Autonomic nervous system functioning associated with psychogenic nonepileptic seizures: Analysis of heart rate variability.

OBJECTIVE: Psychogenic nonepileptic seizures (PNESs) resemble epileptic seizures but originate from psychogenic rather than organic causes. Patients with PNESs are often unable or unwilling to reflect on underlying emotions. To gain more insight into the internal states of patients during PNES episodes, this study explored the time course of heart rate variability (HRV) measures, which provide information about autonomic nervous system functioning and arousal. METHODS: Heart rate variability measures were extracted from double-lead electrocardiography data collected during 1-7days of video-electroencephalography monitoring of 20 patients with PNESs, in whom a total number of 118 PNESs was recorded. Heart rate (HR) and HRV measures in time and frequency domains (standard deviation of average beat-to-beat intervals (SDANN), root mean square of successive differences (RMSSD), high-frequency (HF) power, low-frequency (LF) power, and very low-frequency (VLF) power) were averaged over consecutive five-minute intervals. Additionally, quantitative analyses of Poincaré plot parameters (SD1, SD2, and SD1/SD2 ratio) were performed. RESULTS: In the five-minute interval before PNES, HR significantly (p<0.05) increased (d=2.5), whereas SDANN (d=-0.03) and VLF power (d=-0.05) significantly decreased. During PNES, significant increases in HF power (d=0.0006), SD1 (d=0.031), and SD2 (d=0.016) were observed. In the five-minute interval immediately following PNES, SDANN (d=0.046) and VLF power (d=0.073) significantly increased, and HR (d=-5.1) and SD1/SD2 ratio (d=-0.14) decreased, compared to the interval preceding PNES. CONCLUSION: The results suggest that PNES episodes are preceded by increased sympathetic functioning, which is followed by an increase in parasympathetic functioning during and after PNES. Future research needs to identify the exact nature of the increased arousal that precedes PNES.

Delayed convergence between brain network structure and function in rolandic epilepsy.

INTRODUCTION: Rolandic epilepsy (RE) manifests during a critical phase of brain development, and has been associated with language impairments. Concordant abnormalities in structural and functional connectivity (SC and FC) have been described before. As SC and FC are under mutual influence, the current study investigates abnormalities in the SC-FC synergy in RE. METHODS: Twenty-two children with RE (age, mean ± SD: 11.3 ± 2.0 y) and 22 healthy controls (age 10.5 ± 1.6 y) underwent structural, diffusion weighted, and resting-state functional magnetic resonance imaging (MRI) at 3T. The probabilistic anatomical landmarks atlas was used to parcellate the (sub)cortical gray matter. Constrained spherical deconvolution tractography and correlation of time series were used to assess SC and FC, respectively. The SC-FC correlation was assessed as a function of age for the non-zero structural connections over a range of sparsity values (0.01-0.75). A modularity analysis was performed on the mean SC network of the controls to localize potential global effects to subnetworks. SC and FC were also assessed separately using graph analysis. RESULTS: The SC-FC correlation was significantly reduced in children with RE compared to healthy controls, especially for the youngest participants. This effect was most pronounced in a left and a right centro-temporal network, as well as in a medial parietal network. Graph analysis revealed no prominent abnormalities in SC or FC network organization. CONCLUSION: Since SC and FC converge during normal maturation, our finding of reduced SC-FC correlation illustrates impaired synergy between brain structure and function. More specifically, since this effect was most pronounced in the youngest participants, RE may represent a developmental disorder of delayed brain network maturation. The observed effects seem especially attributable to medial parietal connections, which forms an intermediate between bilateral centro-temporal modules of epileptiform activity, and bear relevance for language function.

Resting-state networks and dissociation in psychogenic non-epileptic seizures.

OBJECTIVE: Psychogenic non-epileptic seizures (PNES) are epilepsy-like episodes which have an emotional rather than organic origin. Although PNES have often been related to the process of dissociation, the psychopathology is still poorly understood. To elucidate underlying mechanisms, the current study applied independent component analysis (ICA) on resting-state fMRI to investigate alterations within four relevant networks, associated with executive, fronto-parietal, sensorimotor, and default mode activation, and within a visual network to examine specificity of between-group differences. METHODS: Twenty-one patients with PNES without psychiatric or neurologic comorbidities and twenty-seven healthy controls underwent resting-state functional MR imaging at 3.0T (Philips Achieva). Additional neuropsychological testing included Raven's Matrices test and dissociation questionnaires. ICA with dual regression was used to identify resting-state networks in all participants, and spatial maps of the networks of interest were compared between patients and healthy controls. RESULTS: Patients displayed higher dissociation scores, lower cognitive performance and increased contribution of the orbitofrontal, insular and subcallosal cortex in the fronto-parietal network; the cingulate and insular cortex in the executive control network; the cingulate gyrus, superior parietal lobe, pre- and postcentral gyri and supplemental motor cortex in the sensorimotor network; and the precuneus and (para-) cingulate gyri in the default-mode network. The connectivity strengths within these regions of interest significantly correlated with dissociation scores. No between-group differences were found within the visual network, which was examined to determine specificity of between-group differences. CONCLUSIONS: PNES patients displayed abnormalities in several resting-state networks that provide neuronal correlates for an underlying dissociation mechanism.

