Altered neurovascular coupling in children with idiopathic generalized epilepsy

Aims

Alterations in neuronal activity and cerebral hemodynamics have been reported in idiopathic generalized epilepsy (IGE) patients, possibly resulting in neurovascular decoupling; however, no neuroimaging evidence confirmed this disruption. This study aimed to investigate the possible presence of neurovascular decoupling and its clinical implications in childhood IGE using resting-state fMRI and arterial spin labeling imaging.

Methods

IGE patients and healthy participants underwent resting-state fMRI and arterial spin labeling imaging to calculate degree centrality (DC) and cerebral blood flow (CBF), respectively. Across-voxel CBF-DC correlations were analyzed to evaluate the neurovascular coupling within the whole gray matter, and the regional coupling of brain region was assessed with the CBF/DC ratio.

Results

The study included 26 children with IGE and 35 sex- and age-matched healthy controls (HCs). Compared with the HCs, the IGE group presented lower across-voxel CBF-DC correlations, higher CBF/DC ratio in the right posterior cingulate cortex/precuneus, middle frontal gyrus, and medial frontal gyrus (MFG), and lower ratio in the left inferior frontal gyrus. The increased CBF/DC ratio in the right MFG was correlated with lower performance intelligence quotient scores in the IGE group.

Conclusion

Children with IGE present altered neurovascular coupling, associated with lower performance intelligence quotient scores. The study shed a new insight into the pathophysiology of epilepsy and provided potential imaging biomarkers of cognitive performances in children with IGE.     

Correlation between quantitative EEG and MRI in idiopathic generalized epilepsy

The objective of this study was to investigate the relationship between the focal discharges sometimes observed in the electroencephalogram of patients with idiopathic generalized epilepsies and subtle structural magnetic resonance imaging abnormalities. The main hypothesis to be assessed is that focal discharges may arise from areas of structural abnormality which can be detected by quantitative neuroimaging. Focal discharges were used for quantitative electroencephalogram source detection. Neuroimaging investigations consisted of voxel‐based morphometry and region of interest volumetry. For voxel‐based morphometry, volumetric MRI were acquired and processed. The images of each patient were individually compared with a control group. Statistical analysis was used to detect differences in gray matter volumes. Region of interest‐based morphometry was automatically performed and used essentially to confirm voxel‐based morphometry findings. The localization of the focal discharges on the electroencephalogram was compared to the neuroimaging results. Twenty‐two patients with idiopathic generalized epilepsies were evaluated. Gray matter abnormalities were detected by voxel‐based morphometry analysis in 77% of the patients. There was a good concordance between EEG source detection and voxel‐based morphometry. On average, the nearest voxels detected by these methods were 19 mm (mm) apart and the most statistically significant voxels were 34 mm apart. This study suggests that in some cases subtle gray matter abnormalities are associated with focal epileptiform discharges observed in the electroencephalograms of patients with idiopathic generalized epilepsies. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.     

Dynamic functional network connectivity in idiopathic generalized epilepsy with generalized tonic–clonic seizure

Idiopathic generalized epilepsy (IGE) has been linked with disrupted intra‐network connectivity of multiple resting‐state networks (RSNs); however, whether impairment is present in inter‐network interactions between RSNs, remains largely unclear. Here, 50 patients with IGE characterized by generalized tonic–clonic seizures (GTCS) and 50 demographically matched healthy controls underwent resting‐state fMRI scans. A dynamic method was implemented to investigate functional network connectivity (FNC) in patients with IGE‐GTCS. Specifically, independent component analysis was first carried out to extract RSNs, and then sliding window correlation approach was employed to obtain dynamic FNC patterns. Finally, k‐mean clustering was performed to characterize six discrete functional connectivity states, and state analysis was conducted to explore the potential alterations in FNC and other dynamic metrics. Our results revealed that state‐specific FNC disruptions were observed in IGE‐GTCS and the majority of aberrant functional connectivity manifested itself in default mode network. In addition, temporal metrics derived from state transition vectors were altered in patients including the total number of transitions across states and the mean dwell time, the fraction of time spent and the number of subjects in specific FNC state. Furthermore, the alterations were significantly correlated with disease duration and seizure frequency. It was also found that dynamic FNC could distinguish patients with IGE‐GTCS from controls with an accuracy of 77.91% (P < 0.001). Taken together, this study not only provided novel insights into the pathophysiological mechanisms of IGE‐GTCS but also suggested that the dynamic FNC analysis was a promising avenue to deepen our understanding of this disease. Hum Brain Mapp 38:957–973, 2017. © 2016 Wiley Periodicals, Inc.     

