Anterior Nucleus Of The Thalamus Deep Brain Stimulation Research Articles

Combination of or Transition between Deep Brain Stimulation and Responsive Neurostimulation for the Treatment of Drug-Resistant Epilepsy

Introduction: Neuromodulation is an important treatment modality for patients with drug-resistant epilepsy who are not candidates for resective or ablative procedures. However, randomized controlled trials and real-world studies reveal that a subset of patients will experience minimal reduction or even an increase in seizure frequency after neuromodulation. We describe our experience with patients who undergo a second intracranial neuromodulation procedure after unsatisfactory initial response to intracranial neuromodulation. Methods: We performed a retrospective chart review to identify all patients who had undergone deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) or responsive neurostimulation (RNS), followed by additional intracranial neuromodulatory procedures, with at least 12 months of follow-up. Demographic and clinical data, including seizure frequencies, were collected. Results: All patients had temporal lobe epilepsy. Six patients were treated with concurrent ANT DBS and temporal lobe RNS, and 3 patients transitioned between neuromodulation systems. Of the patients treated concurrently with ANT DBS and temporal lobe RNS, 5 of the 6 patients experienced additional reduction in seizure frequency after adding a second neuromodulation system. Of the patients who switched between neuromodulation modalities, all patients experienced further reduction in seizure frequency. Conclusions: For patients who do not experience adequate benefit from initial therapy with ANT DBS or temporal lobe RNS, the addition of a neuromodulation system or switching to a different form of neuromodulation may allow for additional reduction in seizure frequency. Larger studies will need to be performed to understand whether the use of multiple systems concurrently leads to improved clinical results in patients who are initially treatment resistant to neuromodulation.

Functional network dynamics between the anterior thalamus and the cortex in deep brain stimulation for epilepsy.

Due to its unique connectivity profile with cortical brain regions, and its suggested role in the subcortical propagation of seizures, the Anterior Nucleus of the Thalamus (ANT) has been proposed as a key Deep Brain Stimulation (DBS) target in drug-resistant epilepsy (DRE). However, the spatio-temporal interaction dynamics of this brain structure, and the functional mechanisms underlying ANT DBS in epilepsy, remain unknown. Here, we study how the ANT interacts with the neocortex in vivo in humans and provide a detailed neurofunctional characterization of mechanisms underlying the effectiveness of ANT DBS, aiming at defining intraoperative neural biomarkers of responsiveness to therapy, assessed at 6 months post-implantation as the reduction in seizure frequency. A cohort of 15 DRE (N = 6 males, age = ) patients underwent bilateral ANT DBS implantation. Using intraoperative cortical and ANT simultaneous electrophysiological recordings, we found that the ANT is characterized by high amplitude (4-8 Hz) oscillations, mostly in its superior part. The strongest functional connectivity between the ANT and the scalp EEG was also found in the band in ipsilateral centro-frontal regions. Upon intraoperative stimulation in the ANT, we found a decrease in higher EEG frequencies (20-70 Hz) and a generalized increase in scalp-to-scalp connectivity. Crucially, we observed that responders to ANT DBS treatment were characterized by higher EEG oscillations, higher power in the ANT, and stronger ANT-to-scalp θ connectivity, highlighting the crucial role of oscillations in the dynamical network characterization of these structures. Our study provides a comprehensive characterization of the interaction dynamic between the ANT and the cortex, delivering crucial information to optimize and predict clinical DBS response in patients with DRE.

Deep brain stimulation of the anterior nucleus of the thalamus increases slow wave activity in NREM sleep.

