Today, neuroimaging techniques are frequently used to investigate the integration of functionally specialized brain regions in a network. Functional connectivity, which quantifies the statistical ...dependencies among the dynamics of simultaneously recorded signals, allows to infer the dynamical interactions of segregated brain regions. In this review we discuss how the functional connectivity patterns obtained from intracranial and scalp electroencephalographic (EEG) recordings reveal information about the dynamics of the epileptic brain and can be used to predict upcoming seizures and to localize the seizure onset zone. The added value of extracting information that is not visibly identifiable in the EEG data using functional connectivity analysis is stressed. Despite the fact that many studies have showed promising results, we must conclude that functional connectivity analysis has not made its way into clinical practice yet.
It has been demonstrated that acute vagus nerve stimulation (VNS) improves word recognition memory in epilepsy patients. Transcutaneous auricular vagus nerve stimulation (taVNS) has gained interest ...as a non-invasive alternative to improve cognition. In this prospective randomized cross-over study, we investigated the effect of both invasive VNS and taVNS on verbal memory performance in 15 patients with drug-resistant epilepsy. All patients conducted a word recognition memory paradigm in 3 conditions: VNS ON, VNS OFF and taVNS (3-period 3-treatment cross-over study design). For each condition, patients memorized 21 highlighted words from text paragraphs. Afterwards, the intervention was delivered for 30 s. Immediate recall and delayed recognition scores were obtained for each condition. This memory paradigm was repeated after 6 weeks of VNS therapy in 2 conditions: VNS ON and VNS OFF (2-period 2-treatment cross-over study design). Acute VNS and taVNS did not improve verbal memory performance. Immediate recall and delayed recognition scores were significantly improved after 6 weeks of VNS treatment irrespective of the acute intervention. We can conclude that the previously described positive effects of invasive VNS on verbal memory performance could not be replicated with invasive VNS and taVNS. An improved verbal memory performance was seen after 6 weeks of VNS treatment, suggesting that longer and more repetitive stimulation of the vagal pathway is required to modulate verbal memory performance.Clinical trial registration number: NCT05031208.
Despite optimal medical treatment, including epilepsy surgery, many epilepsy patients have uncontrolled seizures. In the last decades, interest has grown in invasive intracranial neurostimulation as ...a treatment for these patients. Intracranial stimulation includes both deep brain stimulation (DBS) (stimulation through depth electrodes) and cortical stimulation (subdural electrodes).
To assess the efficacy, safety and tolerability of deep brain and cortical stimulation for refractory epilepsy based on randomized controlled trials.
We searched PubMed (6 August 2013), the Cochrane Epilepsy Group Specialized Register (31 August 2013), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 7 of 12) and reference lists of retrieved articles. We also contacted device manufacturers and other researchers in the field. No language restrictions were imposed.
Randomized controlled trials (RCTs) comparing deep brain or cortical stimulation to sham stimulation, resective surgery or further treatment with antiepileptic drugs.
Four review authors independently selected trials for inclusion. Two review authors independently extracted the relevant data and assessed trial quality and overall quality of evidence. The outcomes investigated were seizure freedom, responder rate, percentage seizure frequency reduction, adverse events, neuropsychological outcome and quality of life. If additional data were needed, the study investigators were contacted. Results were analysed and reported separately for different intracranial targets for reasons of clinical heterogeneity.
