Potential new roles for glycogen in epilepsy.

Seizures often originate in epileptogenic foci. Between seizures (interictally), these foci and some of the surrounding tissue often show low signals with 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in many epileptic patients, even when there are no radiologically detectable structural abnormalities. Low FDG-PET signals are thought to reflect glucose hypometabolism. Here, we review knowledge about metabolism of glucose and glycogen and oxidative stress in people with epilepsy and in acute and chronic rodent seizure models. Interictal brain glucose levels are normal and do not cause apparent glucose hypometabolism, which remains unexplained. During seizures, high amounts of fuel are needed to satisfy increased energy demands. Astrocytes consume glycogen as an additional emergency fuel to supplement glucose during high metabolic demand, such as during brain stimulation, stress, and seizures. In rodents, brain glycogen levels drop during induced seizures and increase to higher levels thereafter. Interictally, in people with epilepsy and in chronic epilepsy models, normal glucose but high glycogen levels have been found in the presumed brain areas involved in seizure generation. We present our new hypothesis that as an adaptive response to repeated episodes of high metabolic demand, high interictal glycogen levels in epileptogenic brain areas are used to support energy metabolism and potentially interictal neuronal activity. Glycogenolysis, which can be triggered by stress or oxidative stress, leads to decreased utilization of plasma glucose in epileptogenic brain areas, resulting in low FDG signals that are related to functional changes underlying seizure onset and propagation. This is (partially) reversible after successful surgery. Last, we propose that potential interictal glycogen depletion in epileptogenic and surrounding areas may cause energy shortages in astrocytes, which may impair potassium buffering and contribute to seizure generation. Based on these hypotheses, auxiliary fuels or treatments that support glycogen metabolism may be useful to treat epilepsy.

The Ictal Signature of Thalamus and Basal Ganglia in Focal Epilepsy: A SEEG Study.

OBJECTIVE: To determine the involvement of subcortical regions in human epilepsy by analyzing direct recordings from these regions during epileptic seizures using stereo-EEG (SEEG). METHODS: We studied the SEEG recordings of a large series of patients (74 patients, 157 seizures) with an electrode sampling the thalamus and in some cases also the basal ganglia (caudate nucleus, 22 patients; and putamen, 4 patients). We applied visual analysis and signal quantification methods (Epileptogenicity Index [EI]) to their ictal recordings and compared electrophysiologic with clinical data. RESULTS: We found that in 86% of patients, thalamus was involved during seizures (visual analysis) and 20% showed high values of epileptogenicity (EI >0.3). Basal ganglia may also disclose high values of epileptogenicity (9% in caudate nucleus) but to a lesser degree than thalamus (p < 0.01). We observed different seizure onset patterns including low voltage high frequency activities. We found high values of thalamic epileptogenicity in different epilepsy localizations, including opercular and motor epilepsies. We found no difference between epilepsy etiologies (cryptogenic vs malformation of cortical development, p = 0.77). Thalamic epileptogenicity was correlated with the extension of epileptogenic networks (p = 0.02, ρ 0.32). We found a significant effect (p < 0.05) of thalamic epileptogenicity regarding the postsurgical outcome (higher thalamic EI corresponding to higher probability of surgical failure). CONCLUSIONS: Thalamic involvement during seizures is common in different seizure types. The degree of thalamic epileptogenicity is a possible marker of the epileptogenic network extension and of postsurgical prognosis.

The effect of medial pulvinar stimulation on temporal lobe seizures.

We investigated the effect of electrical stimulation of the medial pulvinar (PuM) in terms of its effect on temporal lobe seizures. Eight patients with drug-resistant temporal lobe epilepsy undergoing stereoelectroencephalographic exploration were included. All had at least one electrode exploring the PuM. High-frequency (50 Hz) stimulations of the PuM were well tolerated in the majority of them. During diagnostic stimulation to confirm the epileptogenic zone, 19 seizures were triggered by stimulating the hippocampus. During some of these seizures, ipsilateral pulvinar stimulation was applied (130 Hz, pulse width = 450 microseconds, duration = 3-7 seconds, 1-2 mA). Compared to non-PuM-stimulated seizures, five of eight patients experienced clinically less severe seizures, particularly in terms of degree of alteration of consciousness. On the electrical level, seizures were more rapidly clonic with a shorter tonic phase. This proof of concept study is the first to suggest that PuM stimulation could be a well-tolerated and effective means of therapeutic deep brain stimulation in drug-resistant epilepsies.

Using EEG-based brain computer interface and neurofeedback targeting sensorimotor rhythms to improve motor skills: Theoretical background, applications and prospects.