Previous studies suggest that intermittent deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) affects physiological sleep architecture. Here, we investigated the impact of continuous ANT-DBS on sleep in epilepsy patients in a multicenter cross-over study in ten patients. We assessed sleep stage distribution, delta power, delta energy, and total sleep time (TST) in standardized 10/20 polysomnography (PSG) investigations before and 12 months after DBS lead implantation. In contrast to previous studies, we found no disruption of sleep architecture or alterations of sleep stage distribution under active ANT-DBS (P = 0.76). On the contrary, we observed more consolidated and deeper slow wave sleep (SWS) under continuous high frequency DBS as compared to baseline sleep prior to DBS lead implantation. In particular, biomarkers of deep sleep (delta power and delta energy) showed a significant increase post-DBS as compared to baseline (36.67 ± 13.68 μV2 and 799.86 ± 407.56 μV2 *s, P < 0.001). Furthermore, the observed increase in delta power was related to the location of the active stimulation contact within the ANT: we found higher delta power and higher delta energy in patients with active stimulation in more superior contacts as compared to inferior ANT stimulation. We also observed significantly less nocturnal EEG discharges in DBS ON condition. In conclusion, our findings suggest that continuous ANT-DBS in the most cranial part of the target region leads to more consolidated SWS. From a clinical perspective, these findings suggest that patients with sleep disruption under cyclic ANT-DBS could benefit from an adaptation of stimulation parameters to more superior contacts and continuous mode stimulation.

Is Thalamic DBS Synergistic With VNS in Drug Resistant Genetic Generalized Epilepsy? (P5-1.001)

<h3>Objective:</h3> To report prolonged seizure freedom and improved quality of life after combining anterior nucleus of the thalamus deep brain stimulation (ANT-DBS) with vagus nerve stimulation (VNS) in a patient with drug resistant genetic generalized epilepsy (GGE). <h3>Background:</h3> Neuromodulation remains at forefront of management in patients with drug-resistant epilepsies though efficacy has been palliative and FDA approved in focal epilepsies. While polytherapy with anti-seizure medications (ASMs) is common, dual neuromodulation has received limited attention. <h3>Design/Methods:</h3> A 32-year-old female patient with drug resistant GGE who failed 10 antiseizure medications underwent video-EEG monitoring. EEG revealed 3–3.5 Hz generalized polyspike-and-wave discharges and generalized paroxysmal fast activity in brief run lasting less than 3 seconds increased during sleep. Seizures were not recorded. VNS model 106 Aspire SR was implanted at age 23 achieving parameters of 1.5 mA, 25 Hz, 250 μs, 14 sec on, 1.1 min off. Despite improvement with seizure reduction, ongoing monthly convulsions resulted in recurrent injuries. The patient subsequently underwent bilateral ANT-DBS placement with inferior most contacts on both sides well-positioned at the junction of the mammillothalamic tracts for monopolar stimulation at 5 V, 145 Hz, and 90 μs. <h3>Results:</h3> Neuro- “modulation” was observed in our patient with VNS following implantation of ANT-DBS by gradual reduction diminishing seizure frequency, intensity, and duration to ultimately become seizure-free for 21 months. Stable doses of Onfi 20 mg po bid and Keppra 1500 mg po bid were continued. After combining ANT-DBS with her incomplete VNS response she married, became employed, and was able to retain driving privileges and lead an independent lifestyle. <h3>Conclusions:</h3> Identifying a subset of patients with GGE responsive to polyneuromodulation promises personalized therapy for those with life-altering effects from generalized seizures. We speculate that the thalamic network connectivity may be modulated by dual ANT-DBS and VNS, leading to targeted neurobiological therapy in some patients with GGE. <b>Disclosure:</b> Dr. Khan has nothing to disclose. Erik Middlebrooks has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Varian Medical Systems Inc. Erik Middlebrooks has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Boston Scientific Corp. The institution of Erik Middlebrooks has received research support from Varian Medical Systems Inc. Dr. Freund has nothing to disclose. Sanjeet S. Grewal, MD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medtronic. Dr. Tatum has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Bioserenity. Dr. Tatum has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Dr. Tatum has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Defense Law Firm on behalf of a patient with epilepsy with funds donated to the Epilepsy Foundation of America. The institution of Dr. Tatum has received research support from Esai. The institution of Dr. Tatum has received research support from Mayo Clinic. The institution of Dr. Tatum has received research support from Liva Nova. The institution of Dr. Tatum has received research support from Engage Pharmaceuticals. The institution of Dr. Tatum has received research support from Xenon. Dr. Tatum has received publishing royalties from a publication relating to health care. Dr. Tatum has received publishing royalties from a publication relating to health care.