Distinct effects of the basal ganglia and cerebellum on the thalamocortical pathway in idiopathic generalized epilepsy

The aberrant thalamocortical pathways of epilepsy have been detected recently, while its underlying effects on epilepsy are still not well understood. Exploring pathoglytic changes in two important thalamocortical pathways, that is, the basal ganglia (BG)‐thalamocortical and the cerebellum‐thalamocortical pathways, in people with idiopathic generalized epilepsy (IGE), could deepen our understanding on the pathological mechanism of this disease. These two pathways were reconstructed and investigated in this study by combining diffusion and functional MRI. Both pathways showed connectivity changes with the perception and cognition systems in patients. Consistent functional connectivity (FC) changes were observed mainly in perception regions, revealing the aberrant integration of sensorimotor and visual information in IGE. The pathway‐specific FC alterations in high‐order regions give neuroimaging evidence of the neural mechanisms of cognitive impairment and epileptic activities in IGE. Abnormal functional and structural integration of cerebellum, basal ganglia and thalamus could result in an imbalance of inhibition and excitability in brain systems of IGE. This study located the regulated cortical regions of BG and cerebellum which been affected in IGE, established possible links between the neuroimaging findings and epileptic symptoms, and enriched the understanding of the regulatory effects of BG and cerebellum on epilepsy.     

Altered functional connectivity in default mode network in absence epilepsy: a resting-state fMRI study

Dysfunctional default mode network (DMN) has been observed in various mental disorders, including epilepsy (see review Broyd et al. [2009]: Neurosci Biobehav Rev 33:279–296). Because interictal epileptic discharges may affect DMN, resting-state fMRI was used in this study to determine DMN functional connectivity in 14 healthy controls and 12 absence epilepsy patients. To avoid interictal epileptic discharge effects, testing was performed within interictal durations when there were no interictal epileptic discharges. Cross-correlation functional connectivity analysis with seed at posterior cingulate cortex, as well as region-wise calculation in DMN, revealed decreased integration within DMN in the absence epilepsy patients. Region-wise functional connectivity among the frontal, parietal, and temporal lobe was significantly decreased in the patient group. Moreover, functional connectivity between the frontal and parietal lobe revealed a significant negative correlation with epilepsy duration. These findings indicated DMN abnormalities in patients with absence epilepsy, even during resting interictal durations without interictal epileptic discharges. Abnormal functional connectivity in absence epilepsy may reflect abnormal anatomo-functional architectural integration in DMN, as a result of cognitive mental impairment and unconsciousness during absence seizure.     

Juvenile myoclonic epilepsy – a generalized epilepsy syndrome?

Juvenile myoclonic epilepsy (JME) has been classified as a syndrome of idiopathic generalized epilepsy and is characterized by specific types of seizures, showing a lack of pathology using magnetic resonance imaging (MRI) and computed tomography scanning. However, JME is associated with a particular personality profile, and behavioral and neuropsychologic studies have suggested the possible involvement of frontal lobe dysfunction. The development of highly sensitive neuroimaging techniques has provided a means of elucidating the underlying mechanisms of JME. For example, positron emission tomography has demonstrated neurotransmitter changes in the cerebral cortex, quantitative MRI has revealed significant abnormalities of cortical gray matter in medial frontal areas, and ¹H-magnetic resonance spectroscopy has shown evidence of thalamic dysfunction, which appears to be progressive. Such techniques provide evidence of multi-focal disease mechanisms, suggesting that JME is a frontal lobe variant of a multi-regional, thalamocortical 'network' epilepsy, rather than a generalized epilepsy syndrome.     

