Hippocampal Stimulation Research Articles

Reproducing the effect of hippocampal network-targeted transcranial magnetic stimulation on episodic memory

Repetitive transcranial magnetic stimulation (rTMS) targeted to the hippocampal network via the inferior parietal cortex (HN-Stim) can strengthen hippocampal-cortical connectivity and improve episodic memory, offering a potential clinical intervention. However, acceptance of this technique has been tempered by the infrequent reproduction of findings in rTMS research on cognitive processes. We tested the reproducibility of the HN-Stim effect on episodic memory in our laboratory using different procedures from those previously published. We tested episodic memory in 29 participants before, one day, and one week after, three consecutive days of 20 Hz HN-Stim. Participants received stimulation targeted to either the area of inferior parietal cortex maximally connected to the left anterior hippocampus (HN-Stim; N = 14) or the vertex (control; N = 15), where we expected no effect. HN-Stim increased episodic memory performance one day, but not one week, after the last stimulation session. While failing to reproduce the lasting beneficial effect on memory found by others after five days of treatment, we found robust effects on behavior 24 h after treatment. HN-Stim is a safe and reliable means of enhancing episodic memory and may have potential for boosting learning and treating memory deficits.

Clustering of Spontaneous Recurrent Seizures in a Mouse Model of Extended Hippocampal Kindling.

Acute repetitive seizures or seizure clusters are common in epileptic patients. Seizure clusters are associated with a high risk of developing status epilepticus and increased morbidity and mortality. Seizure clusters are also recognizable in spontaneous recurrent seizures (SRS) that occur in animal models of epilepsy. The electrical kindling of a limbic structure is a commonly used model of temporal lobe epilepsy. Although classic kindling over the course of a few weeks does not generally induce SRS, extended kindling over the course of a few months can induce SRS in several animal species. SRS in kindled cats often occur in clusters, but the existence of seizure clusters in rodent models of extended kindling remains to be demonstrated. We explored the existence of seizure clusters in mice following extended hippocampal kindling. Adult male mice (C57BL/6) experienced twice daily hippocampal stimulations and underwent continuous 24-hour electroencephalogram (EEG)-video monitoring after ≥80 stimulations. SRS events were recognized by EEG discharges and associated motor seizures. Seizure clusters, defined as ≥4 seizures per cluster and intra-cluster inter-seizure intervals ≤ 120 min, were observed in 19 of the 20 kindled mice. Individual mice showed variable seizure clusters in terms of cluster incidence and circadian-like expression patterns. For clusters consisting of 4–7 seizures and intra-seizure intervals ≤ 20 min, no consistent changes in inter-seizure intervals, EEG discharge duration, or motor seizure severity scores were observed approaching cluster termination. These results suggested that seizure clustering represents a prominent feature of SRS in hippocampal kindled mice. We speculate that, despite experimental limitations and confounding factors, systemic homeostatic mechanisms that have yet to be explored may play an important role in governing the occurrence and termination of seizure clusters.

Task-dependent effects of intracranial hippocampal stimulation on human memory

Abstract Background: Despite its potential to revolutionize the treatment of memory dysfunction, the efficacy of direct electrical hippocampal stimulation for memory performance has not yet been well characterized. One of the main challenges to cross-study comparison in this area of research is the diversity of the cognitive tasks used to measure memory performance. Objective: We hypothesized that the tasks that differentially engage the hippocampus may be differentially influenced by hippocampal stimulation and the behavioral effects would be related to the underlying hippocampal activity. Methods: To investigate this issue, we recorded intracranial EEG from and directly applied stimulation to the hippocampus of 10 epilepsy patients while they performed two different verbal memory tasks e a word pair associative memory task and a single item memory task. Results: Hippocampal stimulation modulated memory performance in a task-dependent manner, improving associative memory performance, while impairing item memory performance. In addition, subjects with poorer baseline cognitive function improved much more with stimulation. iEEG recordings from the hippocampus during non-stimulation encoding blocks revealed that the associative memory task elicited stronger theta oscillations than did item memory and that stronger theta power was related to memory performance. Conclusions: We show here for the first time that stimulation-induced associative memory enhancement was linked to increased theta power during retrieval. These results suggest that hippocampal stimulation enhances associative memory but not item memory because it engages more hippocampal theta activity and that, in general, increasing hippocampal theta may provide a neural mechanism for successful memory enhancement. Keywords: Memory enhancement, iEEG, deep brain stimulation, hippocampus

