Hippocampal Deep Brain Stimulation Research Articles

Deep brain stimulation of hippocampus in treatment of refractory temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most common cause of focal onset seizures, affecting 40% of adolescents and adults with epilepsy. TLE is also one of the most common drug resistant forms of epilepsy. Surgical resection remains the treatment of choice for TLE, but not all patients with TLE are suitable candidates for resective neurosurgery. For such patients, deep brain stimulation (DBS) of the hippocampus remains a reversible and efficient treatment alternative. We undertook a systematic review of the literature on hippocampal DBS efficacy and safety in the management of patients with TLE. A search using two electronic databases, the Medical Literature, Analysis, and Retrieval System on-line (MEDLINE) and the Cochrane Central Register of Controlled Trials (CEN-TRAL), was conducted. We found 14 articles related to hippocampal DBS for the treatment of TLE. The responder rate (defined as at least 50% reduction in seizure frequency) for all patients was 83.4%, Of 99 patients treated by hippocampal DBS, 82 were regarded as responders, and 17 as non-responders. Hippocampal DBS appears to be a safe and efficacious treatment alternative for patients who are not candidates for temporal lobectomy or selective amygdalohippocampectomy due to serious postoperative cognitive deficits. In selected patients with TLE, this neuromodulatory therapy may be very safe and efficacious.

Effect of the closed-loop hippocampal low-frequency stimulation on seizure severity, learning, and memory in pilocarpine epilepsy rat model.

In this study, the anticonvulsant action of closed-loop, low-frequency deep brain stimulation (DBS) was investigated. In addition, the changes in brain rhythms and functional connectivity of the hippocampus and prefrontal cortex were evaluated. Epilepsy was induced by pilocarpine in male Wistar rats. After the chronic phase, a tripolar electrode was implanted in the right ventral hippocampus and a monopolar electrode in medial prefrontal cortex (mPFC). Subjects' spontaneous seizure behaviors were observed in continuous video recording, while the local field potentials (LFPs) were recorded simultaneously. In addition, spatial memory was evaluated by the Barnes maze test. Applying hippocampal DBS, immediately after seizure detection in epileptic animals, reduced their seizure severity and duration, and improved their performance in Barnes maze test. DBS reduced the increment in power of delta, theta, and gamma waves in pre-ictal, ictal, and post-ictal periods. Meanwhile, DBS increased the post-ictal-to-pre-ictal ratio of theta band. DBS decreased delta and increased theta coherences, and also increased the post-ictal-to-pre-ictal ratio of coherence. In addition, DBS increased the hippocampal-mPFC coupling in pre-ictal period and decreased the coupling in the ictal and post-ictal periods. Applying closed-loop, low-frequency DBS at seizure onset reduced seizure severity and improved memory. In addition, the changes in power, coherence, and coupling of the LFP oscillations in the hippocampus and mPFC demonstrate low-frequency DBS efficacy as an antiepileptic treatment, returning LFPs to a seemingly non-seizure state in subjects that received DBS.

Deep brain stimulation targets in epilepsy: Systematic review and meta-analysis of anterior and centromedian thalamic nuclei and hippocampus.

Deep brain stimulation (DBS) is a neuromodulatory treatment used in patients with drug-resistant epilepsy (DRE). The primary goal of this systematic review and meta-analysis is to describe recent advancements in the field of DBS for epilepsy, to compare the results of published trials, and to clarify the clinical utility of DBS in DRE. A systematic literature search was performed by two independent authors. Forty-four articles were included in the meta-analysis (23 for anterior thalamic nucleus [ANT], 8 for centromedian thalamic nucleus [CMT], and 13 for hippocampus) with a total of 527 patients. The mean seizure reduction after stimulation of the ANT, CMT, and hippocampus in our meta-analysis was 60.8%, 73.4%, and 67.8%, respectively. DBS is an effective and safe therapy in patients with DRE. Based on the results of randomized controlled trials and larger clinical series, the best evidence exists for DBS of the anterior thalamic nucleus. Further randomized trials are required to clarify the role of CMT and hippocampal stimulation. Our analysis suggests more efficient deep brain stimulation of ANT for focal seizures, wider use of CMT for generalized seizures, and hippocampal DBS for temporal lobe seizures. Factors associated with clinical outcome after DBS for epilepsy are electrode location, stimulation parameters, type of epilepsy, and longer time of stimulation. Recent advancements in anatomical targeting, functional neuroimaging, responsive neurostimulation, and sensing of local field potentials could potentially lead to improved outcomes after DBS for epilepsy and reduced sudden, unexpected death of patients with epilepsy. Biomarkers are needed for successful patient selection, targeting of electrodes and optimization of stimulation parameters.