Distinct basal ganglia hyperechogenicity in idiopathic basal ganglia calcification

We report a 67‐year‐old patient with idiopathic basal ganglia calcification (IBGC). He presented with progressive cognitive impairment, frontal lobe dysfunction, mild leg spasticity, and levodopa (L ‐dopa)‐responsive parkinsonism. Transcranial sonography (TCS) revealed marked hyperechogenicity of the basal ganglia and periventricular spaces bilaterally. The detected signal alterations showed a fairly symmetric distribution and corresponded to the hyperintense calcifications depicted on the computer tomography brain scan. The combination of symmetric hyperechogenic areas adjacent to the lateral ventricles and of the basal ganglia may serve as an imaging marker characteristic of IBGC. Hyperechogenicity due to extended basal ganglia calcification as presented here is distinct from the pattern of hyperechogenicity caused by heavy metal accumulation, which is described to be less striking. In addition to atypical parkinsonian syndromes such as progressive supranuclear palsy and multiple system atrophy, IBGC is thus another differential diagnosis of parkinsonism with basal ganglia hyperechogenicity. © 2010 Movement Disorder Society.     

Language lateralization from task‐based and resting state functional MRI in patients with epilepsy

We compared resting state (RS) functional connectivity and task‐based fMRI to lateralize language dominance in 30 epilepsy patients (mean age = 33; SD = 11; 12 female), a measure used for presurgical planning. Language laterality index (LI) was calculated from task fMRI in frontal, temporal, and frontal + temporal regional masks using LI bootstrap method from SPM12. RS language LI was assessed using two novel methods of calculating RS language LI from bilateral Broca's area seed based connectivity maps across regional masks and multiple thresholds (p < .05, p < .01, p < .001, top 10% connections). We compared LI from task and RS fMRI continuous values and dominance classifications. We found significant positive correlations between task LI and RS LI when functional connectivity thresholds were set to the top 10% of connections. Concordance of dominance classifications ranged from 20% to 30% for the intrahemispheric resting state LI method and 50% to 63% for the resting state LI intra‐ minus interhemispheric difference method. Approximately 40% of patients left dominant on task showed RS bilateral dominance. There was no difference in LI concordance between patients with right‐sided and left‐sided resections. Early seizure onset (<6 years old) was not associated with atypical language dominance during task‐based or RS fMRI. While a relationship between task LI and RS LI exists in patients with epilepsy, language dominance is less lateralized on RS than task fMRI. Concordance of language dominance classifications between task and resting state fMRI depends on brain regions surveyed and RS LI calculation method.     

Resting cerebral oxygen metabolism exhibits archetypal network features

Standard magnetic resonance imaging approaches offer high‐resolution but indirect measures of neural activity, limiting understanding of the physiological processes associated with imaging findings. Here, we used calibrated functional magnetic resonance imaging during the resting state to recover low‐frequency fluctuations of the cerebral metabolic rate of oxygen (CMRO₂). We tested whether functional connections derived from these fluctuations exhibited organization properties similar to those established by previous standard functional and anatomical connectivity studies. Seventeen participants underwent 20 min of resting imaging during dual‐echo, pseudocontinuous arterial spin labeling, and blood‐oxygen‐level dependent (BOLD) signal acquisition. Participants also underwent a 10 min normocapnic and hypercapnic procedure. Brain‐wide, CMRO₂ low‐frequency fluctuations were subjected to graph‐based and voxel‐wise functional connectivity analyses. Results demonstrated that connections derived from resting CMRO₂ fluctuations exhibited complex, small‐world topological properties (i.e., high integration and segregation, cost efficiency) consistent with those observed in previous studies using functional and anatomical connectivity approaches. Voxel‐wise CMRO₂ connectivity also exhibited spatial patterns consistent with four targeted resting‐state subnetworks: two association (i.e., frontoparietal and default mode) and two perceptual (i.e., auditory and occipital‐visual). These are the first findings to support the use of calibration‐derived CMRO₂ low‐frequency fluctuations for detecting brain‐wide organizational properties typical of healthy participants. We discuss interpretations, advantages, and challenges in using calibration‐derived oxygen metabolism signals for examining the intrinsic organization of the human brain.     

