CONCLUSION: We found impaired language development in children with SeLECTS, particularly in those with active SeLECTS, as well as abnormalities in the superficial centrotemporal white matter as well as the fibers connecting these regions, the arcuate fasciculus. Although relationships between language performance and white matter abnormalities did not pass correction for multiple comparisons, taken together, these results provide evidence of atypical white matter maturation in fibers involved in language processing, which may contribute to the aspects of language function that are commonly affected by the disorder.

Source EEG reveals that Rolandic epilepsy is a regional epileptic encephalopathy.

Rolandic epilepsy is the most common form of epileptic encephalopathy, characterized by sleep-potentiated inferior Rolandic epileptiform spikes, seizures, and cognitive deficits in school-age children that spontaneously resolve by adolescence. We recently identified a paucity of sleep spindles, physiological thalamocortical rhythms associated with sleep-dependent learning, in the Rolandic cortex during the active phase of this disease. Because spindles are generated in the thalamus and amplified through regional thalamocortical circuits, we hypothesized that: 1) deficits in spindle rate would involve but extend beyond the inferior Rolandic cortex in active epilepsy and 2) regional spindle deficits would better predict cognitive function than inferior Rolandic spindle deficits alone. To test these hypotheses, we obtained high-resolution MRI, high-density EEG recordings, and focused neuropsychological assessments in children with Rolandic epilepsy during active (n = 8, age 9-14.7 years, 3F) and resolved (seizure free for > 1 year, n = 10, age 10.3-16.7 years, 1F) stages of disease and age-matched controls (n = 8, age 8.9-14.5 years, 5F). Using a validated spindle detector applied to estimates of electrical source activity in 31 cortical regions, including the inferior Rolandic cortex, during stages 2 and 3 of non-rapid eye movement sleep, we compared spindle rates in each cortical region across groups. Among detected spindles, we compared spindle features (power, duration, coherence, bilateral synchrony) between groups. We then used regression models to examine the relationship between spindle rate and cognitive function (fine motor dexterity, phonological processing, attention, and intelligence, and a global measure of all functions). We found that spindle rate was reduced in the inferior Rolandic cortices in active but not resolved disease (active P = 0.007; resolved P = 0.2) compared to controls. Spindles in this region were less synchronous between hemispheres in the active group (P = 0.005; resolved P = 0.1) compared to controls; but there were no differences in spindle power, duration, or coherence between groups. Compared to controls, spindle rate in the active group was also reduced in the prefrontal, insular, superior temporal, and posterior parietal regions (i.e., "regional spindle rate", P < 0.039 for all). Independent of group, regional spindle rate positively correlated with fine motor dexterity (P < 1e-3), attention (P = 0.02), intelligence (P = 0.04), and global cognitive performance (P < 1e-4). Compared to the inferior Rolandic spindle rate alone, models including regional spindle rate trended to improve prediction of global cognitive performance (P = 0.052), and markedly improved prediction of fine motor dexterity (P = 0.006). These results identify a spindle disruption in Rolandic epilepsy that extends beyond the epileptic cortex and a potential mechanistic explanation for the broad cognitive deficits that can be observed in this epileptic encephalopathy.

Dysmature superficial white matter microstructure in developmental focal epilepsy.

