Altered fMRI Connectivity Dynamics in Temporal Lobe Epilepsy Might Explain Seizure Semiology

Temporal lobe epilepsy (TLE) can be conceptualized as a network disease. The network can be characterized by inter-regional functional connectivity, i.e., blood oxygen level-dependent (BOLD) signal correlations between any two regions. However, functional connectivity is not constant over time, thus computing correlation at a given time and then at some later time could give different results (non-stationarity). We hypothesized (1) that non-stationarities can be induced by epilepsy (e.g., interictal epileptic activity) increasing local signal variance and that (2) these transient events contribute to fluctuations in connectivity leading to pathological functioning, i.e., TLE semiology. We analyzed fMRI data from 27 patients with TLE and 22 healthy controls focusing on EEG-confirmed wake epochs only to protect against sleep-induced connectivity changes. Testing hypothesis (1), we identified brain regions where the BOLD signal variance was significantly greater in TLE than in controls: the temporal pole – including the hippocampus. Taking the latter as the seed region and testing hypothesis (2), we calculated the time-varying inter-regional correlation values (dynamic functional connectivity) to other brain regions and found greater connectivity variance in the TLE than the control group mainly in the precuneus, the supplementary and sensorimotor, and the frontal cortices. We conclude that the highest BOLD signal variance in the hippocampi is highly suggestive of a specific epilepsy-related effect. The altered connectivity dynamics in TLE patients might help to explain the hallmark semiological features of dyscognitive seizures including impaired consciousness (precuneus, frontal cortex), sensory disturbance, and motor automatisms (sensorimotor cortices, supplementary motor cortex). Accounting for the non-stationarity and state-dependence of functional connectivity are a prerequisite in the search for potential connectivity-derived biomarkers in TLE

Neuronal networks in children with continuous spikes and waves during slow sleep

Epileptic encephalopathy with continuous spikes and waves during slow sleep is an age-related disorder characterized by the presence of interictal epileptiform discharges during at least >85% of sleep and cognitive deficits associated with this electroencephalography pattern. The pathophysiological mechanisms of continuous spikes and waves during slow sleep and neuropsychological deficits associated with this condition are still poorly understood. Here, we investigated the haemodynamic changes associated with epileptic activity using simultaneous acquisitions of electroencephalography and functional magnetic resonance imaging in 12 children with symptomatic and cryptogenic continuous spikes and waves during slow sleep. We compared the results of magnetic resonance to electric source analysis carried out using a distributed linear inverse solution at two time points of the averaged epileptic spike. All patients demonstrated highly significant spike-related positive (activations) and negative (deactivations) blood oxygenation-level-dependent changes (P < 0.05, family-wise error corrected). The activations involved bilateral perisylvian region and cingulate gyrus in all cases, bilateral frontal cortex in five, bilateral parietal cortex in one and thalamus in five cases. Electrical source analysis demonstrated a similar involvement of the perisylvian brain regions in all patients, independent of the area of spike generation. The spike-related deactivations were found in structures of the default mode network (precuneus, parietal cortex and medial frontal cortex) in all patients and in caudate nucleus in four. Group analyses emphasized the described individual differences. Despite aetiological heterogeneity, patients with continuous spikes and waves during slow sleep were characterized by activation of the similar neuronal network: perisylvian region, insula and cingulate gyrus. Comparison with the electrical source analysis results suggests that the activations correspond to both initiation and propagation pathways. The deactivations in structures of the default mode network are consistent with the concept of epileptiform activity impacting on normal brain function by inducing repetitive interruptions of neurophysiological functio

Resection planning in extratemporal epilepsy surgery using 3D multimodality imaging and intraoperative MRI

Surgical resection in non-lesional, extratemporal epilepsy, informed by stereoEEG recordings, is challenging. There are no clear borders of resection, and the surgeon is often operating in deep areas of the brain that are difficult to access. We present a technical note where 3D multimodality image integration in EpiNav(TM) is used to build a planned resection model, based on a previous intracranial EEG evaluation. Intraoperative MRI is then used to ensure a complete resection of the planned model. As stereoEEG becomes more common in the presurgical evaluation of epilepsy, these tools will become increasingly important to facilitate targeted cortical resections