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.

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.

Deep brain stimulation reduces evoked potentials with a dual time course in freely moving rats: Potential neurophysiological basis for intermittent as an alternative to continuous stimulation.

Deep brain stimulation (DBS) is an increasingly applied treatment for various neuropsychiatric disorders including drug-resistant epilepsy, and it may be optimized by rationalizing the stimulation protocol based on increased knowledge of its mechanism of action. We evaluated the effects of minutes to hours of hippocampal DBS on hippocampal evoked potentials (EPs) and local field potentials (LFPs) in freely moving male rats to further investigate some of the previously proposed mechanisms of action. Hippocampal high-frequency (130Hz) DBS was administered for 0, 1, or 6min every 10min for 160min. Stimulation parameter settings were similar to those that had previously been shown to reduce seizures in epileptic rats. EPs and LFPs were recorded in the stimulation-free intervals. We investigated both the immediate temporary effects of 1 or 6min of DBS and the effects of 160min of intermittent DBS. Input specificity was investigated by using two different stimulation electrodes. Relatively low DBS intensities corresponding to only 1.8% of the intensity evoking a maximum EP were required to prevent unintended seizure occurrence in healthy rats. Both 1 and 6min of DBS caused input-specific short-lasting (<60 s) reductions (5%-7%) of the field excitatory postsynaptic potential (fEPSP) slope (P=.005). We observed longer-lasting, input-specific EP reductions during the 160min intermittent DBS, with statistically significant reductions (3%-4%) of the fEPSP slope (P=.009-.018). The LFP spectrogram remained unaltered. Deep brain stimulation induced both acute temporary effects compatible with axonal block and/or synaptic depression, and longer-lasting potentially cumulative EP reductions, suggesting the involvement of homeostatic plasticity or long-term depression. This dual time course may parallel the different temporal patterns of improvement observed in clinical trials. The longer-lasting reductions provide a potential neurophysiological basis for the use of intermittent DBS-as typically used in epilepsy patients-as an alternative to continuous DBS.

Activation of NMDA receptor ion channels by deep brain stimulation in the pig visualised with [18F]GE-179 PET

BackgroundNo PET radioligand has yet demonstrated the capacity to map glutamate N-methyl-d-aspartate receptor ion channel (NMDAR-IC) function. [18F]GE-179 binds to the phencyclidine (PCP) site in open NMDAR-ICs and potentially provides a use-dependent PET biomarker of these ion channels. ObjectiveTo show [18F]GE-179 PET can detect increased NMDAR-IC activation during electrical deep brain stimulation (DBS) of pig hippocampus. MethodsSix minipigs had an electrode implanted into their right hippocampus. They then had a baseline [18F]GE-179 PET scan with DBS turned off followed by a second scan with DBS turned on. Brain [18F]GE-179 uptake at baseline and then during DBS was measured with PET. Cerebral blood flow (CBF) was measured with [15O]H2O PET at baseline and during DBS and parametric CBF images were generated to evaluate DBS induced CBF changes. Functional effects of injecting the PCP blocker MK-801 were also evaluated. Electrode positions were later histologically verified. ResultsDBS induced a 47.75% global increase in brain [18F]GE-179 uptake (p = 0.048) compared to baseline. Global CBF was unchanged by hippocampal DBS. [18F]GE-179 PET detected a 5% higher uptake in the implanted compared with the non-implanted temporo-parietal cortex at baseline (p = 0.012) and during stimulation (p = 0.022). Administration of MK-801 before DBS failed to block [18F]GE-179 uptake during stimulation. ConclusionPET detected an increase in global brain [18F]GE-179 uptake during unilateral hippocampal DBS while CBF remained unchanged. These findings support that [18F]GE-179 PET provides a use-dependent marker of abnormal NMDAR-IC activation.

Optogenetic inhibition of ventral hippocampal neurons alleviates associative motor learning dysfunction in a rodent model of schizophrenia.