Tractography-guided hippocampal theta burst stimulation to improve memory performance and increase hippocampal connectivity in mild cognitive impairment

Abstract A personalized, image-guided theta-burst stimulation (TBS) protocol was developed for individuals with mild cognitive impairment (MCI). MCI is a transitional stage between normal aging and Alzheimer's disease (AD). There is a need for interventions to alleviate the deterioration of memory. Targeting the hippocampus, which still exhibits plasticity at the stage of MCI, may be an effective strategy to enhance memory functions. By using white matter tractography maps as a guide, we were able to effectively relay the modulation effects of the superficial TBS to the hippocampus. Nine right-handed older adults (aged 65 to 74 years old) classified as MCI based on the Uniform Data Set version 3 (UDS3) neuropsychological battery participated in our study. Diffusion-weighted images were acquired for each participant at baseline to determine the optimal superficial stimulation site. White matter tractography of the left hippocampus was generated using MRtrix. In this cross-over design, participants were exposed to each of these conditions twice: excitatory intermittent TBS (iTBS), inhibitory continuous TBS (cTBS), and sham stimulation. A minimum of 5 days separates each TBS session to avoid potential carry-over effects. Outcome measures including resting-state fMRI and the Face-Name associative memory test (FNAME) were acquired immediately before and after each TBS session. Excitatory iTBS significantly improved associative memory and increased resting-state functional connectivity along the inferior longitudinal fasciculus (ILF) to the hippocampus compared to the sham TBS. Individuals who had a greater increase in functional connectivity between subfields of the hippocampus (i.e., CA1 and hippocampal fissures) and the superficial stimulation site following active TBS had greater memory enhancement (p < 0.05). New insights are provided about TBS propagation along the ILF from the surface stimulation site to the hippocampus. This tractography-guided TBS may be a useful strategy to guide the design of future TBS protocols to treat MCI. Keywords: Transcranial magnetic stimulation, Tractography, Mild Cognitive Impairment, Memory

Evidence from theta-burst stimulation that age-related de-differentiation of the hippocampal network is functional for episodic memory

Episodic memory is supported by hippocampal interactions with a distributed network. Aging is associated with memory decline and network de-differentiation. However, the role of de-differentiation in memory decline has not been directly tested. We reasoned that hippocampal network-targeted stimulation could test these theories, as age-related changes in the network response to stimulation would indicate network reorganization, and corresponding changes in memory would suggest that this reorganization is functional. We compared effects of stimulation on fMRI connectivity and memory in younger versus older adults. Theta-burst network-targeted stimulation of left lateral parietal cortex selectively increased hippocampal network connectivity and modulated memory in younger adults. In contrast, stimulation in older adults increased connectivity throughout the brain, without network selectivity, and did not influence memory. These findings provide evidence that network responses to stimulation are de-differentiated in aging and suggest that age-related de-differentiation is relevant for memory. This manuscript is part of the Special Issue entitled “Cognitive Neuroscience of Healthy and Pathological Aging” edited by Drs. M. N. Rajah, S. Belleville, and R. Cabeza. This article is part of the Virtual Special Issue titled COGNITIVE NEUROSCIENCE OF HEALTHY AND PATHOLOGICAL AGING. The full issue can be found on ScienceDirect at https://www.sciencedirect.com/journal/neurobiology-of-aging/special-issue/105379XPWJP.

Disruption of hippocampal rhythms via optogenetic stimulation during the critical period for memory development impairs spatial cognition