Human hippocampal theta power indicates movement onset and distance travelled

Theta frequency oscillations in the 6- to 10-Hz range dominate the rodent hippocampal local field potential during translational movement, suggesting that theta encodes self-motion. Increases in theta power have also been identified in the human hippocampus during both real and virtual movement but appear as transient bursts in distinct high- and low-frequency bands, and it is not yet clear how these bursts relate to the sustained oscillation observed in rodents. Here, we examine depth electrode recordings from the temporal lobe of 13 presurgical epilepsy patients performing a selfpaced spatial memory task in a virtual environment. In contrast to previous studies, we focus on movement-onset periods that incorporate both initial acceleration and an immediately preceding stationary interval associated with prominent theta oscillations in the rodent hippocampal formation. We demonstrate that movementonset periods are associated with a significant increase in both low (2–5 Hz)- and high (6–9 Hz)-frequency theta power in the human hippocampus. Similar increases in low- and high-frequency theta power are seen across lateral temporal lobe recording sites and persist throughout the remainder of movement in both regions. In addition, we show that movement-related theta power is greater both before and during longer paths, directly implicating human hippocampal theta in the encoding of translational movement. These findings strengthen the connection between studies of theta-band activity in rodents and humans and offer additional insight into the neural mechanisms of spatial navigation

Mapping preictal and ictal haemodynamic networks using video-electroencephalography and functional imaging

Ictal patterns on scalp-electroencephalography are often visible only after propagation, therefore rendering localization of the seizure onset zone challenging. We hypothesized that mapping haemodynamic changes before and during seizures using simultaneous video-electroencephalography and functional imaging will improve the localization of the seizure onset zone. Fifty-five patients with ≥2 refractory focal seizures/day, and who had undergone long-term video-electroencephalography monitoring were included in the study. ‘Preictal' (30 s immediately preceding the electrographic seizure onset) and ictal phases, ‘ictal-onset'; ‘ictalestablished' and ‘late ictal', were defined based on the evolution of the electrographic pattern and clinical semiology. The functional imaging data were analysed using statistical parametric mapping to map ictal phase-related haemodynamic changes consistent across seizures. The resulting haemodynamic maps were overlaid on co-registered anatomical scans, and the spatial concordance with the presumed and invasively defined seizure onset zone was determined. Twenty patients had typical seizures during functional imaging. Seizures were identified on video-electroencephalography in 15 of 20, on electroencephalography alone in two and on video alone in three patients. All patients showed significant ictal-related haemodynamic changes. In the six cases that underwent invasive evaluation, the ictal-onset phase-related maps had a degree of concordance with the presumed seizure onset zone for all patients. The most statistically significant haemodynamic cluster within the presumed seizure onset zone was between 1.1 and 3.5 cm from the invasively defined seizure onset zone, which was resected in two of three patients undergoing surgery (Class I post-surgical outcome) and was not resected in one patient (Class III post-surgical outcome). In the remaining 14 cases, the ictal-onset phase-related maps had a degree of concordance with the presumed seizure onset zone in six of eight patients with structural-lesions and five of six non-lesional patients. The most statistically significant haemodynamic cluster was localizable at sub-lobar level within the presumed seizure onset zone in six patients. The degree of concordance of haemodynamic maps was significantly better (P < 0.05) for the ictal-onset phase [entirely concordant/concordant plus (13/20; 65%) + some concordance (4/20; 20%) = 17/20; 85%] than ictal-established [entirely concordant/concordant plus (5/13; 38%) + some concordance (4/13; 31%) = 9/13; 69%] and late ictal [concordant plus (1/9; 11%) + some concordance (4/9; 44%) = 5/9; 55%] phases. Ictal propagation-related haemodynamic changes were also seen in symptomatogenic areas (9/20; 45%) and the default mode network (13/20; 65%). A common pattern of preictal changes was seen in 15 patients, starting between 98 and 14 s before electrographic seizure onset, and the maps had a degree of concordance with the presumed seizure onset zone in 10 patients. In conclusion, preictal and ictal haemodynamic changes in refractory focal seizures can non-invasively localize seizure onset at sub-lobar/gyral level when ictal scalp-electroencephalography is not helpfu

Inactivation of SAM-methyltransferase is the mechanism of attenuation of a historic louse borne typhus vaccine strain