Ten RCTs comparing one to three months of intracranial neurostimulation to sham stimulation were identified. One trial was on anterior thalamic DBS (n = 109; 109 treatment periods); two trials on centromedian thalamic DBS (n = 20; 40 treatment periods), but only one of the trials (n = 7; 14 treatment periods) reported sufficient information for inclusion in the quantitative meta-analysis; three trials on cerebellar stimulation (n = 22; 39 treatment periods); three trials on hippocampal DBS (n = 15; 21 treatment periods); and one trial on responsive ictal onset zone stimulation (n = 191; 191 treatment periods). Evidence of selective reporting was present in four trials and the possibility of a carryover effect complicating interpretation of the results could not be excluded in 4 cross-over trials without any washout period. Moderate-quality evidence could not demonstrate statistically or clinically significant changes in the proportion of patients who were seizure-free or experienced a 50% or greater reduction in seizure frequency (primary outcome measures) after 1 to 3 months of anterior thalamic DBS in (multi)focal epilepsy, responsive ictal onset zone stimulation in (multi)focal epilepsy patients and hippocampal DBS in (medial) temporal lobe epilepsy. However, a statistically significant reduction in seizure frequency was found for anterior thalamic DBS (-17.4% compared to sham stimulation; 95% confidence interval (CI) -32.1 to -1.0; high-quality evidence), responsive ictal onset zone stimulation (-24.9%; 95% CI -40.1 to 6.0; high-quality evidence) ) and hippocampal DBS (-28.1%; 95% CI -34.1 to -22.2; moderate-quality evidence). Both anterior thalamic DBS and responsive ictal onset zone stimulation do not have a clinically meaningful impact on quality life after three months of stimulation (high-quality evidence). Electrode implantation resulted in asymptomatic intracranial haemorrhage in 3% to 4% of the patients included in the two largest trials and 5% to 13% had soft tissue infections; no patient reported permanent symptomatic sequelae. Anterior thalamic DBS was associated with fewer epilepsy-associated injuries (7.4 versus 25.5%; P = 0.01) but higher rates of self-reported depression (14.8 versus 1.8%; P = 0.02) and subjective memory impairment (13.8 versus 1.8%; P = 0.03); there were no significant differences in formal neuropsychological testing results between the groups. Responsive ictal-onset zone stimulation was well tolerated with few side effects but SUDEP rate should be closely monitored in the future (4 per 340 = 11.8 per 1000 patient-years; literature: 2.2-10 per 1000 patient-years). The limited number of patients preclude firm statements on safety and tolerability of hippocampal DBS. With regards to centromedian thalamic DBS and cerebellar stimulation, no statistically significant effects could be demonstrated but evidence is of only low to very low quality.
Only short term RCTs on intracranial neurostimulation for epilepsy are available. Compared to sham stimulation, one to three months of anterior thalamic DBS ((multi)focal epilepsy), responsive ictal onset zone stimulation ((multi)focal epilepsy) and hippocampal DBS (temporal lobe epilepsy) moderately reduce seizure frequency in refractory epilepsy patients. Anterior thalamic DBS is associated with higher rates of self-reported depression and subjective memory impairment. SUDEP rates require careful monitoring in patients undergoing responsive ictal onset zone stimulation. There is insufficient evidence to make firm conclusive statements on the efficacy and safety of hippocampal DBS, centromedian thalamic DBS and cerebellar stimulation. There is a need for more, large and well-designed RCTs to validate and optimize the efficacy and safety of invasive intracranial neurostimulation treatments.
Conventional gel electrodes are widely used for biopotential measurements, despite important drawbacks such as skin irritation, long set-up time and uncomfortable removal. Recently introduced dry ...electrodes with rigid metal pins overcome most of these problems; however, their rigidity causes discomfort and pain. This paper presents dry electrodes offering high user comfort, since they are fabricated from EPDM rubber containing various additives for optimum conductivity, flexibility and ease of fabrication. The electrode impedance is measured on phantoms and human skin. After optimization of the polymer composition, the skin-electrode impedance is only ~10 times larger than that of gel electrodes. Therefore, these electrodes are directly capable of recording strong biopotential signals such as ECG while for low-amplitude signals such as EEG, the electrodes need to be coupled with an active circuit. EEG recordings using active polymer electrodes connected to a clinical EEG system show very promising results: alpha waves can be clearly observed when subjects close their eyes, and correlation and coherence analyses reveal high similarity between dry and gel electrode signals. Moreover, all subjects reported that our polymer electrodes did not cause discomfort. Hence, the polymer-based dry electrodes are promising alternatives to either rigid dry electrodes or conventional gel electrodes.