Deep Brain Stimulation and Responsive Neurostimulation Implantation for Medically Refractory Epilepsy: A Case Report Study of a Single-Center's Experience

BACKGROUND AND IMPORTANCE: Nearly 25% of all epilepsy is drug-resistant epilepsy. Responsive neurostimulation (RNS) and deep brain stimulation (DBS) offer viable options when resection or ablation is not feasible. Neuromodulation leads to improved seizure control. However, in patients with highly complex epileptogenic networks, a multimodality approach using simultaneous RNS and DBS may provide a summative benefit. CLINICAL PRESENTATION: We present 2 cases of drug-resistant epilepsy who received simultaneous anterior nucleus of the thalamus DBS and RNS neuromodulation. To our knowledge, this is the first report of simultaneous DBS and RNS neurostimulation for the treatment of epilepsy. Given the complexity of their seizure networks, a combined neuromodulatory approach was deemed best to achieve seizure control. Both experienced multiple seizure semiology patterns consistent with multifocal onsets which were confirmed on phase I monitoring, nuclear medicine, and magnetoencephalography studies. Case 1 had a seizure reduction of 75% to 89% at 12 months which has remained stable at last follow-up (26 months) and case 2 achieved near seizure freedom and remained seizure-free at last follow-up (16 months). CONCLUSION: Neuromodulation has proven efficacious and safe in randomized controlled trials for the treatment of epilepsy. This is particularly important in multifocal epilepsy or if resective surgery is not an option. The optimal stimulation pathways and multimodal neuromodulation technique remains under investigation. We are the first to report that RNS and DBS implantation in the same patient is feasible, without major adverse effects and potentially effective.

Deep brain stimulation of the anterior nucleus of the thalamus for drug‐resistant epilepsy: Long‐term efficacy and outcomes from a prospective cohort

AbstractAimThe anterior nucleus of the thalamus (ANT) has been one of the deep brain stimulation (DBS) targets for drug‐resistant epilepsy. This study aims to investigate the control of seizures among patients with ANT DBS for epilepsy. We have pioneered DBS for epilepsy in Hong Kong since 2015 and this study aims to report the long‐term outcomes from a prospective cohort.MethodsThis is a prospective cohort study of ANT DBS for adult patients with drug‐resistant epilepsy, who are unsuitable for resective epilepsy surgery.ResultsSix patients (3 females and 3 males, mean age 31.3) received bilateral ANT DBS in a tertiary university hospital from 2015 to 2018 (one in 2015, two in 2017 and three in 2018). Both frontal transventricular and parietal approaches were used. The active contacts were selected based on the closest Euclidean distance to the mammillothalamic tract and ANT junction. Five of the six cases (83.3%) achieved greater than 50% reduction in seizures after the operations. The median percentage of reduction in seizures was 58.5% at 3 years after DBS (range, 32.7%–80%). Overall, there was a trend of improving seizure control rate from year 1 to year 6 after the ANT DBS operations.ConclusionsThis is the first report of ANT DBS for drug‐resistant epilepsy in Hong Kong. The results are encouraging. ANT DBS for drug‐resistant epilepsy is effective and sustained in long term. The treatment option of ANT DBS should be considered in suitable candidates with drug‐resistant epilepsy in our locality.

Analysis of power spectrum and phase lag index changes following deep brain stimulation of the anterior nucleus of the thalamus in patients with drug-resistant epilepsy: A retrospective study