Many Brain Computer Interface (BCI) and neurofeedback studies have investigated the impact of sensorimotor rhythm (SMR) self-regulation training procedures on motor skills enhancement in healthy subjects and patients with motor disabilities. This critical review aims first to introduce the different definitions of SMR EEG target in BCI/Neurofeedback studies and to summarize the background from neurophysiological and neuroplasticity studies that led to SMR being considered as reliable and valid EEG targets to improve motor skills through BCI/neurofeedback procedures. The second objective of this review is to introduce the main findings regarding SMR BCI/neurofeedback in healthy subjects. Third, the main findings regarding BCI/neurofeedback efficiency in patients with hypokinetic activities (in particular, motor deficit following stroke) as well as in patients with hyperkinetic activities (in particular, Attention Deficit Hyperactivity Disorder, ADHD) will be introduced. Due to a range of limitations, a clear association between SMR BCI/neurofeedback training and enhanced motor skills has yet to be established. However, SMR BCI/neurofeedback appears promising, and highlights many important challenges for clinical neurophysiology with regards to therapeutic approaches using BCI/neurofeedback.

A case-control study of skin conductance biofeedback on seizure frequency and emotion regulation in drug-resistant temporal lobe epilepsy.

This study investigates the physiological basis of effects of skin conductance biofeedback on anxiety disorders, depressive disorders and stress in drug-resistant temporal lobe epilepsy (TLE). This method presents an interest in seizure reduction and improvement in psychiatric comorbidities frequently associated with TLE. Our goal was to better understand the impact of biofeedback on seizure control and on emotional regulation. Fifteen patients with TLE were treated with 12 skin conductance biofeedback sessions and compared with 15 control TLE patients on a waiting list. They were evaluated in terms of seizure frequency, clinical evaluations of anxiety and depression and skin conductance responses (SCR) to five emotions: fear, disgust, sadness, happiness and peacefulness induced by short films. Biofeedback training significantly reduced seizure frequency with a mean reduction of -47.42% in the biofeedback group, while the control group did not differ at the two time measures. A significant improvement was found for depression and trait-anxiety in the biofeedback group but not in the control group. There were no differences on SCR on any emotion after biofeedback treatment. A correlation was found between mean change in SCR over the biofeedback treatment and the reduction of seizure frequency, but not between SCR changes and scores on psychiatric comorbidities. These results show independent effect of biofeedback on mood and seizure control. Improvements in anxiety and depressive symptoms were not related to SCR, whereas improved seizure control was, suggesting differential mechanisms underlying these two phenomena.

Skin conductance biofeedback training in adults with drug-resistant temporal lobe epilepsy and stress-triggered seizures: a proof-of-concept study.

The present proof-of-concept study investigated the feasibility of skin conductance biofeedback training in reducing seizures in adults with drug-resistant temporal lobe epilepsy (TLE), whose seizures are triggered by stress. Skin conductance biofeedback aims to increase levels of peripheral sympathetic arousal in order to reduce cortical excitability. This might seem somewhat counterintuitive, since such autonomic arousal may also be associated with increased stress and anxiety. Thus, this sought to verify that patients with TLE and stress-triggered seizures are not worsened in terms of stress, anxiety, and negative emotional response to this nonpharmacological treatment. Eleven patients with drug-resistant TLE with seizures triggered by stress were treated with 12 sessions of biofeedback. Patients did not worsen on cognitive evaluation of attentional biases towards negative emotional stimuli (P>.05) or on psychometric evaluation with state anxiety inventory (P = .059); in addition, a significant improvement was found in the Negative Affect Schedule (P = .014) and in the Beck Depression Inventory (P = .009). Biofeedback training significantly reduced seizure frequency with a mean reduction of -48.61% (SD = 27.79) (P = .005). There was a correlation between the mean change in skin conductance activity over the biofeedback treatment and the reduction of seizure frequency (r(11) = .62, P = .042). Thus, the skin conductance biofeedback used in the present study, which teaches patients to achieve an increased level of peripheral sympathetic arousal, was a well-tolerated nonpharmacological treatment. Further, well-controlled studies are needed to confirm the therapeutic value of this nonpharmacological treatment in reducing seizures in adults with drug-resistant TLE with seizures triggered by stress.

The role of corticothalamic coupling in human temporal lobe epilepsy.

The EEG activity of the thalamus and temporal lobe structures (hippocampus, entorhinal cortex and neocortex) was obtained using intracerebral recordings (stereoelectroencephalography, SEEG) performed in patients with TLE seizures undergoing pre-surgical evaluation. Synchrony was studied using a statistical measure of SEEG signal interdependencies (non-linear correlation). The results demonstrated an overall increase of synchrony between the thalamus and temporal lobe structures during seizures. Moreover, although there was great inter-individual variability, we found that values from seizure onset period were significantly higher than values from the background period (P = 0.001). Values at the end of seizure were significantly higher than values from the seizure onset (P < 0.0001). Several indices were also defined in order to correlate some clinical features to the degree of coupling between cortical structures and the thalamus. In patients with mesial TLE seizures, a correlation was found between the degree of thalamocortical synchrony and the presence of an early loss of consciousness but not with other clinical parameters. In addition, surgical prognosis seemed better in patients with low values of thalamocortical couplings at the seizure onset. This report demonstrates that the thalamus and remote cortical structures synchronize their activity during TLE seizures and suggest that the extension of the epileptogenic network to the thalamus is a potential important factor determining surgical prognosis.