Neurophysiological correlates of dissociative symptoms.

OBJECTIVE: Dissociation is a mental process with psychological and somatoform manifestations, which is closely related to hypnotic suggestibility and essentially shows the ability to obtain distance from reality. An increased tendency to dissociate is a frequently reported characteristic of patients with functional neurological symptoms and syndromes (FNSS), which account for a substantial part of all neurological admissions. This review aims to investigate what heart rate variability (HRV), EEG and neuroimaging data (MRI) reveal about the nature of dissociation and related conditions. METHODS: Studies reporting HRV, EEG and neuroimaging data related to hypnosis, dissociation and FNSS were identified by searching the electronic databases Pubmed and ScienceDirect. RESULTS: The majority of the identified studies concerned the physiological characteristics of hypnosis; relatively few investigations on dissociation related FNSS were identified. General findings were increased parasympathetic functioning during hypnosis (as measured by HRV), and lower HRV in patients with FNSS. The large variety of EEG and functional MRI investigations with diverse results challenges definite conclusions, but evidence suggests that subcortical as well as (pre)frontal regions serve emotion regulation in dissociative conditions. Functional connectivity analyses suggest the presence of altered brain networks in patients with FNSS, in which limbic areas have an increased influence on motor preparatory regions. CONCLUSIONS: HRV, EEG and (functional) MRI are sensitive methods to detect physiological changes related to dissociation and dissociative disorders such as FNSS, and can possibly provide more information about their aetiology. The use of such measures could eventually provide biomarkers for earlier identification of patients at risk and appropriate treatment of dissociative conditions.

Reduced structural connectivity between sensorimotor and language areas in rolandic epilepsy.

INTRODUCTION: Rolandic epilepsy (RE) is a childhood epilepsy with centrotemporal (rolandic) spikes, that is increasingly associated with language impairment. In this study, we tested for a white matter (connectivity) correlate, employing diffusion weighted MRI and language testing. METHODS: Twenty-three children with RE and 23 matched controls (age: 8-14 years) underwent structural (T1-weighted) and diffusion-weighted MRI (b = 1200 s/mm(2), 66 gradient directions) at 3T, as well as neuropsychological language testing. Combining tractography and a cortical segmentation derived from the T1-scan, the rolandic tract were reconstructed (pre- and postcentral gyri), and tract fractional anisotropy (FA) values were compared between patients and controls. Aberrant tracts were tested for correlations with language performance. RESULTS: Several reductions of tract FA were found in patients compared to controls, mostly in the left hemisphere; the most significant effects involved the left inferior frontal (p = 0.005) and supramarginal (p = 0.004) gyrus. In the patient group, lower tract FA values were correlated with lower language performance, among others for the connection between the left postcentral and inferior frontal gyrus (p = 0.043, R = 0.43). CONCLUSION: In RE, structural connectivity is reduced for several connections involving the rolandic regions, from which the epileptiform activity originates. Most of these aberrant tracts involve the left (typically language mediating) hemisphere, notably the pars opercularis of the inferior frontal gyrus (Broca's area) and the supramarginal gyrus (Wernicke's area). For the former, reduced language performance for lower tract FA was found in the patients. These findings provide a first microstructural white matter correlate for language impairment in RE.

Aberrant functional connectivity between motor and language networks in rolandic epilepsy.