Benign epilepsy with centrotemporal spikes is a common childhood epilepsy syndrome that predominantly affects boys, characterized by self-limited focal seizures arising from the perirolandic cortex and fine motor abnormalities. Concurrent with the age-specific presentation of this syndrome, the brain undergoes a developmentally choreographed sequence of white matter microstructural changes, including maturation of association u-fibres abutting the cortex. These short fibres mediate local cortico-cortical communication and provide an age-sensitive structural substrate that could support a focal disease process. To test this hypothesis, we evaluated the microstructural properties of superficial white matter in regions corresponding to u-fibres underlying the perirolandic seizure onset zone in children with this epilepsy syndrome compared with healthy controls. To verify the spatial specificity of these features, we characterized global superficial and deep white matter properties. We further evaluated the characteristics of the perirolandic white matter in relation to performance on a fine motor task, gender and abnormalities observed on EEG. Children with benign epilepsy with centrotemporal spikes (n = 20) and healthy controls (n = 14) underwent multimodal testing with high-resolution MRI including diffusion tensor imaging sequences, sleep EEG recordings and fine motor assessment. We compared white matter microstructural characteristics (axial, radial and mean diffusivity, and fractional anisotropy) between groups in each region. We found distinct abnormalities corresponding to the perirolandic u-fibre region, with increased axial, radial and mean diffusivity and fractional anisotropy values in children with epilepsy (P = 0.039, P = 0.035, P = 0.042 and P = 0.017, respectively). Increased fractional anisotropy in this region, consistent with decreased integrity of crossing sensorimotor u-fibres, correlated with inferior fine motor performance (P = 0.029). There were gender-specific differences in white matter microstructure in the perirolandic region; males and females with epilepsy and healthy males had higher diffusion and fractional anisotropy values than healthy females (P ≤ 0.035 for all measures), suggesting that typical patterns of white matter development disproportionately predispose boys to this developmental epilepsy syndrome. Perirolandic white matter microstructure showed no relationship to epilepsy duration, duration seizure free, or epileptiform burden. There were no group differences in diffusivity or fractional anisotropy in superficial white matter outside of the perirolandic region. Children with epilepsy had increased radial diffusivity (P = 0.022) and decreased fractional anisotropy (P = 0.027) in deep white matter, consistent with a global delay in white matter maturation. These data provide evidence that atypical maturation of white matter microstructure is a basic feature in benign epilepsy with centrotemporal spikes and may contribute to the epilepsy, male predisposition and clinical comorbidities observed in this disorder.

Beta oscillations in the sensorimotor cortex correlate with disease and remission in benign epilepsy with centrotemporal spikes.

INTRODUCTION: Benign epilepsy with centrotemporal spikes (BECTS) is a common form of childhood epilepsy with the majority of those afflicted remitting during their early teenage years. Seizures arise from the lower half of the sensorimotor cortex of the brain (e.g. seizure onset zone) and the abnormal epileptiform discharges observed increase during NREM sleep. To date no clinical factors reliably predict disease course, making determination of ongoing seizure risk a significant challenge. Prior work in BECTS have shown abnormalities in beta band (14.9-30 Hz) oscillations during movement and rest. Oscillations in this frequency band are modulated by state of consciousness and thought to reflect intrinsic inhibitory mechanisms. METHODS: We used high density EEG and source localization techniques to examine beta band activity in the seizure onset zone (sensorimotor cortex) in a prospective cohort of children with BECTS and healthy controls during sleep. We hypothesized that beta power in the sensorimotor cortex would be different between patients and healthy controls, and that beta abnormalities would improve with resolution of disease in this self-limited epilepsy syndrome. We further explored the specificity of our findings and correlation with clinical features. Statistical testing was performed using logistic and standard linear regression models. RESULTS: We found that beta band power in the seizure onset zone is different between healthy controls and BECTS patients. We also found that a longer duration of time spent seizure-free (corresponding to disease remission) correlates with lower beta power in the seizure onset zone. Exploratory spatial analysis suggests this effect is not restricted to the sensorimotor cortex. Exploratory frequency analysis suggests that this phenomenon is also observed in alpha and gamma range activity. We found no relationship between beta power and the presence or rate of epileptiform discharges in the sensorimotor cortex or a test of sensorimotor performance. CONCLUSION: These results provide evidence that cortical beta power in the seizure onset zone may provide a dynamic physiological biomarker of disease in BECTS.

Loss of resting-state posterior cingulate flexibility is associated with memory disturbance in left temporal lobe epilepsy.