Objective . Investigate whether the disruption of normal hippocampal rhythms via optogenetic stimulation of the medial septum (MS) during late postnatal development has enduring effects on the allocentric memory of rat pups. Methods . Hippocampal theta oscillations were non-endogenously regulated in rat pups using blue light (465-nm) pan-neuronal optogenetic activation of the MS from postnatal day (P)21–25 using random sinewave frequencies ranging from 0.5 to 110 Hz. Non-stimulated and yellow light (590-nm) stimulated rats were used as controls, and local field potentials from the hippocampus and MS were recorded unilaterally during stimulations. In early adulthood, spatial cognition was assessed using the active avoidance task. Rats were perfused and tissue containing the MS and hippocampus was harvested and sectioned to assess cell density. Power spectrum density of both the MS and hippocampus; coherence, and voltage correlation analysis between both structures were used to compare baseline to the disruptive stimulation. Results . During late postnatal development, non-selective optogenetic activation of the MS tightly regulated hippocampal oscillations. Disruptive stimulation increased power but reduced coherence and voltage correlations; and resulted in impaired spatial learning compared with controls. Impairment of spatial cognition was not attributed to MS or hippocampal cell loss. Conclusions. These results demonstrate that hippocampal oscillations can be precisely regulated with non-selective optogenetic stimulation of the MS in weanling rats. A disruptive hippocampal stimulation protocol during the critical period of memory development results in long-standing spatial cognitive deficits that is not attributed to cell loss. Significance . Disruptive activity during postnatal development, such as occurs during early life seizures, has complex effects on developing neural circuits relevant to cognition. By mimicking disruption of MS-hippocampal entrainment in an isolated fashion, it may be possible to pinpoint mechanisms through which ELS may affect cognition.

Connectivity and Neuronal Synchrony during Seizures.

There is uncertainty regarding when and which groups of neurons fire synchronously during seizures. While several studies found heterogeneous firing during seizures, others suggested synchronous neuronal firing in the seizure core. We tested whether neuronal activity during seizures is orderly in the direction of the excitatory neuronal connections in the circuit. There are strong excitatory connections laterally within the septotemporally organized lamella and inhibitory trans-lamellar connections in the hippocampus, which allow testing of the connectivity hypothesis. We further tested whether epileptogenesis enhances synchrony and antiseizure drug administration disrupts it. We recorded local field potentials from CA1 pyramidal neurons using a small microelectrode array and kindled rats by a rapid, recurrent hippocampal stimulation protocol. We compared cross-correlation, theta phase synchronization, entropy, and event synchronization. These analyses revealed that the firing pattern was correlated along the lamellar, but not the septotemporal, axis during evoked seizures. During kindling, neuronal synchrony increased along the lamellar axis, while synchrony along the septotemporal axis remained relatively low. Additionally, the theta phase distribution demonstrated that CA1 pyramidal cell firing became preferential for theta oscillation negative peak as kindling progressed in the lamellar direction but not in the trans-lamellar direction. Last, event synchronization demonstrated that neuronal firings along the lamellar axis were more synchronized than those along the septotemporal axis. There was a marked decrease in synchronization and phase preference after treatment with phenytoin and levetiracetam. The synchrony structure of CA1 pyramidal neurons during seizures and epileptogenesis depends on anatomic connectivity and plasticity.SIGNIFICANCE STATEMENT We could improve the efficacy of brain stimulation to treat seizures by understanding the structure of synchrony. Electrical stimulation may disrupt seizures by desynchronizing neurons, but there is an uncertainty on which groups of neurons fire synchronously or chaotically during seizures. Here, we demonstrate that neurons linked by excitatory connections fire synchronously during seizures, and this synchrony is modulated by epileptogenesis and antiseizure drugs. Closed-loop brain stimulation carefully targeted to disrupt synchrony may improve the treatment of seizures.

Chronic limbic epilepsy models for therapy discovery: Protocols to improve efficiency.

There have been recommendations to improve therapy discovery for epilepsy by incorporating chronic epilepsy models into the preclinical process, but unpredictable seizures and difficulties in maintaining drug levels over prolonged periods have been obstacles to using these animals. We report new protocols in which drugs are administered through a new chronic gastric tube to rats with higher seizure frequencies to minimize these obstacles. Adult rats with spontaneous limbic seizures following an episode of limbic status epilepticus induced by electrical hippocampal stimulation were monitored with long-term video- electroencephalography (EEG). Animals with a predetermined baseline seizure frequency received an intragastric tube for drug administration. Carbamazepine, levetiracetam, phenobarbital, and phenytoin were tested with either an acute protocol (an increasing single dose every other day for a maximum of three doses) or with a chronic protocol (multiple administrations of one dose for a week). Drug levels were obtained to correlate the effect with the level. With the acute protocol, all four drugs induced a clear dose-related response. Similar dose-related responses were seen following the week-long dosing protocol for carbamazepine, phenobarbital, and phenytoin, and these responses were associated with drug levels that were in the human therapeutic range. The response to chronic levetiracetam was much less robust. The gastric tube route of administration was well tolerated over a number of months. Using rats with stable, higher seizure frequencies made it possible to identify the potential of a drug to suppress seizures in a realistic model of epilepsy with drug levels that are similar to those of human therapeutic levels. The acute protocol provided a full dose response in 1 week. The chronic administration protocol further differentiated drugs that may be effective long term. The gastric tube facilitates a less stressful, humane, and consistent administration of multiple doses.