Magnetoencephalography (MEG) in the field of epilepsy has multiple advantages; just like electroencephalography (EEG), MEG is able to measure the epilepsy specific information (i.e., the brain ...activity reflecting seizures and/or interictal epileptiform discharges) directly, non-invasively and with a very high temporal resolution (millisecond-range). In addition MEG has a unique sensitivity for tangential sources, resulting in a full picture of the brain activity when combined with EEG. It accurately allows to perform source imaging of focal epileptic activity and functional cortex and shows a specific high sensitivity for a source in the neocortex. In this paper the current evidence and practice for using magnetic source imaging of focal interictal and ictal epileptic activity during the presurgical evaluation of drug resistant patients is being reviewed.
The locus coeruleus (LC) is a small brainstem nucleus and is the sole source of noradrenaline in the neocortex, hippocampus and cerebellum. Noradrenaline is a powerful neuromodulator involved in the ...regulation of excitability and plasticity of large-scale brain networks. In this study, we performed a detailed assessment of the activity of locus coeruleus neurons and changes in noradrenergic transmission during acute hippocampal seizures evoked with perforant path stimulation, using state-of-the-art methodology. Action potentials of LC neurons, of which some were identified by means of optogenetics, were recorded in anesthetized rats using a multichannel high-density electrophysiology probe. The seizure-induced change in firing rate differed between LC neurons: 55% of neurons decreased in firing rate during seizures, while 28% increased their firing rate. Topographic analysis of multi-unit activity over the electrophysiology probe showed a topographic clustering of neurons that were inhibited or excited during seizures. Changes in hippocampal noradrenaline transmission during seizures were assessed using a fluorescent biosensor for noradrenaline, GRAB
, in combination with fiber photometry, in both anesthetized and awake rats. Although our neuronal recordings indicated both inhibition and excitation of LC neurons during seizures, a consistent release of noradrenaline was observed. Concentrations of noradrenaline increased at seizure onset and decreased during or shortly after the seizure. In conclusion, this study showed consistent but heterogeneous modulation of LC neurons and a consistent time-locked release of hippocampal noradrenaline during acute hippocampal seizures.
•How well ECoG and EEG can locate sources of deep brain activity is unresolved.•First study with simultaneous EEG/ECoG/depth electrodes focused on resting state.•Dipole modeling shows deep source ...localization accuracy of EEG is comparable to ECoG.
To what extent electrocorticography (ECoG) and electroencephalography (scalp EEG) differ in their capability to locate sources of deep brain activity is far from evident. Compared to EEG, the spatial resolution and signal-to-noise ratio of ECoG is superior but its spatial coverage is more restricted, as is arguably the volume of tissue activity effectively measured from. Moreover, scalp EEG studies are providing evidence of locating activity from deep sources such as the hippocampus using high-density setups during quiet wakefulness. To address this question, we recorded a multimodal dataset from 4 patients with refractory epilepsy during quiet wakefulness. This data comprises simultaneous scalp, subdural and depth EEG electrode recordings. The latter was located in the hippocampus or insula and provided us with our “ground truth” for source localization of deep activity. We applied independent component analysis (ICA) for the purpose of separating the independent sources in theta, alpha and beta frequency band activity. In all patients subdural- and scalp EEG components were observed which had a significant zero-lag correlation with one or more contacts of the depth electrodes. Subsequent dipole modeling of the correlating components revealed dipole locations that were significantly closer to the depth electrodes compared to the dipole location of non-correlating components. These findings support the idea that components found in both recording modalities originate from neural activity in close proximity to the depth electrodes. Sources localized with subdural electrodes were ~70% closer to the depth electrode than sources localized with EEG with an absolute improvement of around ~2cm. In our opinion, this is not a considerable improvement in source localization accuracy given that, for clinical purposes, ECoG electrodes were implanted in close proximity to the depth electrodes. Furthermore, the ECoG grid attenuates the scalp EEG, due to the electrically isolating silastic sheets in which the ECoG electrodes are embedded. Our results on dipole modeling show that the deep source localization accuracy of scalp EEG is comparable to that of ECoG.
