Involvement of fast-spiking cells in ictal sequences during spontaneous seizures in rats with chronic temporal lobe epilepsy

Epileptic seizures represent altered neuronal network dynamics, but the temporal evolution and cellular substrates of the neuronal activity patterns associated with spontaneous seizures are not fully understood. We used simultaneous recordings from multiple neurons in the hippocampus and neocortex of rats with chronic temporal lobe epilepsy to demonstrate that subsets of cells discharge in a highly stereotypical sequential pattern during ictal events, and that these stereotypical patterns were reproducible across consecutive seizures. In contrast to the canonical view that principal cell discharges dominate ictal events, the ictal sequences were predominantly composed of fast-spiking, putative inhibitory neurons, which displayed unusually strong coupling to local field potential even before seizures. The temporal evolution of activity was characterized by unique dynamics where the most correlated neuronal pairs before seizure onset displayed the largest increases in correlation strength during the seizures. These results demonstrate the selective involvement of fast spiking interneurons in structured temporal sequences during spontaneous ictal events in hippocampal and neocortical circuits in experimental models of chronic temporal lobe epilepsy

Deep brain and cortical stimulation for epilepsy

Background : Despite optimal medical treatment, including epilepsy surgery, many epilepsy patients have uncontrolled seizures. Since the 1970s 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). This is an updated version of a previous Cochrane review published in 2014. Objectives : To assess the efficacy, safety and tolerability of DBS and cortical stimulation for refractory epilepsy based on randomized controlled trials (RCTs). Search methods : We searched the Cochrane Epilepsy Group Specialized Register on 29 September 2015, but it was not necessary to update this search, because records in the Specialized Register are included in CENTRAL. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 11, 5 November 2016), PubMed (5 November 2016), ClinicalTrials. gov (5 November 2016), the WHO International Clinical Trials Registry Platform ICTRP (5 November 2016) and reference lists of retrieved articles. We also contacted device manufacturers and other researchers in the field. No language restrictions were imposed. Selection criteria : RCTs comparing deep brain or cortical stimulation versus sham stimulation, resective surgery, further treatment with antiepileptic drugs or other neurostimulation treatments (including vagus nerve stimulation). Data collection and analysis : 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. Main results : Twelve RCTs were identified, eleven of these compared one to three months of intracranial neurostimulation with sham stimulation. 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); one trial on nucleus accumbens DBS (n = 4; 8 treatment periods); and one trial on responsive ictal onset zone stimulation (n = 191; 191 treatment periods). In addition, one small RCT (n = 6) compared six months of hippocampal DBS versus sham stimulation. 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 five cross-over trials without any or a sufficient 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 one to three 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 (mean difference (MD), -17.4% compared to sham stimulation; 95% confidence interval (CI) -31.2 to -1.0; high-quality evidence), responsive ictal onset zone stimulation (MD -24.9%; 95% CI -40.1 to -6.0; high-quality evidence) and hippocampal DBS (MD -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 postoperative asymptomatic intracranial haemorrhage in 1.6% to 3.7% of the patients included in the two largest trials and 2.0% to 4.5% had postoperative soft tissue infections (9.4% to 12.7% after five years); 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 seemed to be well-tolerated with few side effects. The limited number of patients preclude firm statements on safety and tolerability of hippocampal DBS. With regards to centromedian thalamic DBS, nucleus accumbens DBS and cerebellar stimulation, no statistically significant effects could be demonstrated but evidence is of only low to very low quality. Authors' conclusions : Except for one very small RCT, 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. There is insufficient evidence to make firm conclusive statements on the efficacy and safety of hippocampal DBS, centromedian thalamic DBS, nucleus accumbens 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

Hypothermia masks most of the effects of rapid cycling VNS on rat hippocampal electrophysiology

AIM. Vagus nerve stimulation (VNS) modulates hippocampal dentate gyrus (DG) electrophysiology and induces hypothermia in freely moving rats. This study evaluated whether hippocampal (CA1) electrophysiology is similarly modulated and to what extent this is associated with VNS-induced hypothermia. METHODS. Six freely moving rats received a first 4 h session of rapid cycling VNS (7 s on/18 s off), while CA1 evoked potentials, EEG and core temperature were recorded. In a second 4 h session, external heating was applied during the 3rd and 4th h of VNS counteracting VNS-induced hypothermia. RESULTS. VNS decreased the slope of the field excitatory postsynaptic potential (fEPSP), increased the population spike (PS) amplitude and latency, decreased theta (4-12 Hz) and gamma (30-100 Hz) band power and theta peak frequency. Normalizing body temperature during VNS through external heating abolished the effects completely for fEPSP slope, PS latency and gamma band power, partially for theta band power and theta peak frequency and inverted the effect on PS amplitude. CONCLUSIONS. Rapid cycle VNS modulates CA1 electrophysiology similarly to DG, suggesting a wide-spread VNS-induced effect on hippocampal electrophysiology. Normalizing core temperature elucidated that VNS-induced hypothermia directly influences several electrophysiological parameters but also masks a VNS-induced reduction in neuronal excitability

Identification of vagus nerve stimulation parameters affecting rat hippocampal electrophysiology without temperature effects