Louse borne typhus (also called epidemic typhus) was one of man's major scourges, and epidemics of the disease can be reignited when social, economic, or political systems are disrupted. The fear of a bioterrorist attack using the etiologic agent of typhus, Rickettsia prowazekii, was a reality. An attenuated typhus vaccine, R. prowazekii Madrid E strain, was observed to revert to virulence as demonstrated by isolation of the virulent revertant Evir strain from animals which were inoculated with Madrid E strain. The mechanism of the mutation in R. prowazekii that affects the virulence of the vaccine was not known. We sequenced the genome of the virulent revertant Evir strain and compared its genome sequence with the genome sequences of its parental strain, Madrid E. We found that only a single nucleotide in the entire genome was different between the vaccine strain Madrid E and its virulent revertant strain Evir. The mutation is a single nucleotide insertion in the methyltransferase gene (also known as PR028) in the vaccine strain that inactivated the gene. We also confirmed that the vaccine strain E did not cause fever in guinea pigs and the virulent revertant strain Evir caused fever in guinea pigs. We concluded that a single nucleotide insertion in the methyltransferase gene of R. prowazekii attenuated the R. prowazekii vaccine strain E. This suggested that an irreversible insertion or deletion mutation in the methyl transferase gene of R. prowazekii is required for Madrid E to be considered a safe vaccine

Causal hierarchy within the thalamo-cortical network in spike and wave discharges

Background: Generalised spike wave (GSW) discharges are the electroencephalographic (EEG) hallmark of absence seizures, clinically characterised by a transitory interruption of ongoing activities and impaired consciousness, occurring during states of reduced awareness. Several theories have been proposed to explain the pathophysiology of GSW discharges and the role of thalamus and cortex as generators. In this work we extend the existing theories by hypothesizing a role for the precuneus, a brain region neglected in previous works on GSW generation but already known to be linked to consciousness and awareness. We analysed fMRI data using dynamic causal modelling (DCM) to investigate the effective connectivity between precuneus, thalamus and prefrontal cortex in patients with GSW discharges. Methodology and Principal Findings: We analysed fMRI data from seven patients affected by Idiopathic Generalized Epilepsy (IGE) with frequent GSW discharges and significant GSW-correlated haemodynamic signal changes in the thalamus, the prefrontal cortex and the precuneus. Using DCM we assessed their effective connectivity, i.e. which region drives another region. Three dynamic causal models were constructed: GSW was modelled as autonomous input to the thalamus (model A), ventromedial prefrontal cortex (model B), and precuneus (model C). Bayesian model comparison revealed Model C (GSW as autonomous input to precuneus), to be the best in 5 patients while model A prevailed in two cases. At the group level model C dominated and at the population-level the p value of model C was ∼1. Conclusion: Our results provide strong evidence that activity in the precuneus gates GSW discharges in the thalamo-(fronto) cortical network. This study is the first demonstration of a causal link between haemodynamic changes in the precuneus - an index of awareness - and the occurrence of pathological discharges in epilepsy. © 2009 Vaudano et al

Assessment of DDAH1 and DDAH2 Contributions to Psychiatric Disorders via In Silico Methods

The contribution of nitric oxide synthases (NOSs) to the pathophysiology of several neuropsychiatric disorders is recognized, but the role of their regulators, dimethylarginine dimethylaminohydrolases (DDAHs), is less understood. This study’s objective was to estimate DDAH1 and DDAH2 associations with biological processes implicated in major psychiatric disorders using publicly accessible expression databases. Since co-expressed genes are more likely to be involved in the same biologic processes, we investigated co-expression patterns with DDAH1 and DDAH2 in the dorsolateral prefrontal cortex in psychiatric patients and control subjects. There were no significant differences in DDAH1 and DDAH2 expression levels in schizophrenia or bipolar disorder patients compared to controls. Meanwhile, the data suggest that in patients, DDAH1 and DDHA2 undergo a functional shift mirrored in changes in co-expressed gene patterns. This disarrangement appears in the loss of expression level correlations between DDAH1 or DDAH2 and genes associated with psychiatric disorders and reduced functional similarity of DDAH1 or DDAH2 co-expressed genes in the patient groups. Our findings evidence the possible involvement of DDAH1 and DDAH2 in neuropsychiatric disorder development, but the underlying mechanisms need experimental validation