Schizophrenia (SZ) is a serious and incurable mental disorder characterized by clinical manifestations of positive and negative symptoms and cognitive dysfunction. High-frequency deep brain stimulation (DBS) of the ventral hippocampus (VHP) has been recently applied as a therapeutic approach for SZ in both experimental and clinical studies. However, little is known about the precise mechanism of VHP-DBS treatment for SZ and the role of hippocampal cell activation in the pathogenesis of SZ. With optogenetic technology in this study, we tried to inhibit neuronal activity in the VHP which has dense projections to the prefrontal cortex, before measuring long stumulus-induced delay eyeblink conditioning (long-dEBC) in a rodent model of SZ. Rats were administrated with phencyclidine (PCP, 3 mg/kg, 1/d, ip) for successive 7 days before optogenetic intervention. The current data show that PCP administration causes significant impairment in the acquisition and timing of long-dEBC; the inhibition of bilateral VHP neurons alleviates the decreased acquisition and impaired timing of longd-dEBC in PCP-administered rats. The results provide direct evidence at the cellular level that the inhibition of VHP neuronal cells may be a prominent effect of hippocampal DBS intervention, and increased activity in the hippocampal network play a pivotal role in SZ.

Seizure outcome after hippocampal deep brain stimulation in patients with refractory temporal lobe epilepsy: A prospective, controlled, randomized, double-blind study.

We designed a prospective, randomized, controlled, double-blind study to evaluate the efficacy of hippocampal deep brain stimulation (Hip-DBS) in patients with refractory temporary lobe epilepsy (TLE). Sixteen adult patients with refractory TLE were studied. Patient's workup included medical history, interictal and ictal electroencephalography (EEG), and high-resolution 1.5T magnetic resonance imaging (MRI). Patients were randomized on a 1:1 proportion to an active (stimulation on) or to a control (no stimulation) arm. After implantation, patients were allowed to recover for 1 month, which was followed by a 1-month titration (or sham) period. The 6-month blinded phase started immediately afterward. A postoperative MRI confirmed the electrode's position in all patients. All patients received bipolar continuous stimulation. Stimulus duration was 300 μs and frequency was 130 Hz; final intensity was 2 V. Patients were considered responders when they had at least 50% seizure frequency reduction. All patients had focal impaired awareness seizures (FIAS, complex partial seizures), and 87% had focal aware seizures (FAS, simple partial seizures). Mean preoperative seizure frequency was 12.5 ± 9.4 (mean ± standard deviation) per month. MRI findings were normal in two patients, disclosed bilateral mesial temporal sclerosis (MTS) in three, left MTS in five, and right MTS in six patients. An insertional effect could be noted in both control and active patients. In the active group (n = 8), four patients became seizure-free; seven of eight were considered responders and one was a nonresponder. There was a significant difference regarding FIAS frequency between the two groups from the first month of full stimulation (p < 0.001) until the end of the blinded phase (p < 0.001). This was also true for FAS, except for the third month of the blinded phase. Hip-DBS was effective in significantly reducing seizure frequency in patients with refractory TLE in the active group, as compared to the control group. Fifty-percent of the patients in the active group became seizure-free. The present study is the larger prospective, controlled, double-blind study to evaluate the effects of Hip-DBS published to date.

Deep brain and cortical stimulation for epilepsy.

Deep brain and cortical stimulation for epilepsy.

Hippocampal deep brain stimulation in nonlesional refractory mesial temporal lobe epilepsy

PurposeTo evaluate the efficacy of chronic continuous hippocampal deep brain stimulation (DBS) in nonlesional refractory mesial temporal lobe epilepsy. MethodsThree adult patients with medically intractable epilepsy treated with hippocampal DBS were studied. Two patients underwent invasive recordings with depth stereo-electroencephalography (SEEG) electrodes to localize ictal onset zone prior to implantation of DBS electrodes. All the patients with no lesion in brain magnetic resonance imaging (MRI) scan received bilateral implantation of DBS electrodes. Chronic continuous high-frequency hippocampal stimulation was applied during treatment. The number of seizures in each patient before and after stimulation was compared. ResultsLong-term hippocampal stimulation produced a median reduction in seizure frequency of 93%. Two out of these patients received unilateral activation of the electrodes and experienced a 95% and 92% reduction in seizure frequency after hippocampal DBS respectively. The last patient had bilateral electrode activation and had a seizure-frequency reduction of 91%. None of the patients had neuropsychological deterioration and showed side effects. Generalized tonic–clonic seizures disappeared completely after hippocampal DBS. ConclusionsChronic continuous hippocampal DBS demonstrated a potential efficiency and safety in nonlesional refractory mesial temporal lobe epilepsy and might represent an effective therapeutic option for these patients.