ObjectivesThe mechanisms underlying the anterior nucleus of the thalamus (ANT) deep brain stimulation (DBS) for the treatment of drug-resistant epilepsy (DRE) have not been fully explored. The present study aimed to measure the changes in whole-brain activity generated by ANT DBS using interictal electroencephalography (EEG). Materials and methodsInterictal EEG signals were retrospectively collected in 20 DRE patients who underwent ANT DBS surgery. Patients were classified as responders or non-responders depending on their response to ANT DBS treatment. The power spectrum (PS) and Phase Lag Index (PLI) were determined and data analyzed using a paired sample t-test to evaluate activity differences between pre-and-post-treatment on different frequency categories. Student's t-test, Mann-Whitney test (non-parametric test) and Fisher exact test were used to compare groups in terms of clinical variables and EEG metrics. P values < 0.05 were considered statistically significant, and FDR-corrected values were used for multiple testing. ResultsPS analysis revealed that whole-brain spectral power had a significant decrease in the beta (p = 0.005) and gamma (p = 0.037) bands following ANT DBS treatment in responders. The analysis of scalp topographic images of all patients showed that ANT DBS decreases PS in the beta band at the F3, F7 and Cz electrode sites. The findings indicated a decrease in PS in the gamma band at the Fp2, F3, Cz, T3, T5 and Oz electrode sites. After ANT DBS treatment, PLI analysis showed a significant decrease in PLI between Fp1 and T3 in the gamma band in responders. ConclusionThe findings showed that ANT DBS induces a decrease in power in the left frontal lobe, left temporal lobe and midline areas in the beta and gamma bands. Lower whole-brain power in the beta and gamma bands can be used as biomarkers for a favorable therapeutic response to ANT DBS, and decreased synchronization between the left frontal pole and temporal lobe in the gamma band can also be used as a biomarker for effective clinical stimulation to guide postoperative programming.

Hippocampal-ANT connectivity and ANT DBS: Circadian trends and response to stimulation

Abstract Although hippocampal (HC)-anterior nucleus of the thalamus (ANT) interactions are implicated in limbic epilepsy, their dynamics over the circadian cycle and following ANT deep brain stimulation (DBS) remain unclear. We used ultra-long, ambulatory, HC and ANT intracranial electroencephalographic recordings to describe HC-ANT connectivity in a patient with bilateral temporal lobe epilepsy. The patient was implanted with the investigational Medtronic Summit RC+S ™ sensing and stimulating DBS device. Electrodes were implanted into the long axis of the hippocampus and ANT bilaterally. Therapeutic stimulation was delivered to the ANT. HC-ANT coherence was calculated in the Berger bands (4-125 Hz) in 10 second segments from one month of baseline recordings and from a three week period of night-off stimulation that followed a month of continuous low frequency ANT stimulation (2Hz). Only coherence measurements wherein both contacts had spectral peaks in the relevant band, without seizures, spikes, or stimulation, were analyzed. Coherence values over the circadian cycle were compared across hemispheres and between baseline and post-stimulation periods. At baseline, concurrent spectral peaks in HC and ANT occurred across the circadian cycle, primarily in the high beta and low gamma frequency bands bilaterally, with the less epileptogenic, right hemisphere showing significantly greater high beta coherence (Wilcoxon Rank-Sum, n1 = 2638, n2 = 2515, p < 0.0001). Post-stimulation, nighttime left HC-ANT high beta coherence did not change, but the central frequency of coherent high beta peaks did increase significantly (Wilcoxon Rank-Sum, n1 = 368, n2 = 492, p < 0.0001). Our finding that HC-ANT high beta coherence was decreased in the more epileptogenic hemisphere is consistent with reports of functional isolation of epileptogenic zone. The stimulation-associated change in central frequency at which beta peaks occurred, but not in overall magnitude of HC-ANT coherence, suggests that low frequency ANT-DBS influences the spectral composition of HC-ANT connectivity. Keywords: Deep brain stimulation, Connectivity, Epilepsy, Anterior nucleus of the thalamus

Anterior nucleus of the thalamus seizure detection in ambulatory humans.

