Identifying Neural Drivers with Functional MRI: An Electrophysiological Validation

Whether functional magnetic resonance imaging (fMRI) allows the identification of neural drivers remains an open question of particular importance to refine physiological and neuropsychological models of the brain, and/or to understand neurophysiopathology. Here, in a rat model of absence epilepsy showing spontaneous spike-and-wave discharges originating from the first somatosensory cortex (S1BF), we performed simultaneous electroencephalographic (EEG) and fMRI measurements, and subsequent intracerebral EEG (iEEG) recordings in regions strongly activated in fMRI (S1BF, thalamus, and striatum). fMRI connectivity was determined from fMRI time series directly and from hidden state variables using a measure of Granger causality and Dynamic Causal Modelling that relates synaptic activity to fMRI. fMRI connectivity was compared to directed functional coupling estimated from iEEG using asymmetry in generalised synchronisation metrics. The neural driver of spike-and-wave discharges was estimated in S1BF from iEEG, and from fMRI only when hemodynamic effects were explicitly removed. Functional connectivity analysis applied directly on fMRI signals failed because hemodynamics varied between regions, rendering temporal precedence irrelevant. This paper provides the first experimental substantiation of the theoretical possibility to improve interregional coupling estimation from hidden neural states of fMRI. As such, it has important implications for future studies on brain connectivity using functional neuroimaging

Rôle du noyau parafasciculaire du thalamus dans le contrôle des activités synchrones oscillatoires pathologiques

Le syndrome d'épilepsie mésio-temporale (EMLT) est la forme d'épilepsie focale pharmacorésistante la plus fréquente chez l'adulte et est associée à une sclérose de la formation hippocampique. Le noyau parafasciculaire (PF) du thalamus est étroitement connecté à la fois à différentes régions corticales et à l'ensemble des structures des ganglions de la base, lui permettant de participer aux fonctions sous-tendues par ces structures, incluant à la fois des processus cognitifs, sensoriels et moteurs. L'objectif de ce travail a donc e té d'étudier l'implication du PF dans le contrôle des crises d'épilepsies focales mésiotemporales dans un modèle d'EMLT chez la souris, présentant à la fois des caractéristiques électrocliniques, histopathologiques et pharmacologiques similaires à celles de l'EMLT humaine. Nous avons montré que l'activité oscillatoire synchrone du PF augmentait dans la seconde précédant la fin des crises hippocampiques, suggérant une communication entre ces deux structures. Ces données ont été corroborées par l'étude de l'activité unitaire des neurones du PF in vivo, montrant une diminution de leur fréquence de décharge pendant la crise et un rebond d'activité concomitant à la fin de crise dans l'hippocampe. Au regard des connexions du PF, nous avons ensuite montré que la modulation pharmacologique et électrique de l'activité du PF avait une incidence sur les crises hippocampiques, suggérant un rôle du PF quant à la survenue et à la modulation des évènements paroxystiques hippocampiques. De ce fait, nous avons pu mettre en évidence l'implication du thalamus intralaminaire dans le contrôle à distance des crises focales mésio-temporales, chez la souris EMLT.The mesial temporal lobe epilepsy (MTLE) syndrome is the most common form of drugresistant focal epilepsy in adults, associated with an hippocampal sclerosis. The parafascicular nucleus (PF) is part of the intralaminar nuclei of the thalamus and is closely and reciprocally connected with different cortical regions and with all the basal ganglia structures, allowing him to participate in physiological functions underlain by these systems, including both cognitive, sensory (sleep cycles, pain modulation) and motor prcesses. The aim of this work was therefore to study the involvement of PF in controlling hippocampal focal seizures in a mouse model of MTLE with both electroclinical, histopathologicaland pharmacological features reminescent of human MTLE. We have shown that the synchronous oscillatory activity of PF increases in the 10-20 Hz frequency band during the second preceding the end of hippocampal seizures, suggesting a communication between these two structures. These data were corroborated by studying the activity of single PF neurons in vivo in MTLE mice, showing a decrease in their firing rate during the seizure and a rebound of activity concomitant with the end of the hippocampal paroxysmal events. Given the connections that the PF establishes with the cortex and subcortical structures such as basal ganglia ot the thalamic reticular nucleus, we then showed that pharmacological modulation of PF activity had an impact on the occurence of hippocampal seizures. Thus, we could highlight the involvement of the intralaminar thalamus in the remote control of focal mesial-temporal seizures, in the MTLE mouse model.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

Dedicated electronics for electrical stimulation and EEG recording using the same electrodes: application to the automatic control of epileptic seizures by neurostimulation

International audienc

The accepting power of unary string logic programs

The set of programs written in a small subset of pure Prolog called US is shown to accept exactly the class of regular languages. The language US contains only unary predicates and unary function symbols. Also, a subset of US called RUS is shown to be equivalent to US in its ability in accepting the class of regular languages. Every clause in RUS contains at most one function symbol in the head and at most one literal with no function symbol in the body. The result is very close to a theorem of Matos (TCS April 1997) but our proof is quite different. Though US and RUS have the same accepting power, their conciseness of expression is dramatically different: if we try to write an RUS program equivalent to a US program, the number of predicates in the RUS program could be O(22N) where N is the sum of the number of predicates and the number of functors in the US program

Short-term changes in bilateral hippocampal coherence precede epileptiform events.