ID 178 – Longitudinal simultaneous DBS fMRI in the rodent brain

Objective The effects of Deep Brain Stimulation (DBS) have been studied primarily by electrophysiological and neurochemical studies, which lack the ability to elucidate DBS-related responses on a whole-brain scale. With this study our aim is to investigate DBS-induced global neuronal network activation in rats with functional Magnetic Resonance Imaging (fMRI). Methods Three times FMRI was done in seven rats, which were stereotactically implanted with a MR-compatible DBS-electrode in the right hippocampus. High frequency Poisson distributed stimulation was applied using a block-design paradigm. Response maps ( p Results Our data indicate that real-time hippocampal DBS evokes a uni- or bilateral BOLD response in hippocampal and mesolimbic structures, depending on the applied stimulation intensity. Results were reproducible in time and in-between subjects. Conclusions We present that DBS-fMRI can be used to detect whole-brain responses to circuit activation with different stimulation intensities, making this technique potentially powerful for exploring DBS-induced cerebral changes for preclinical and clinical DBS. Key message A better understanding of the whole-brain effect of DBS is necessary to improve treatment efficacy in patients. Successful translation of this research to patients might reduce the number of non-responders to this invasive and expensive treatment.

Functional MRI during Hippocampal Deep Brain Stimulation in the Healthy Rat Brain.

Deep Brain Stimulation (DBS) is a promising treatment for neurological and psychiatric disorders. The mechanism of action and the effects of electrical fields administered to the brain by means of an electrode remain to be elucidated. The effects of DBS have been investigated primarily by electrophysiological and neurochemical studies, which lack the ability to investigate DBS-related responses on a whole-brain scale. Visualization of whole-brain effects of DBS requires functional imaging techniques such as functional Magnetic Resonance Imaging (fMRI), which reflects changes in blood oxygen level dependent (BOLD) responses throughout the entire brain volume. In order to visualize BOLD responses induced by DBS, we have developed an MRI-compatible electrode and an acquisition protocol to perform DBS during BOLD fMRI. In this study, we investigate whether DBS during fMRI is valuable to study local and whole-brain effects of hippocampal DBS and to investigate the changes induced by different stimulation intensities. Seven rats were stereotactically implanted with a custom-made MRI-compatible DBS-electrode in the right hippocampus. High frequency Poisson distributed stimulation was applied using a block-design paradigm. Data were processed by means of Independent Component Analysis. Clusters were considered significant when p-values were <0.05 after correction for multiple comparisons. Our data indicate that real-time hippocampal DBS evokes a bilateral BOLD response in hippocampal and other mesolimbic structures, depending on the applied stimulation intensity. We conclude that simultaneous DBS and fMRI can be used to detect local and whole-brain responses to circuit activation with different stimulation intensities, making this technique potentially powerful for exploration of cerebral changes in response to DBS for both preclinical and clinical DBS.

Seizure Outcome After Battery Depletion in Epileptic Patients Submitted to Deep Brain Stimulation.

We studied patients treated with chronic DBS in whom there was depletion of the generator's battery, in order to get insight on the modulatory potential of chronic DBS in refractory epilepsy. Nine adult patients with refractory epilepsy treated with at least three years of deep brain stimulation (DBS), and who were followed up for at least six months after battery depletion were studied. One patient was treated with hippocampal DBS (Hip-DBS), two to centro-median DBS (CM-DBS) and six to anterior nucleus stimulation (AN-DBS). Two patients did not have seizure's frequency modification after battery depletion; the other seven patients had seizure frequency increase, including those three patients that were seizure-free. Five of those seven patients who had seizure frequency increase after battery's depletion had seizure's frequency lower than their pre-DBS baseline seizure frequency; two of such patients returned to their pre-DBS baseline seizure frequency. In the majority of the patients, three years of chronic DBS did not show a permanent effect on epileptogenesis. On the other hand, the post-battery depletion seizure's frequency was usually much lower than the baseline (pre-DBS) seizure's frequency, suggesting that there was actual network neuromodulation.