Adjust Neuronal Reactions to Pulses of High-Frequency Stimulation with Designed Inter-Pulse-Intervals in Rat Hippocampus In Vivo.

Sequences of electrical pulses have been applied in the brain to treat certain disorders. In recent years, altering inter-pulse-interval (IPI) regularly or irregularly in real time has emerged as a promising way to modulate the stimulation effects. However, algorithms to design IPI sequences are lacking. This study proposed a novel strategy to design pulse sequences with varying IPI based on immediate neuronal reactions. Firstly, to establish the correlationship between the neuronal reactions with varying IPIs, high-frequency stimulations with varying IPI in the range of 5–10 ms were applied at the alveus of the hippocampal CA1 region of anesthetized rats in vivo. Antidromically-evoked population spikes (APS) following each IPI were recorded and used as a biomarker to evaluate neuronal reactions to each pulse. A linear mapping model was established to estimate the varied APS amplitudes by the two preceding IPIs. Secondly, the mapping model was used to derive an algorithm for designing an IPI sequence that would be applied for generating a desired neuronal reaction pre-defined by a particular APS distribution. Finally, examples of stimulations with different IPI sequences designed by the algorithm were verified by rat experiments. The results showed that the designed IPI sequences were able to reproduce the desired APS responses of different distributions in the hippocampal stimulations. The novel algorithm of IPI design provides a potential way to obtain various stimulation effects for brain stimulation therapies.

Saccharin and naltrexone prevent increased pain sensitivity and impaired long-term memory induced by repetitive neonatal noxious stimulation: role of BDNF and enkephalin.

This study aim to examine the hypothesis that repetitive painful stimuli during infancy will alter pain sensitivity and impair learning and memory during adulthood and that saccharin will prevent this through its analgesic effect. Naltrexone is used to examine if saccharin effect is mediated via the endogenous opioid system. Pain in rat pups was induced via needle pricks of the paws on day 1 of their birth (P0). All treatments/ manipulations started on day 1 and continued for 2 weeks. The radial arm water maze (RAWM) test was used to assess learning and memory. Pain threshold through foot-withdrawal response to a hot plate was also assessed. At the end of behavioral tests, animals were killed, hippocampus was dissected, and hippocampal levels of β-endorphin, enkephalin, and brain-derived neurotropic factor (BDNF) were assessed using ELISA. Naltrexone and saccharin combined normalized noxious stimulation induced increased pain sensitivity later in life. Furthermore, naltrexone and saccharin together mitigated the deficiency in learning and memory induced by noxious stimulation. Saccharin treatment prevented reduction in hippocampal enkephalin. Additionally, saccharin prevented hippocampal noxious stimulation induced BDNF decrement. Saccharin prevented long-term memory impairment during adulthood induced by repeated neonatal pain via mechanisms that appear to involve BDNF. Interestingly, naltrexone did not antagonize the effects of saccharin, instead naltrexone augmented saccharin effects.

Prospects for immunotherapy of depression based on cell technologies

IntroductionCell technologies actively used in the treatment of many diseases. These technologies are based on manipulating the patient’s cells outside the body, as a result of which cells acquire a higher therapeutic potential.ObjectivesNo doubt the essential role of immune cells and their biologically active products in the pathogenesis of depression, which allows to view the modulated immune cells as model objects for developing new approaches to immunotherapy for depression.Methods(CBAxC57Bl/6) F1 depressive-like male mice, developed under the long-term social stress, were undergoing the transplantation of syngeneic immune cells with in vitro caffeine-modulated functional activity. Recipient’s behavior, immune and nervous systems functional activity were studied.ResultsIt was found that immune cells isolated from depressive-like mice and treated in vitro with caffeine change their properties and after intravenous administration to syngeneic depressive-like recipients have a significant positive psycho- and neuroimmunomodulatory effects, affecting the main depression pathogenetic mechanisms: behavioral editing (reduction of anhedonia, stimulation of exploratory behavior and activity in the forced swimming test); hippocampal neurogenesis stimulation against the background of increased BDNF; modulation of cytokine production by brain cells, indicating a decrease in neuroinflammation; modulation of the immune system functional activity (stimulation of the immune response, splenocytes proliferation, reducing systemic inflammation, decrease spleen tryptophan catabolism).ConclusionsThe results serve as an experimental substantiation of a fundamentally new approach to immunotherapy of depression based on the introduction of immune cells with functional activity modulated outside the body and open up the possibility of developing new methods of immunotherapy of depressive states in humans.DisclosureNo significant relationships.