Association between serotonin denervation and resting‐state functional connectivity in mild cognitive impairment

Resting‐state functional connectivity alterations have been demonstrated in Alzheimer's disease (AD) and mild cognitive impairment (MCI) before the observation of AD neuropathology, but mechanisms driving these changes are not well understood. Serotonin neurodegeneration has been observed in MCI and AD and is associated with cognitive deficits and neuropsychiatric symptoms, but the role of the serotonin system in relation to brain network dysfunction has not been a major focus of investigation. The current study investigated the relationship between serotonin transporter availability (SERT; measured using positron emission tomography) and brain network functional connectivity (measured using resting‐state functional MRI) in 20 participants with MCI and 21 healthy controls. Two SERT regions of interest were selected for the analysis: the Dorsal Raphe Nuclei (DRN) and the precuneus which represent the cell bodies of origin and a cortical target of projections of the serotonin system, respectively. Both regions show decreased SERT in MCI compared to controls and are the site of early AD pathology. Average resting‐state functional connectivity did not differ between MCI and controls. Decreased SERT in DRN was associated with lower hippocampal resting‐state connectivity in MCI participants compared to controls. Decreased SERT in the right precuneus was also associated with lower resting‐state connectivity of the retrosplenial cortex to the dorsal lateral prefrontal cortex and higher resting‐state connectivity of the retrosplenial cortex to the posterior cingulate and in patients with MCI but not in controls. These results suggest that a serotonergic mechanism may underlie changes in brain functional connectivity in MCI. Hum Brain Mapp 38:3391–3401, 2017. © 2017 Wiley Periodicals, Inc.     

Connectivity and functional profiling of abnormal brain structures in pedophilia

Despite its 0.5–1% lifetime prevalence in men and its general societal relevance, neuroimaging investigations in pedophilia are scarce. Preliminary findings indicate abnormal brain structure and function. However, no study has yet linked structural alterations in pedophiles to both connectional and functional properties of the aberrant hotspots. The relationship between morphological alterations and brain function in pedophilia as well as their contribution to its psychopathology thus remain unclear. First, we assessed bimodal connectivity of structurally altered candidate regions using meta‐analytic connectivity modeling (MACM) and resting‐state correlations employing openly accessible data. We compared the ensuing connectivity maps to the activation likelihood estimation (ALE) maps of a recent quantitative meta‐analysis of brain activity during processing of sexual stimuli. Second, we functionally characterized the structurally altered regions employing meta‐data of a large‐scale neuroimaging database. Candidate regions were functionally connected to key areas for processing of sexual stimuli. Moreover, we found that the functional role of structurally altered brain regions in pedophilia relates to nonsexual emotional as well as neurocognitive and executive functions, previously reported to be impaired in pedophiles. Our results suggest that structural brain alterations affect neural networks for sexual processing by way of disrupted functional connectivity, which may entail abnormal sexual arousal patterns. The findings moreover indicate that structural alterations account for common affective and neurocognitive impairments in pedophilia. The present multimodal integration of brain structure and function analyses links sexual and nonsexual psychopathology in pedophilia. Hum Brain Mapp 36:2374–2386, 2015. © 2015 Wiley Periodicals, Inc.     

Altered resting‐state connectivity during interictal generalized spike‐wave discharges in drug‐naïve childhood absence epilepsy

Purpose: To investigate the intrinsic brain connections at the time of interictal generalized spike‐wave discharges (GSWDs) to understand their mechanism of effect on brain function in untreated childhood absence epilepsy (CAE). Methods: The EEG‐functional MRI (fMRI) was used to measure the resting state functional connectivity during interictal GSWDs in drug‐naïve CAE, and three different brain networks—the default mode network (DMN), cognitive control network (CCN), and affective network (AN)—were investigated. Results: Cross‐correlation functional connectivity analysis with priori seed revealed decreased functional connectivity within each of these three networks in the CAE patients during interictal GSWDS. It included precuneus‐dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC), and inferior parietal lobule in the DMN; DLPFC‐inferior frontal junction (IFJ), and pre‐supplementary motor area (pre‐SMA) subregions connectivity disruption in CCN; ACC‐ventrolateral prefrontal cortex (VLPFC) and DMPFC in AN; There were also some regions, primarily the parahippcampus, paracentral in AN, and the left frontal mid orb in the CCN, which showed increased connectivity. Conclusions: The current findings demonstrate significant alterations of resting‐state networks in drug naïve CAE subjects during interictal GSWDs and interictal GSWDs can cause dysfunction in specific networks important for psychosocial function. Impairment of these networks may cause deficits both during and between seizures. Our study may contribute to the understanding of neuro‐pathophysiological mechanism of psychosocial function impairments in patients with CAE. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