INTRODUCTION: Rolandic epilepsy (RE) is an idiopathic focal childhood epilepsy with a well-established neuropsychological profile of language impairment. The aim of this study is to provide a functional correlate that links rolandic (sensorimotor) pathology to language problems using functional MRI. MATERIALS AND METHODS: Twenty-three children with RE (8-14 years old) and 21 matched controls underwent extensive language assessment (Clinical Evaluation of Language Fundamentals). fMRI was performed at rest and using word generation, reading, and finger tapping paradigms. Since no activation group differences were found, regions of interest (ROIs) were defined at pooled (patients and controls combined) activation maxima and in contralateral homotopic cortex, and used to assess language lateralization as well as for a resting-state connectivity analysis. Furthermore, the association between connection strength and language performance was investigated. RESULTS: Reduced language performance was found in the children with RE. Bilateral activation was found for both language tasks with some predominance of the left hemisphere in both groups. Compared to controls, patient connectivity was decreased between the left sensorimotor area and right inferior frontal gyrus (p<0.01). For this connection, lower connectivity was associated with lower language scores in the patient group (r=0.49, p=0.02), but not in the controls. CONCLUSION: Language laterality analysis revealed bilateral language representation in the age range under study (8-14 years). As a consequence, the connection of reduced functional connectivity we found represents an impaired interplay between motor and language networks, and aberrant functional connectivity associated with poorer language performance. These findings provide a first neuronal correlate in terms of aberrant resting-state functional connectivity for language impairment in RE.

Reduced functional integration of the sensorimotor and language network in rolandic epilepsy.

INTRODUCTION: Over the last years, evidence has accumulated that rolandic epilepsy (RE) is associated with serious cognitive comorbidities, including language impairment. However, the cerebral mechanism through which epileptiform activity in the rolandic (sensorimotor) areas may affect the language system is unknown. To investigate this, the connectivity between rolandic areas and regions involved in language processing is studied using functional MRI (fMRI). MATERIALS AND METHODS: fMRI data was acquired from 22 children with rolandic epilepsy and 22 age-matched controls (age range: 8-14 years), both at rest and using word-generation and reading tasks. Activation map analysis revealed no group differences (FWE-corrected, p < 0.05) and was therefore used to define regions of interest for pooled (patients and controls combined) language activation. Independent component analysis with dual regression was used to identify the sensorimotor resting-state network in all subjects. The associated functional connectivity maps were compared between groups at the regions of interest for language activation identified from the task data. In addition, neuropsychological language testing (Clinical Evaluation of Language Fundamentals, 4th edition) was performed. RESULTS: Functional connectivity with the sensorimotor network was reduced in patients compared to controls (p = 0.011) in the left inferior frontal gyrus, i.e. Broca's area as identified by the word-generation task. No aberrant functional connectivity values were found in the other regions of interest, nor were any associations found between functional connectivity and language performance. Neuropsychological testing confirmed language impairment in patients relative to controls (reductions in core language score, p = 0.03; language content index, p = 0.01; receptive language index, p = 0.005). CONCLUSION: Reduced functional connectivity was demonstrated between the sensorimotor network and the left inferior frontal gyrus (Broca's area) in children with RE, which might link epileptiform activity/seizures originating from the sensorimotor cortex to language impairment, and is in line with the identified neuropsychological profile of anterior language dysfunction.

Early onset of cortical thinning in children with rolandic epilepsy.

INTRODUCTION: Rolandic epilepsy, a childhood epilepsy associated with language impairments, was investigated for language-related cortical abnormalities. METHODS: Twenty-four children with rolandic epilepsy and 24 controls (age 8-14 years) were recruited and underwent the Clinical Evaluation of Language Fundamentals test. Structural MRI was performed at 3 T (voxel size 1 × 1 × 1 mm(3)) for fully automated quantitative assessment of cortical thickness. Regression analysis was used to test for differences between patients and controls and to assess the effect of age and language indices on cortical thickness. RESULTS: For patients the core language score (mean ± SD: 92 ± 18) was lower than for controls (106 ± 11, p = 0.0026) and below the norm of 100 ± 15 (p = 0.047). Patients showed specific impairments in receptive language index (87 ± 19, p = 0.002) and language content index (87 ± 18, p = 0.0016). Cortical thickness was reduced in patients (p < 0.05, multiple-comparisons corrected) in left perisylvian regions. Furthermore, extensive cortical thinning with age was found in predominantly left-lateralized frontal, centro-parietal and temporal regions. No associations were found between cortical thickness and language indices in the regions of aberrant cortex. CONCLUSION: The cortical abnormalities described represent subtle but significant pathomorphology in this critical phase of brain development (8-14 years) and suggest that rolandic epilepsy should not be considered merely a benign condition. Future studies employing longitudinal designs are prompted for further investigations into cerebral abnormalities in RE and associations with cognitive impairment and development.

Bone disease during chronic antiepileptic drug therapy: general versus specific risk factors.

An increasing number of studies suggest a direct effect of antiepileptic drug (AED) therapy on bone health: Patients on chronic AED therapy may have an increased risk of fractures, reduced bone mineral density, osteopenia, and osteoporosis. In an attempt to distinguish general and specific risk factors, this review examines the available empirical research. The pathophysiology is discussed and guidelines for early detection and treatment options are proposed.