Prefrontal α7nAChR Signaling Differentially Modulates Afferent Drive and Trace Fear Conditioning Behavior in Adolescent and Adult Rats.

Increased level of kynurenic acid is thought to contribute to the development of cognitive deficits in schizophrenia through an α7nAChR-mediated mechanism in the prefrontal cortex (PFC). However, it remains unclear to what extent disruption of PFC α7nAChR signaling impacts afferent transmission and its modulation of behavior. Using male rats, we found that PFC infusion of methyllycaconitine (MLA; α7nAChR antagonist) shifts ventral hippocampal-induced local field potential (LFP) suppression to LFP facilitation, an effect only observed in adults. Hippocampal stimulation can also elicit a GluN2B-mediated LFP potentiation (when PFC GABAAR is blocked) that is insensitive to MLA. Conversely, PFC infusion of MLA diminished the gain of amygdalar transmission, which is already enabled by postnatal day (P)30. Behaviorally, the impact of prefrontal MLA on trace fear-conditioning and extinction was also age related. While freezing behavior during conditioning was reduced by MLA only in adults, it elicited opposite effects in adolescent and adult rats during extinction as revealed by the level of reduced and increased freezing response, respectively. We next asked whether the late-adolescent onset of α7nAChR modulation of hippocampal inputs contributes to the age-dependent effect of MLA during extinction. Data revealed that the increased freezing behavior elicited by MLA in adult rats could be driven by a dysregulation of the GluN2B transmission in the PFC. Collectively, these results indicate that distinct neural circuits are recruited during the extinction of trace fear memory in adolescents and adults, likely because of the late-adolescent maturation of the ventral hippocampal-PFC functional connectivity and its modulation by α7nAChR signaling.SIGNIFICANCE STATEMENT Abnormal elevation of the astrocyte-derived metabolite kynurenic acid in the prefrontal cortex (PFC) is thought to impair cognitive functions in schizophrenia through an α7nAChR-mediated mechanism. Here, we found that prefrontal α7nAChR signaling is recruited to control the gain of hippocampal and amygdalar afferent transmission in an input-specific, age-related manner during the adolescent transition to adulthood. Behaviorally, prefrontal α7nAChR modulation of trace fear memory was also age-related, likely because of the late-adolescent maturation of the ventral hippocampal pathway and its recruitment of PFC GABAergic transmission enabled by local α7nAChR signaling. Collectively, these results reveal that distinct α7nAChR-sensitive neural circuits contribute to regulate behavior responses in adolescents and adults, particularly those requiring proper integration of hippocampal and amygdalar inputs by the PFC.

Long-Term Effects of Hippocampal Low-Frequency Stimulation on Pro-Inflammatory Factors and Astrocytes Activity in Kindled Rats.

Objective Epilepsy is accompanied by inflammation, and the anti-inflammatory agents may have anti-seizure effects. In this investigation, the effect of deep brain stimulation, as a potential therapeutic approach in epileptic patients, was investigated on seizure-induced inflammatory factors. Materials and Methods In the present experimental study, rats were kindled by chronic administration of pentylenetetrazol (PTZ; 34 mg/Kg). The animals were divided into intact, sham, low-frequency deep brain stimulation (LFS), kindled, and kindled +LFS groups. In kindled+LFS and LFS groups, animals received four trains of intra-hippocampal low-frequency deep brain stimulation (LFS) at 20 minutes, 6, 24, and 30 hours after the last PTZ injection. Each train of LFS contained 200 pulses at 1 Hz, 200 µA, and 0.1 ms pulse width. One week after the last PTZ injection, the Y-maze test was run, and then the rats’ brains were removed, and hippocampal samples were extracted for molecular assessments. The gene expression of two pro-inflammatory factors [interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α)], and glial fibrillary acidic protein (GFAP) immunoreactivity (as a biological marker of astrocytes reactivation) were evaluated. Results Obtained results showed a significant increase in the expression of of interleukin-6 (IL-6), tumor necrosis factor (TNF)-α, and GFAP at one-week post kindling seizures. The application of LFS had a long-lasting effect and restored all of the measured changes toward normal values. These effects were gone along with the LFS improving the effect on working memory in kindled animals. ConclusionThe anti-inflammatory action of LFS may have a role in its long-lasting improving effects on seizure-induced cognitive disorders.