Specific somatotopic organization of functional connections of the primary motor network during resting state

Regions of the primary motor network are known to show a high level of spontaneous functional connectivity during rest. Resting‐state functional magnetic resonance imaging (fMRI) studies have reported the left and right motor cortex to form a single resting‐state network, without examining the specific organization of the functional connections between subregions of the primary motor network. The primary motor cortex has a somatotopic organization, clearly separating regions that control our feet from regions that control our fingers and other body parts. In this study, 3 T resting‐state fMRI time‐series of 46 healthy subjects were acquired; and for all subregions along the precentral gyrus, the location of the maximum level of functional connectivity within the contralateral primary motor cortex was computed, together with whole brain functional connectivity maps, to examine a possible somatotopic organization of the functional connections of the motor network. Subregions of the primary motor cortex were found to be most strongly functionally linked to regions in the contralateral hemisphere with a similar spatial location along the contralateral primary motor cortex as the selected seed regions. On the basis of the knowledge of a somatopic organization of the primary motor network, these findings suggest that functional subregions of the motor network are one‐on‐one linked to their functional homolog in the contralateral hemisphere and organized in a somatotopic fashion. Examining the specific organization of the functional connections within the primary motor network could enhance our overall understanding of the organization of resting‐state functional communication within the brain. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.     

Resting state functional connectivity of the hippocampus associated with neurocognitive function in left temporal lobe epilepsy

The majority of patients with temporal lobe epilepsy (TLE) experience disturbances of episodic memory from structural damage or dysfunction of the hippocampus. The objective of this study was to use functional Magnetic Resonance Imaging (fMRI) to identify regions where resting state connectivity to the left hippocampus (LH) is correlated with neuropsychological measures of verbal memory retention in TLE patients. Eleven left TLE (LTLE) patients and 15 control subjects participated in resting state fMRI scans. All LTLE patients underwent neuropsychological testing. Resting state functional connectivity maps to the LH were calculated for each patient, and subsequently used in a multiple regression analysis with verbal memory retention scores as a covariate. The analysis identified brain regions whose connectivity to the LH was linearly related to memory retention scores across the group of patients. In LTLE patients, right sided (contralateral) clusters in the precuneus and inferior parietal lobule (IPL) exhibited increased connectivity to the LH with increased memory retention score; left sided (ipsilateral) regions in the precuneus and IPL showed increased connectivity to the LH with decreased retention score. Patients with high memory retention scores had greater connectivity between the LH–right parietal clusters than between the LH–left parietal clusters; in contrast, control subjects had significantly and consistently greater LH–left hemisphere than LH–right hemisphere connectivity. Our results suggest that increased connectivity in contralateral hippocampal functional pathways within the episodic verbal memory network represents a strengthening of alternative pathways in LTLE patients with strong verbal memory retention abilities. Hum Brain Mapp 35:735–744, 2014. © 2012 Wiley Periodicals, Inc.     

Structural findings in the basal ganglia in genetically determined and idiopathic Parkinson's disease

A bilateral compensatory increase of basal ganglia (BG) gray matter value (GMV) was recently demonstrated in asymptomatic Parkin mutation carriers, who likely have an increased risk to develop Parkinson's disease (PD). We hypothesized BG morphological changes in symptomatic Parkin mutation carriers (sPARKIN-MC) and idiopathic PD patients (iPD) after the occurrence of PD symptoms, reflecting the breakdown of compensatory mechanisms. Nine sPARKIN-MC, 14 iPD, and 24 controls were studied clinically and with voxel-based morphometry. Analysis of variance revealed mainly BG decrease of GMV in sPARKIN-MC and to a lesser extent in iPD. However, a slight increase in GMV was also found in the right globus pallidus externus in sPARKIN-MC and in the right putamen in iPD. This may reflect a structural correlate of functional compensation that can only partially be maintained when nigrostriatal neurodegeneration becomes manifest. Simple regression analyses with the UPDRS-III and disease duration score revealed a distinct more bilateral linear decrease of BG GMV in sPARKIN-MC than in iPD that may correspond to previous findings showing a symmetric reduction in putaminal (18)F-DOPA-uptake and bilateral manifestation of symptoms in sPARKIN-MC. In symptomatic PD, BG are subject to a progressive atrophy, which gradually increases with disease severity and duration.