There is a paucity of data to guide anterior nucleus of the thalamus (ANT) deep brain stimulation (DBS) with brain sensing. The clinical Medtronic Percept DBS device provides constrained brain sensing power within a frequency band (power-in-band [PIB]), recorded in 10-min averaged increments. Here, four patients with temporal lobe epilepsy were implanted with an investigational device providing full bandwidth chronic intracranial electroencephalogram (cEEG) from bilateral ANT and hippocampus (Hc). ANT PIB-based seizure detection was assessed. Detection parameters were cEEG PIB center frequency, bandwidth, and epoch duration. Performance was evaluated against epileptologist-confirmed Hc seizures, and assessed by area under the precision-recall curve (PR-AUC). Data included 99days of cEEG, and 20, 278, 3, and 18 Hc seizures for Subjects 1-4. The best detector had 7-Hz center frequency, 5-Hz band width, and 10-s epoch duration (group PR-AUC = .90), with 75% sensitivity and .38 false alarms per day for Subject 1, and 100% and .0 for Subjects 3 and 4. Hc seizures in Subject 2 did not propagate to ANT. The relative change of ANT PIB was maximal ipsilateral to seizure onset for all detected seizures. Chronic ANT and Hc recordings provide direct guidance for ANT DBS with brain sensing.

Centromedian thalamic nucleus with or without anterior thalamic nucleus deep brain stimulation for epilepsy in children and adults: A retrospective case series

The centromedian (CM) and anterior nucleus of the thalamus (ANT) are deep brain stimulation (DBS) targets for management of generalized, and focal drug resistant epilepsy (DRE), respectively. We report on a single center retrospective case series of 16 children and adults with DRE who underwent CM with simultaneous ANT (69 %) or CM without simultaneous ANT DBS (31 %). Seizure frequency, epilepsy severity, life satisfaction, and quality of sleep before and after DBS were compared. Baseline median seizure frequency was 323 seizures per month (IQR, 71–563 sz/mo). Median follow up time was 80 months (IQR 37–97 mo). Median seizure frequency reduction was 58 % (IQR 13–87 %, p = 0.002). Ten patients (63 %) reported ≥50 % seizure frequency reduction. Median seizure frequency reduction and responder rate were not significantly different for CM + ANT versus CM only. Seizure severity and life satisfaction were significantly improved. Three patients (19 %) developed device-related side effects, 2 of them (12.5 %) required surgical intervention. In a heterogenous population of children and adults with generalized, multifocal, posterior onset, and poorly localized DRE, CM with or without ANT DBS is feasible, relatively safe and is associated with reduced seizure frequency and severity, as well as improved life satisfaction.

What have we learned from 8 years of deep brain stimulation of the anterior thalamic nucleus? Experiences and insights of a single center.

In the absence of a standard or guideline for the treatment of epilepsy patients with deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT), systematic single-center investigations are essential to establish effective approaches. Here, the authors report on the long-term results of one of the largest single-center ANT DBS cohorts. The outcome data of 23 consecutive patients with transventricularly implanted electrodes were retrospectively analyzed with regard to adverse events, lead placement, stimulation-related side effects, and changes in seizure frequency. Depression and quality-of-life scores were collected in a subgroup of 9 patients. All but 2 patients initially underwent bilateral implantation, and 84.4% of all DBS leads were successfully located within the ANT. The mean follow-up time was 46.57 ± 23.20 months. A seizure reduction > 50% was documented in 73.9% of patients, and 34.6% achieved an Engel class I outcome. In 3 patients, clinical response was achieved by switching the electrode contact or changing from the monopolar to bipolar stimulation mode. Unilateral implantation seemed ineffective, whereas bilateral stimulation with successful ANT implantation only on one side led to a clinical response. Double stimulation with additional vagus nerve stimulation was safe. Changes in cycling mode or stimulation amplitude influenced therapy tolerability and, only to a lesser extent, seizure frequency. Side effects were rare and typically vanished by lowering the stimulation amplitude or changing the active electrode contact. Furthermore, depression and aspects of quality of life significantly improved with ANT DBS treatment. The transventricular approach as well as double stimulation proved safe. The anteroventral ANT appeared to be the most efficacious stimulation site. This systematic investigation with reluctant medication changes allowed for the development of a better idea of the association between parameter changes and outcome in ANT DBS patients, but larger samples are still needed to assess the potential of bipolar stimulation and distinct cycling frequencies. Furthermore, more multifaceted and objective assessments of treatment outcome are needed to fully assess the effects of ANT DBS treatment.

Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy: A Canadian Experience.

To describe the experience with Anterior Nucleus of the Thalamus-Deep Brain Stimulation (ANT-DBS) for the treatment of epilepsy at a Canadian Center. All patients who underwent ANT-DBS implantation between 2013 (first patient implanted at our center) and 2020 were included. These patients had therapy-resistant epilepsy (TRE), were not candidates for resective surgery, and failed vagus nerve stimulation (VNS) treatment. Baseline of monthly seizure frequency was calculated within 3 months prior to VNS placement. Monthly seizure frequency was assessed at different points along the timeline: 3 months before ANT-DBS implantation as well as 3, 6, 12, 24, 36, 48, 60, and 72 months after ANT-DBS device placement. At each time point, seizure frequency was compared to baseline. Six patients were implanted with ANT-DBS. Three (50%) patients had multifocal epilepsy, one (16.6%) had focal epilepsy, and two (33.4%) had combined generalized and focal epilepsy. Two patients with multifocal epilepsy experienced a seizure reduction >50% in the long-term follow-up. Three (50%) patients did not showed improvement: two with combined generalized and focal epilepsy and one with focal epilepsy. There were not surgical or device-related side effects. Two (33.3%) patients presented mild and transient headaches as a stimulation-related side effect. ANT-DBS is an effective and safe treatment for focal TRE. Our experience suggests that patients with multifocal epilepsy due to regional lesion may benefit from ANT-DBS the most. Further investigations are required to determine optimal parameters of stimulation.

Functional Activation Patterns of Deep Brain Stimulation of the Anterior Nucleus of the Thalamus

Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a recently approved therapy for patients with drug-resistant epilepsy. To date, there is a poor understanding of the mechanism of action and lack of invivo biomarkers. We propose a method for investigating the invivo stimulation effects using blood-oxygen-level-dependent (BOLD) magnetic resonance imaging (MRI) and present the brain activation pattern associated with ANT DBS. Two patients undergoing ANT DBS for epilepsy underwent BOLD MRI using a block design after the DBS was programmed to alternate ON/OFF in 30-second blocks. The scanner was triggered using surface electrophysiologic recordings to detect the DBS cycle. Nine total runs were obtained and were analyzed using a general linear model. Active ANT stimulation produced activation within several areas of the brain, including the thalamus, bilateral anterior cingulate and posterior cingulate cortex, precuneus, medial prefrontal cortex, amygdala, ventral tegmental area, hippocampus, striatum, and right angular gyrus. Using block-design BOLD MRI, we were able to show widespread activation resulting from ANT DBS. Overlap with multiple areas of both the default mode and limbic networks was shown, suggesting that these nodes may modulate the effect of seizure control with ANT DBS.

Probing circuit of Papez with stimulation of anterior nucleus of the thalamus and hippocampal evoked potentials

PurposeDespite documented clinical effectiveness, deep brain stimulation (DBS) therapy for drug-resistant epilepsy rarely yields long-term seizure free outcomes. MethodsThis pilot study in five patients investigated circuit of Papez evoked potentials (EPs) using hippocampal sensing during anterior nucleus of the thalamus (ANT) electrical stimulation. We hypothesize that hippocampal EP is a potential biomarker that could be useful for ANT electrode targeting and improving seizure reduction. We obtained bilateral circuit of Papez EPs in five patients with bilateral temporal lobe epilepsy (TLE). The circuit of Papez EPs were measured and assessed by signal amplitude. Volumetric analysis of relevant mesial temporal structures and ANT stimulation analysis was performed on immediate post-implantation images. ResultsThe patient with the most favorable seizure outcome, which meant long-term seizure reduction greater than 50 % compared to baseline, had strong bilateral EPs and normal hippocampal structure. Conversely, those without clinical benefit with ANT DBS had absent or weak bilateral EPs as well as MRI findings consistent with mesial temporal sclerosis (MTS). ConclusionThe data support the hypothesis that hippocampal EPs with ANT stimulation may be used to as a surrogate marker to probe circuit of Papez and predict ANT DBS efficacy.