Hippocampal low-frequency stimulation prevents seizure generation in a mouse model of mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy (MTLE) is the most common form of focal, pharmacoresistant epilepsy in adults and is often associated with hippocampal sclerosis. Here, we established the efficacy of optogenetic and electrical low-frequency stimulation (LFS) in interfering with seizure generation in a mouse model of MTLE. Specifically, we applied LFS in the sclerotic hippocampus to study the effects on spontaneous subclinical and evoked generalized seizures. We found that stimulation at 1 Hz for 1 hr resulted in an almost complete suppression of spontaneous seizures in both hippocampi. This seizure-suppressive action during daily stimulation remained stable over several weeks. Furthermore, LFS for 30 min before a pro-convulsive stimulus successfully prevented seizure generalization. Finally, acute slice experiments revealed a reduced efficacy of perforant path transmission onto granule cells upon LFS. Taken together, our results suggest that hippocampal LFS constitutes a promising approach for seizure control in MTLE.

Long-term seizure outcome during continuous bipolar hippocampal deep brain stimulation in patients with temporal lobe epilepsy with or without mesial temporal sclerosis: An observational, open-label study.

We present the findings related to seizure outcome during hippocampal deep brain stimulation (Hip-DBS) in patients with refractory temporal lobe epilepsy. Twenty-five patients submitted to Hip-DBS were studied. All patients were evaluated with interictal and ictal electroencephalography (EEG) and high-resolution 1.5T magnetic resonance imaging (MRI). The hippocampus was targeted directly on MRI using a posterior occipital burr hole approach. Bipolar continuous stimulation was ramped up until 3.0V (300µs, 130Hz). Patients were considered responders if at least 50% seizure frequency reduction was obtained. Median age was 39years; median follow-up time was 57months (16 women). All patients had focal with impaired awareness seizure (FIAS) and 23 patients had focal aware seizure (FAS). Baseline median FAS and FIAS frequency was 8. Ictal EEG showed unilateral (n=10) or bilateral (n=15) seizure onset. MRI showed unilateral (n=11) or bilateral (n=8) mesial temporal sclerosis (MTS) and was normal in six6 patients. Fifteen patients were submitted to bilateral and 10 patients to unilateral Hip-DBS. Median reduction in FAS frequency was 66%. Eighteen patients with FAS were considered responders and five (21%) were free of FAS. Median FIAS frequency (n=25) reduction was 91%. Twenty-two patients were considered responders and eight (32%) were free of FIAS. FIAS were significantly more reduced then FAS (P=.017). There was no relation between any contact's position within the hippocampus and outcome for either FAS (P=.727) or FIAS (P=.410). There was no difference in outcome in patients submitted to either unilateral or bilateral Hip-DBS regarding FAS (P=.978) or FIAS (P=.693). Hip-DBS significantly reduced the frequency of both FAS and FIAS in this cohort of patients with refractory temporal lobe epilepsy. Hip-DBS might represent a good therapeutic option in such patients not amenable to resective surgery.

Electrical Stimulation of Subiculum for the Treatment of Refractory Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis: A 2-Year Follow-Up Study