The association between cognition and resting-state fMRI (rs-fMRI) has been the focus of many recent studies, most of which use stationary connectivity. The dynamics or flexibility of connectivity, however, may be seminal for understanding cognitive functioning. In temporal lobe epilepsy (TLE), stationary connectomic correlates of impaired memory have been reported mainly for the hippocampus and posterior cingulate cortex (PCC). We therefore investigate resting-state and task-based hippocampal and PCC flexibility in addition to stationary connectivity in left TLE (LTLE) patients. Sixteen LTLE patients were analyzed with respect to rs-fMRI and task-based fMRI (t-fMRI), and underwent clinical neuropsychological testing. Flexibility of connectivity was calculated using a sliding-window approach by determining the standard deviation of Fisher-transformed Pearson correlation coefficients over all windows. Stationary connectivity was also calculated. Disturbed memory was operationalized as having at least one memory subtest score equal to or below the 5th percentile compared to normative data. Lower PCC flexibility, particularly in the contralateral (i.e. right) hemisphere, was found in memory-disturbed LTLE patients, who had up to 22% less flexible connectivity. No significant group differences were found with respect to hippocampal flexibility, stationary connectivity during both rs-fMRI and t-fMRI, or flexibility during t-fMRI. Contralateral resting-state PCC flexibility was able to classify all but one patient with respect to their memory status (94% accuracy). Flexibility of the PCC during rest relates to memory functioning in LTLE patients. Loss of flexible connectivity to the rest of the brain originating from the PCC, particularly contralateral to the seizure focus, is able to discern memory disturbed patients from their preserved counterparts. This study indicates that the dynamics of resting-state connectivity are associated with cognitive status of LTLE patients, rather than stationary connectivity.

Functional anatomic dissociation of description and picture naming in the left temporal lobe.

Functional magnetic resonance imaging (fMRI) was used in a non-patient experimental sample to assess the neuroanatomical dissociation of picture and description naming (PN and DN) in temporal lobe (TL). The purpose was to determine the generalizability of findings in semantic organization in the epilepsy patient population to the broader population. It was hypothesized that, akin to patient derived findings, DN would uniquely activate left TL regions anterior to those associated with PN, while overlapping in middle and posterior left TL. Participants (n = 16) underwent fMRI while silently naming target words during a picture naming task (PNT; line drawings) and description naming task (DNT; orthographic phrases). Analysis was a priori restricted to the left TL. Group results of direct contrasts (DNT > PNT and PNT > DNT) confirmed the hypothesized dissociation with DNT > PNT activating anterior left TL. Within-condition contrasts (DNT and PNT alone) yielded additional support, revealing areas of shared and unique activation in each condition. This is the first imaging study to contrast DN and PN in the same sample. The results suggest DN and PN are meaningfully different constructs subserved by converging and diverging TL neuroanatomy and may be differentially affected by disease.

Prefrontal regional correlates of self-control in male psychiatric patients: Impulsivity facets and aggression.

Investigating the organization of trait aggression and impulsivity in the prefrontal cortex (PFC) advances our understanding of the neuropsychobiology of self-control. While the orbital aspect of the PFC (OFC) has received attention, there is reason to believe the lateral aspect is also relevant. In the current study using magnetic resonance imaging, gray matter volumes in lateral PFC (LPFC) were derived in a heterogeneous male psychiatric sample (N=36) in which OFC volumes had previously been reported. In an analysis using self-report measures of trait impulsivity and aggression, the left LPFC accounted for significant variance in attentional aspects of impulsivity (13%) and aggression (10%) but not motor aspects of impulsivity, as hypothesized. The OFC was associated with motor impulsivity (left-20%; right-14%) and was also more robustly associated with aggression (left-36%; right-16%). A social/emotional information processing model was explored, based upon whether the LPFC or the OFC depended upon one another for their association to trait aggression and impulsivity. It was demonstrated that association of the LPFC to both aggression and attentional impulsivity depended upon the OFC, while the converse was not supported. The LPFC appears relevant to the higher-order aspects of a cortical self-control network, and that relevance is dependent upon the robust contribution of the OFC.

Functional MT + lesion impairs contralateral motion processing.

Human motion processing region MT + is retinotopically organized with perception of and attention to motion in the right visual field preferentially associated with left MT + activity and vice versa. However, the degree to which MT + is crucial for motion processing is uncertain. We report an epilepsy patient with visual symptoms early in his seizure evolution and a left temporal-occipital seizure onset electrographically in whom we hypothesized a functional left MT + lesion. The patient was impaired in his right but not left visual field on a hemifield motion attention task and demonstrated worse performance on a hemifield picture identification task when pictures implying motion were presented in the right as opposed to the left visual field. Functional MRI (fMRI) during a full-field motion detection task activated right MT + but failed to activate left MT + despite activating both left and right MT + in each of 10 controls. Furthermore, fMRI during a hemifield motion attention task also showed a lack of left MT + attention effects in the patient. Together these results suggest that MT + is necessary for normal motion processing.