International audienceThe mesial temporal lobe epilepsy syndrome (MTLE) is the most common form of focal epilepsies. MTLE patients usually respond very little to pharmacological therapy and surgical resection of temporal brain areas is mandatory. Finding less invasive therapies than resection of the sclerotic hippocampus requires knowledge of the network structures and dynamics involved in seizure generation. Investigation of the time interval immediately preceding seizure onset would help in understanding the initiation mechanisms of the seizure proper and, thereby, possibly improve therapeutical options. Here, we employed the in vivo intrahippocampal kainate model in mice, which is characterized by unilateral histological changes, resembling hippocampal sclerosis observed in human MTLE, and recurrent focal seizures. In these epileptic mice, population spikes occurred during epileptiform events (EEs) in the ipsilateral, histologically changed hippocampus, but also concomitantly in the contralateral, intact hippocampus. We studied synchronization processes between the ipsilateral, sclerotic hippocampus and the contralateral hippocampus immediately preceding the onset of EEs. We show that coherence between the two hippocampi decreased consistently and reliably for all EEs at 8 to 12 s before their onset at high frequencies (>100 Hz), without changes in power in these bands. This early decoupling of the two hippocampi indicates the time range for cellular and network mechanisms leading to increased excitability and/or synchronicity in the tissue and thus ultimately to epileptic seizures

Controlling seizures is not controlling epilepsy: a parametric study of deep brain stimulation for epilepsy.

International audiencePharmacological inhibition and high-frequency stimulation (HFS) of the substantia nigra pars reticulata (SNr) suppress seizures in different animal models of epilepsy. The aim of the present study was to determine the optimal parameters of HFS to control spontaneous seizures in a genetic model of absence epilepsy in the rat. Single SNr stimulation that was bilateral, bipolar and monophasic at 60 Hz frequency and with 60-micros pulse width was optimal. However, when used for repeated stimulations, long-term suppression did not occur and even the number of seizures increased. A delay of at least 60 s between stimulations was necessary to be fully effective. Although single HFS of the SNr can be used to suppress ongoing seizures, repeated HFS is ineffective and could even aggravate seizures in our model. Thus investigations of accurate stimulation procedures are still needed

Deep layer somatosensory cortical neurons initiate spike-and-wave discharges in a genetic model of absence seizures.

International audienceTypical absence has long been considered as the prototypic form of generalized nonconvulsive epileptic seizures. Recent investigations in patients and animal models suggest that absence seizures could originate from restricted regions of the cerebral cortex. However, the cellular and local network processes of seizure initiation remain unknown. Here, we show that absence seizures in Genetic Absence Epilepsy Rats from Strasbourg, a well established genetic model of this disease, arise from the facial somatosensory cortex. Using in vivo intracellular recordings, we found that epileptic discharges are initiated in layer 5/6 neurons of this cortical region. These neurons, which show a distinctive hyperactivity associated with a membrane depolarization, lead the firing of distant cortical cells during the epileptic discharge. Consistent with their ictogenic properties, neurons from this "focus" exhibit interictal and preictal oscillations that are converted into epileptic pattern. These results confirm and extend the "focal hypothesis" of absence epilepsy and provide a cellular scenario for the initiation and generalization of absence seizures

Assessing Susceptibility to Epilepsy in Three Rat Strains Using Brain Metabolic Profiling Based on HRMAS NMR Spectroscopy and Chemometrics

The possibility that a metabolomic approach can inform about the pathophysiology of a given form of epilepsy was addressed. Using chemometric analyses of HRMAS NMR data, we compared several brain structures in three rat strains with different susceptibilities to absence epilepsy: Genetic Absence Epilepsy Rats from Strasbourg (GAERS), Non Epileptic Control rats (NEC), and Wistar rats. Two ages were investigated: 14 days postnatal (P14) before the onset of seizures and 5 month old adults with fully developed seizures (Adults). The relative concentrations of 19 metabolites were assessed using ¹H HRMAS NMR experiments. Univariate and multivariate analyses including multiblock models were used to identify the most discriminant metabolites. A strain-dependent evolution of glutamate, glutamine, scyllo-inositol, alanine, and glutathione was highlighted during cerebral maturation. In Adults, data from somatosensory and motor cortices allowed discrimination between GAERS and NEC rats with higher levels of scyllo-inositol, taurine, and phosphoethanolamine in NEC. This epileptic metabolic phenotype was in accordance with current pathophysiological hypothesis of absence epilepsy (i.e., seizure-generating and control networks) and putative resistance of NEC rats and was observed before seizure onset. This methodology could be very efficient in a clinical context

Involvement of the thalamic parafascicular nucleus in mesial temporal lobe epilepsy.

International audienceMesial temporal lobe epilepsy (MTLE) is characterized by focal seizures, associated with hippocampal sclerosis, and often resistance to antiepileptic drugs. The parafascicular nucleus (PF) of the thalamus is involved in the generation of physiological oscillatory rhythms. It receives excitatory inputs from the cortex and inhibitory inputs from the basal ganglia, a system implicated in the control of epileptic seizures. The aim of this study was to examine the involvement of the PF in the occurrence of hippocampal paroxysmal discharges (HPDs) in a chronic animal model of MTLE in male mice. We recorded the local field potential (LFP) and the extracellular and intracellular activity of hippocampal and PF neurons during spontaneous HPDs in vivo. The end of the HPDs was concomitant with a slow repolarization in hippocampal neurons leading to an electrical silence. In contrast, it was associated in the PF with a transient increase in the power of the 10-20 Hz band in LFPs and a depolarization of PF neurons resulting in a sustained firing. We tested the role of the PF in the control of HPDs by single 130 Hz electrical stimulation of this nucleus and bilateral intra-PF injection of NMDA and GABA(A) antagonist and agonist. High-frequency PF stimulation interrupted ongoing HPDs at an intensity devoid of behavioral effects. NMDA antagonist and GABA(A) agonist suppressed hippocampal discharges in a dose-dependent way, whereas NMDA agonist and GABA(A) antagonist increased HPDs. Altogether, these data suggest that the PF nucleus plays a role in the modulation of MTLE seizures