Introduction: Evidence has been provided that the subiculum may play an important role in the generation of seizures. Electrical stimulation at this target has been reported to have anticonvulsive effects in kindling and pilocarpine rat models, while in a clinical study of hippocampal deep brain stimulation (DBS), contacts closest to the subiculum were associated with a better anticonvulsive effect. Objectives: To evaluate the effect of electrical stimulation of the subiculum in patients with refractory mesial temporal lobe epilepsy (MTLE) who have hippocampal sclerosis (HS). Methods: Six patients with refractory MTLE and HS, who had focal impaired awareness seizures (FIAS) and focal to bilateral tonic-clonic seizures (FBTCS), had DBS electrodes implanted in the subiculum. During the first month after implantation, all patients were OFF stimulation, then they all completed an open-label follow-up of 24 months ON stimulation. DBS parameters were set at 3 V, 450 µs, 130 Hz, cycling stimulation 1 min ON, 4 min OFF. Results: There was a mean reduction of 49.16% (±SD 41.65) in total seizure number (FIAS + FBTCS) and a mean reduction of 67.93% (±SD 33.33) in FBTCS at 24 months. FBTCS decreased significantly with respect to baseline, starting from month 2 ON stimulation. Conclusions: Subiculum stimulation is effective for FBTCS reduction in patients with MTLE and HS, suggesting that the subiculum mediates the generalization rather than the genesis of mesial temporal lobe seizures. Better results are observed at longer follow-up times.

Study on the mechanism of high-frequency stimulation inhibiting low-Mg2+-induced epileptiform discharges in juvenile rat hippocampal slices

Study on the mechanism of high-frequency stimulation inhibiting low-Mg2+-induced epileptiform discharges in juvenile rat hippocampal slicesHigh-frequency stimulation (HFS) has been demonstrated to be an effective treatment for inhibiting epilepsy in some clinical and laboratory studies. However, the mechanisms underlying the therapeutic effects of HFS are not yet fully understood. In our present study, epileptiform discharges (EDs) in acutely isolated hippocampal slices of male Sprague–Dawley (SD) juvenile rats induced by low-Mg2+ artificial cerebrospinal fluid (ACSF), and electrical stimulation (square wave, 900 pulses, 50 % duty-cycle, 130 Hz) was performed on the CA3 using concentric bipolar electrodes. EDs of neurons in hippocampal were recorded by multi-electrode arrays (MEA). After stable EDs events had been recorded for at least 20 min, HFS was added, followed by 10 μmol/L gamma-aminobutyric acid type A (GABAA) receptors blocker bicuculline (BIC). The results show that the HFS can increase the discharges frequency of inter-ictal discharges (IIDs) and decrease the duration of ictal discharges (IDs). However, the HFS had no effect on the slices with 10 μmol/L BIC. These results indicated that the GABAA receptors are activated when HFS inhibited EDs, thereby achieving the inhibition of low-Mg2+-induced EDs in slices.

Disruption of hippocampal rhythms via optogenetic stimulation during the critical period for memory development impairs spatial cognition

BackgroundHippocampal oscillations play a critical role in the ontogeny of allocentric memory in rodents. During the critical period for memory development, hippocampal theta is the driving force behind the temporal coordination of neuronal ensembles underpinning spatial memory. While known that hippocampal oscillations are necessary for normal spatial cognition, whether disrupted hippocampal oscillatory activity during the critical period impairs long-term spatial memory is unknown. Here we investigated whether disruption of normal hippocampal rhythms during the critical period have enduring effects on allocentric memory in rodents. Objective/hypothesisWe hypothesized that disruption of hippocampal oscillations via artificial regulation of the medial septum during the critical period for memory development results in long-standing deficits in spatial cognition. MethodsAfter demonstrating that pan-neuronal medial septum (MS) optogenetic stimulation (465 nm activated) regulated hippocampal oscillations in weanling rats we used a random pattern of stimulation frequencies to disrupt hippocampal theta rhythms for either 1Hr or 5hr a day between postnatal (P) days 21–25. Non-stimulated and yellow light-stimulated (590 nm) rats served as controls. At P50-60 all rats were tested for spatial cognition in the active avoidance task. Rats were then sacrificed, and the MS and hippocampus assessed for cell loss. Power spectrum density of the MS and hippocampus, coherences and voltage correlations between MS and hippocampus were evaluated at baseline for a range of stimulation frequencies from 0.5 to 110 Hz and during disruptive hippocampal stimulation. Unpaired t-tests and ANOVA were used to compare oscillatory parameters, behavior and cell density in all animals. ResultsNon-selective optogenetic stimulation of the MS in P21 rats resulted in precise regulation of hippocampal oscillations with 1:1 entrainment between stimulation frequency (0.5–110 Hz) and hippocampal local field potentials. Across bandwidths MS stimulation increased power, coherence and voltage correlation at all frequencies whereas the disruptive stimulation increased power and reduced coherence and voltage correlations with most statistical measures highly significant (p < 0.001, following correction for false detection). Rats receiving disruptive hippocampal stimulation during the critical period for memory development for either 1Hr or 5hr had marked impairment in spatial learning as measured in active avoidance test compared to non-stimulated or yellow light-control rats (p < 0.001). No cell loss was measured between the blue-stimulated and non-stimulated or yellow light-stimulated controls in either the MS or hippocampus. ConclusionThe results demonstrated that robust regulation of hippocampal oscillations can be achieved with non-selective optogenetic stimulation of the MS in rat pups. A disruptive hippocampal stimulation protocol, which markedly increases power and reduces coherence and voltage correlations between the MS and hippocampus during the critical period of memory development, results in long-standing spatial cognitive deficits. This spatial cognitive impairment is not a result of optogenetic stimulation-induced cell loss.