Clinical evaluation of language fundamentals in Rolandic epilepsy, an assessment with CELF-4.

BACKGROUND: In clinical practice, Rolandic epilepsy is in many cases associated with developmental language impairment. However, from the literature it is unclear exactly which domains are affected; A wide variety of investigations are reported that each provide a different representation of language performance in these patients. AIMS: The aim of this study is to compare performance on the language domains between children with Rolandic epilepsy and healthy controls. METHODS: Prospective study of children with Rolandic epilepsy compared to healthy controls. 25 children (mean age 136.6 months, SD 23.0) with Rolandic epilepsy and 25 age-matched healthy controls were tested on their language function using the CELF-4 (Clinical evaluation of Language Fundamentals, Dutch edition). The healthy control were not matched regard to other important factors, particularly educational attainment and co-morbidity. Expressive language, receptive language, language content, language structure and language working memory were tested. RESULTS: In children with Rolandic epilepsy, the core language score was significant lower compared with healthy controls. They scored specifically lower on the receptive language index and language content index (both p = 0.002). A trend towards decreased expressive language index was observed (p = 0.054). Language structure and language working memory were in the normal range. CONCLUSION: Language was found to be impaired in children with typical Rolandic epilepsy. Especially semantic language processing including receptive language and language content was significantly impaired. The common denominator of these functions is semantic language processing.

Microstructural and functional MRI studies of cognitive impairment in epilepsy.

Cognitive impairment is the most common comorbidity in children with epilepsy, but its pathophysiology and predisposing conditions remain unknown. Clinical epilepsy characteristics are not conclusive in determining cognitive outcome. Because many children with epilepsy do not have macrostructural magnetic resonance imaging (MRI) abnormalities, the underlying substrate for cognitive impairment may be found at the microstructural or functional level. In the last two decades, new MRI techniques have been developed that have the potential to visualize microstructural or functional abnormalities associated with cognitive impairment. These include volumetric MRI, voxel-based morphometry (VBM), diffusion tensor imaging (DTI), MR spectroscopy (MRS), and functional MRI (fMRI). All of these techniques have shed new light on various aspects associated with, or underlying, cognitive impairment, although their use in epilepsy has been limited and focused mostly on adults. Therefore, in this review, the use of all these different MRI techniques to unravel cognitive impairment in epilepsy is discussed both in adults and children with epilepsy. Volumetric MRI and VBM have revealed significant volume losses in the area of the seizure focus as well as in distant areas. DTI adds evidence of loss of integrity of connections from the seizure focus to distant areas as well as between distant areas. MRS and fMRI have shown impaired function both in the area of the seizure focus as well as in distant structures. For this review we have compiled and compared findings from the various techniques to conclude that cognitive impairment in epilepsy results from a network disorder in which the (micro)structures as well as the functionality can be disturbed.

Functional connectivity of dissociation in patients with psychogenic non-epileptic seizures.

INTRODUCTION: Psychogenic non-epileptic seizures (PNES) resemble epileptic seizures, but lack epileptiform brain activity. Instead, the cause is assumed to be psychogenic. An abnormal coping strategy may be exhibited by PNES patients, as indicated by their increased tendency to dissociate. Investigation of resting-state networks may reveal altered routes of information and emotion processing in PNES patients. The authors therefore investigated whether PNES patients differ from healthy controls in their resting-state functional connectivity characteristics and whether these connections are associated with the tendency to dissociate. METHODS: 11 PNES patients without psychiatric comorbidity and 12 healthy controls underwent task-related paradigms (picture-encoding and Stroop paradigms) and resting-state functional MRI (rsfMRI). Global cognitive performance was tested using the Raven's Matrices test and participants completed questionnaires for evaluating dissociation. Functional connectivity analysis on rsfMRI was based on seed regions extracted from task-related fMRI activation maps. RESULTS: The patients displayed a significantly lower cognitive performance and significantly higher dissociation scores. No significant differences were found between the picture-encoding and Stroop colour-naming activation maps between controls and patients with PNES. However, functional connectivity maps from the rsfMRI were statistically different. For PNES patients, stronger connectivity values between areas involved in emotion (insula), executive control (inferior frontal gyrus and parietal cortex) and movement (precentral sulcus) were observed, which were significantly associated with dissociation scores. CONCLUSION: The abnormal, strong functional connectivity in PNES patients provides a neurophysiological correlate for the underlying psychoform and somatoform dissociation mechanism where emotion can influence executive control, resulting in altered motor function (eg, seizure-like episodes).