In search of optimal DBS paradigms to treat epilepsy: bilateral versus unilateral hippocampal stimulation in a rat model for temporal lobe epilepsy.

In many temporal lobe epilepsy (TLE) patients both hippocampi are seizure onset zones. These patients are unsuitable candidates for epilepsy surgery but may be amenable to hippocampal deep brain stimulation (DBS). The optimal DBS parameters for these patients are unknown. Recent observations suggest that even in patients with a unilateral focus switching from unilateral hippocampal DBS to bilateral hippocampal DBS could improve seizure control. Compare the effect of unilateral with bilateral hippocampal DBS on seizures in a rat model for TLE. In the post status epilepticus (SE) kainic acid rat model for TLE continuous EEG monitoring was performed for 50 days during which rats were subjected to 10 days of unilateral and 10 days of bilateral Poisson-distributed high frequency hippocampal DBS in a cross-over trial. During bilateral DBS, each hippocampus was stimulated with a separate stimulator and its own generated Poisson distribution with a mean and variance of 1/130s. Electrographic seizure rate was 23% lower during bilateral compared to unilateral hippocampal DBS (P<0.05). No effect of unilateral nor bilateral hippocampal DBS was observed on seizure duration. When bilateral hippocampal DBS was applied, lower stimulation intensities were required to evoke after discharges (P<0.05), reflecting a higher potency of bilateral hippocampal DBS compared to unilateral hippocampal DBS to affect hippocampal networks. Superior outcome in seizure control with bilateral compared to unilateral hippocampal DBS indicates that targeting larger regions of the hippocampal formation with more than one stimulation electrode may be more successful in suppressing seizures in TLE.

Hippocampal deep brain stimulation reduces glucose utilization in the healthy rat brain.

The effects of deep brain stimulation (DBS) have been studied primarily by cellular studies, which lack the ability to elucidate DBS-related responses on a whole-brain scale. 2-Deoxy-2-[(18)F]fluoro-D-glucose positron emission tomography ([(18)F]FDG-PET) reflects changes in neural activity throughout the entire brain volume. The aim of this study was to investigate the whole-brain effect of DBS on the glucose utilization in healthy rats. Seven rats were implanted with a DBS electrode in the right hippocampus and injected with [(18)F]FDG to measure the glucose metabolism during DBS. Analysis reveals significant DBS-induced decreases in the glucose metabolism in the bilateral hippocampus and other limbic structures. This study demonstrates that DBS exhibits not only a local effect around the electrode tip but also in other limbic regions. [(18)F]FDG-PET studies have the potential to provide better insight into the mechanism of action of DBS by simultaneously observing activity at multiple sites in the brain.

Deep brain and cortical stimulation for epilepsy.

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.

Brain Stimulation for Epilepsy – Local and Remote Modulation of Network Excitability

The use of Deep Brain Stimulation (DBS) as a potential therapy for treatment resistant epilepsy remains an area of active clinical investigation. We recently reported the first chronic evaluation of an implantable, clinical-grade system that permits concurrent stimulation and recording, in a large animal (ovine) model developed to study DBS for epilepsy. In this study we extended this work to compare the effects of remote (anterior thalamic) and direct (hippocampal) stimulation on local field potential (LFP) activity and network excitability, and to assess closed-loop stimulation within this neural network. Following anesthesia and 1.5T MRI acquisition, unilateral anterior thalamic and hippocampal DBS leads were implanted in three subjects using a frameless stereotactic system. Chronic, awake recordings of evoked potentials (EPs) and LFPs in response to thalamic and hippocampal stimulation were collected with the implanted device and analyzed off-line. Consistent with earlier reports, thalamic DBS and direct stimulation of the hippocampus produced parameter-dependent effects on hippocampal activity. LFP suppression could be reliably induced with specific stimulation parameters, and was shown to reflect a state of reduced network excitability, as measured by effects on hippocampal EP amplitudes and after-discharge thresholds. Real-time modulation of network excitability via the implanted device was demonstrated using hippocampal theta-band power level as a control signal for closed-loop stimulation. The results presented provide evidence of network excitability changes induced by stimulation that could underlie the clinical effects that have been reported with both thalamic and direct cortical stimulation.

Hippocampal DBS affects disease development in the kainic acid rat model for temporal lobe epilepsy

Hippocampal DBS affects disease development in the kainic acid rat model for temporal lobe epilepsy