Thalamic Stimulation Improves Postictal Cortical Arousal and Behavior.

The postictal state following seizures is characterized by impaired consciousness and has a major negative impact on individuals with epilepsy. Previous work in disorders of consciousness including the postictal state suggests that bilateral deep brain stimulation (DBS) of the thalamic intralaminar central lateral nucleus (CL) may improve level of arousal. We tested the effects of postictal thalamic CL DBS in a rat model of secondarily generalized seizures elicited by electrical hippocampal stimulation. Thalamic CL DBS was delivered at 100 Hz during the postictal period in 21 female rats while measuring cortical electrophysiology and behavior. The postictal period was characterized by frontal cortical slow waves, like other states of depressed consciousness. In addition, rats exhibited severely impaired responses on two different behavioral tasks in the postictal state. Thalamic CL stimulation prevented postictal cortical slow wave activity but produced only modest behavioral improvement on a spontaneous licking sucrose reward task. We therefore also tested responses using a lever-press shock escape/avoidance (E/A) task. Rats achieved high success rates responding to the sound warning on the E/A task even during natural slow wave sleep but were severely impaired in the postictal state. Unlike the spontaneous licking task, thalamic CL DBS during the E/A task produced a marked improvement in behavior, with significant increases in lever-press shock avoidance with DBS compared with sham controls. These findings support the idea that DBS of subcortical arousal structures may be a novel therapeutic strategy benefitting patients with medically and surgically refractory epilepsy.SIGNIFICANCE STATEMENT The postictal state following seizures is characterized by impaired consciousness and has a major negative impact on individuals with epilepsy. For the first time, we developed two behavioral tasks and demonstrate that bilateral deep brain stimulation (DBS) of the thalamic intralaminar central lateral nucleus (CL) decreased cortical slow wave activity and improved task performance in the postictal period. Because preclinical task performance studies are crucial to explore the effectiveness and safety of DBS treatment, our work is clinically relevant as it could support and help set the foundations for a human neurostimulation trial to improve postictal responsiveness in patients with medically and surgically refractory epilepsy.

Long-term efficacy and cognitive effects of bilateral hippocampal deep brain stimulation in patients with drug-resistant temporal lobe epilepsy.

Temporal lobe epilepsy patients treated with hippocampal deep brain stimulation (Hip-DBS) have rarely been reported before. Preoperative and postoperative cognitive function is seldom analyzed. Seven patients with drug-resistant temporal lobe epilepsy were included in this study. Bilateral Hip-DBS was performed in these patients. The stimulator was activated 1month after the implantation. Then, the patients returned for further adjustments 4months after the surgery and reprogramming every year. The seizure frequency, Wechsler Adult Intelligence Scale-IV, and Wechsler memory scale-IV were assessed blindly as the outcomes at each follow-up. After a mean 48-month follow-up, the mean seizure frequency significantly decreased (p = 0.011, paired t test; decrease of 78.1%). One patient (14.3%) was seizure-free by the last follow-up; six of seven (85.7%) patients had reductions in seizure frequency of at least 50%; one patient (14.3%) who did not comply with the antiepileptic drug instructions had a less than 50% reduction in seizure frequency. In addition, there were no significant decreases in intelligence or verbal and visual memory from baseline to the last follow-up (p = 0.736, paired t test; p = 0.380, paired t test, respectively). Hip-DBS could provide acceptable long-term efficacy and safety. For patients with drug-resistant temporal lobe epilepsy who are not suitable for resective surgery, Hip-DBS could become a potential therapeutic option.