Deep and subcortical regions play an important role in brain function. However, as joint recordings at multiple spatial scales to study brain function in humans are still scarce, it is still unresolved to what extent ECoG and EEG differ in their capability to locate sources of deep brain activity. To the best of our knowledge, this is the first study presenting a dataset of simultaneously recorded EEG, ECoG and depth electrodes in the hippocampus or insula, with a focus on non-epileptiform activity (quiet wakefulness). Furthermore, we are the first study to provide experimental findings on the comparison of source localization of deep cortical structures between invasive and non-invasive brain activity measured from the cortical surface.
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Epilepsy affects about 1% of the population. Approximately one third of patients with epilepsy are drug-resistant (DRE). Resective surgery is an effective treatment for DRE, yet invasive, and not all ...DRE patients are suitable resective surgery candidates. Focused ultrasound, a novel non-invasive neurointerventional method is currently under investigation as a treatment alternative for DRE. By emitting one or more ultrasound waves, FUS can target structures in the brain at millimeter resolution. High intensity focused ultrasound (HIFU) leads to ablation of tissue and could therefore serve as a non-invasive alternative for resective surgery. It is currently under investigation in clinical trials following the approval of HIFU for essential tremor and Parkinson’s disease. Low intensity focused ultrasound (LIFU) can modulate neuronal activity and could be used to lower cortical neuronal hyper-excitability in epilepsy patients in a non-invasive manner. The seizure-suppressive effect of LIFU has been studied in several preclinical trials, showing promising results. Further investigations are required to demonstrate translation of preclinical results to human subjects.
J. Neurochem. (2011) 117, 461–469.
Vagus nerve stimulation (VNS) is an effective adjunctive treatment for medically refractory epilepsy. In this study, we measured VNS‐induced changes in hippocampal ...neurotransmitter levels and determined their potential involvement in the anticonvulsive action of VNS, to elucidate the mechanism of action responsible for the seizure suppressing effect of VNS in an animal model for limbic seizures. We used in vivo intracerebral microdialysis to measure VNS‐induced changes in hippocampal extracellular concentrations of noradrenaline, dopamine, serotonin and GABA in freely moving, male Wistar rats. During the same experiment, the effect of VNS on pilocarpine‐induced limbic seizures was assessed using video‐EEG monitoring. The involvement of VNS‐induced increases in hippocampal noradrenaline in the mechanims of action of VNS was evaluated by blocking hippocampal α2‐receptors. VNS produced a significant increase in hippocampal noradrenaline concentration (69 ± 16% above baseline levels). VNS also increased the latency between pilocarpine infusion and the onset of epileptiform discharges, and reduced the duration and severity of pilocarpine‐induced limbic seizures. A strong positive correlation was found between the noradrenergic and anticonvulsive effects of VNS. Blockade of hippocampal α2‐receptors reversed the seizure‐suppressing effect of VNS. VNS induces increases in extracellular hippocampal noradrenaline, which are at least partly responsible for its seizure‐suppressing effect in a model for limbic seizures, and constitute a potential biomarker for the efficacy of VNS in temporal lobe epilepsy.
Epilepsy and psychogenic non-epileptic seizures (PNES) often show over-lap in symptoms, especially at an early disease stage. During a PNES, the electrical activity of the brain remains normal but in ...case of an epileptic seizure the brain will show epileptiform discharges on the electroencephalogram (EEG). In many cases an accurate diagnosis can only be achieved after a long-term video monitoring combined with EEG recording which is quite expensive and time-consuming. In this paper using short-term EEG data, the classification of epilepsy and PNES subjects is analyzed based on signal, functional network and EEG microstate features. Our results showed that the beta-band is the most useful EEG frequency sub-band as it performs best for classifying subjects. Also the results depicted that when the coverage feature of the EEG microstate analysis is calculated in beta-band, the classification shows fairly high accuracy and precision. Hence, the beta-band and the coverage are the most important features for classification of epilepsy and PNES patients.
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