Background: Recent experiments in rats have demonstrated significant effects of VNS on hippocampal excitability but were partially attributed to hypothermia, induced by the applied VNS parameters. Objective: To allow meaningful preclinical research on the mechanisms of VNS and translation of rodent results to clinical VNS trials, we aimed to identify non-hypothermia inducing VNS parameters that significantly affect hippocampal excitability. Methods: VNS was administered in cycles of 30 s including either 0.1, 0.16, 0.25, 0.5, 1.5, 3 or 7 s of VNS ON time (biphasic pulses, 250ms/phase, 1 mA, 30 Hz) and the effect of different VNS ON times on brain temperature was evaluated. VNS paradigms with and without hypothermia were compared for their effects on hippocampal neurophysiology in freely moving rats. Results: Using VNS parameters with an ON time/OFF time of up to 0.5 s/30 s did not cause hypothermia, while clear hypothermia was detected with ON times of 1.5, 3 and 7 s/30 s. Relative to SHAM VNS, the normothermic 0.5 s VNS condition significantly decreased hippocampal EEG power and changed dentate gyrus evoked potentials with an increased field excitatory postsynaptic potential slope and a decreased population spike amplitude. Conclusion: VNS can be administered in freely moving rats without causing hypothermia, while profoundly affecting hippocampal neurophysiology suggestive of reduced excitability of hippocampal neurons despite increased synaptic transmission efficiency. (C) 2020 The Authors. Published by Elsevier Inc

Seizures and Interictal Epileptiform Activity in the Rat Collagenase Model for Intracerebral Hemorrhage

AimsIntracerebral hemorrhage (ICH) is a known risk factor for the development of acute symptomatic as well as late unprovoked seizures. The underlying pathophysiology of post-ICH seizures is incompletely understood and there are no reliable predictive biomarkers. An animal model to study post-ICH seizures is currently lacking. The aim of this study was to investigate (1) the occurrence of seizures and interictal epileptiform activity in the ICH rat collagenase model using long-term video-EEG monitoring (VEM) and (2) whether seizure occurrence was associated with interictal epileptiform activity and histological features.MethodsMale Sprague-Dawley rats were implanted with epidural electrodes. After 1 week of baseline VEM, collagenase was injected in left striatum to induce an ICH. VEM was continued for 180 days to assess the occurrence of post-ICH seizures and interictal epileptiform activity (spikes and epileptiform discharges). At the end of the experiment, animals were euthanized for histological characterization of the hemorrhagic lesion, using cresyl violet, Prussian blue and immunofluorescence staining.ResultsAcute symptomatic seizures occurred in 4/12 animals between 46 and 80 h after ICH induction. Late unprovoked seizures were present in 2/12 animals and started at 90 and 103 days post-ICH. Animals with late unprovoked seizures did not have acute symptomatic seizures. All electrographic seizures were accompanied by clear behavioral changes. Interictal spikes and epileptiform discharges were observed in all animals but occurred more frequently in rats with late seizures (p = 0.019 and p < 0.001, respectively). Animals with acute symptomatic seizures had more extended hemorrhagic lesions and hemosiderin deposits in the piriform cortex.ConclusionBoth acute symptomatic and late unprovoked seizures were observed in the rat collagenase model. Interictal epileptiform activity was more frequently seen in animals with late seizures. Rats with acute symptomatic seizures showed more extensive lesions and hemosiderin deposits in the piriform cortex. This model could be used to further explore possible biomarkers for epileptogenesis

Deep brain stimulation of the anterior nucleus of the thalamus in drug-resistant epilepsy in the MORE multicenter patient registry

Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background and objectives: The efficacy of deep brain stimulation of the anterior nucleus of the thalamus (ANT DBS) in patients with drug-resistant epilepsy (DRE) was demonstrated in the double-blind Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy randomized controlled trial. The Medtronic Registry for Epilepsy (MORE) aims to understand the safety and longer-term effectiveness of ANT DBS therapy in routine clinical practice. Methods: MORE is an observational registry collecting prospective and retrospective clinical data. Participants were at least 18 years old, with focal DRE recruited across 25 centers from 13 countries. They were followed for at least 2 years in terms of seizure frequency (SF), responder rate (RR), health-related quality of life (Quality of Life in Epilepsy Inventory 31), depression, and safety outcomes. Results: Of the 191 patients recruited, 170 (mean [SD] age of 35.6 [10.7] years, 43% female) were implanted with DBS therapy and met all eligibility criteria. At baseline, 38% of patients reported cognitive impairment. The median monthly SF decreased by 33.1% from 15.8 at baseline to 8.8 at 2 years (p 10 implantations) had 42.8% reduction in median monthly SF by 2 years in comparison with 25.8% in low-volume center. In patients with cognitive impairment, the reduction in median monthly SF was 26.0% by 2 years compared with 36.1% in patients without cognitive impairment. The most frequently reported adverse events were changes (e.g., increased frequency/severity) in seizure (16%), memory impairment (patient-reported complaint, 15%), depressive mood (patient-reported complaint, 13%), and epilepsy (12%). One definite sudden unexpected death in epilepsy case was reported. Discussion: The MORE registry supports the effectiveness and safety of ANT DBS therapy in a real-world setting in the 2 years following implantation. Classification of evidence: This study provides Class IV evidence that ANT DBS reduces the frequency of seizures in patients with drug-resistant focal epilepsy.The MORE registry was sponsored and funded by Medtronic, plc.info:eu-repo/semantics/publishedVersio