Differences in functional connectivity profiles as a predictor of response to anterior thalamic nucleus deep brain stimulation for epilepsy: a hypothesis for the mechanism of action and a potential biomarker for outcomes.

OBJECTIVE Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a promising therapy for refractory epilepsy. Unfortunately, the variability in outcomes from ANT DBS is not fully understood. In this pilot study, the authors assess potential differences in functional connectivity related to the volume of tissue activated (VTA) in ANT DBS responders and nonresponders as a means for better understanding the mechanism of action and potentially improving DBS targeting. METHODS This retrospective analysis consisted of 6 patients who underwent ANT DBS for refractory epilepsy. Patients were classified as responders (n = 3) if their seizure frequency decreased by at least 50%. The DBS electrodes were localized postoperatively and VTAs were computationally generated based on DBS programming settings. VTAs were used as seed points for resting-state functional MRI connectivity analysis performed using a control dataset. Differences in cortical connectivity to the VTA were assessed between the responder and nonresponder groups. RESULTS The ANT DBS responders showed greater positive connectivity with the default mode network compared to nonresponders, including the posterior cingulate cortex, medial prefrontal cortex, inferior parietal lobule, and precuneus. Interestingly, there was also a consistent anticorrelation with the hippocampus seen in responders that was not present in nonresponders. CONCLUSIONS Based on their pilot study, the authors observed that successful ANT DBS in patients with epilepsy produces increased connectivity in the default mode network, which the authors hypothesize increases the threshold for seizure propagation. Additionally, an inhibitory effect on the hippocampus mediated through increased hippocampal γ-aminobutyric acid (GABA) concentration may contribute to seizure suppression. Future studies are planned to confirm these findings.

Technical Implications in Revision Surgery for Deep Brain Stimulation (DBS) of the Thalamus for Refractory Epilepsy.

Background and PurposeImplantation of deep brain stimulation (DBS) electrodes in the anterior nucleus of the thalamus (ANT) or the centromedian nucleus (CM), for the treatment of refractory epilepsy, is technically demanding. To enhance the accuracy of electrode placement within the ANT and CM, we analyzed our experience with electrode revision surgery in ANT and CM DBS and investigated the cause of misplacement and verifying methods for accurate placement.MethodsA retrospective analysis of the medical records of 23 patients who underwent DBS for refractory epilepsy during the period from 2013 to 2016 was performed.ResultsMisplacement of the electrode occurred in 1 (25%) of 4 ANT DBS and 2 (14.3%) of 14 patients with CM DBS performed in our institute, and revision surgery was performed in three patients. During this period, we performed three revision surgeries for misplaced electrodes in ANT DBS that were performed at another hospital. Therefore, we performed six revision surgeries (four in ANT, two in CM) for mistargeted DBS electrodes for thalamic DBS. Transventricular lead placement and an anatomical targeting of the ANT was the cause of misplacement in the ANT and intraoperative brain shift was found to be the cause in the CM. For verification of the location of lead placement, magnetic resonance imaging (MRI) was superior to computed tomography and electroencephalography (EEG).ConclusionsTo reduce the rate of electrode misplacement for refractory epilepsy, image-based targeting of the ANT according to individual anatomical variation, and efforts to minimize intraoperative brain shift are essential. To verify the location of the electrode, MRI examination is mandatory in DBS for refractory epilepsy.

Memory and mood outcomes after anterior thalamic stimulation for refractory partial epilepsy

PurposeBilateral deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) reduces seizures and is relatively safe but may be accompanied by complaints of memory problems and depression. This study examined incidence of memory and depression adverse events (AE) in the SANTE study blinded phase and their relationship to objective neurobehavioral measures, baseline characteristics, quality of life and long-term neurobehavioral outcome. MethodThe neurobehavioral AE and neuropsychological data from a previously reported prospective randomized trial (SANTE) were analyzed. Reliable change indices (RCI) were calculated for memory and mood measures. Analyses examined relationships among AEs, RCIs, demographic and seizure variables, and long-term neurobehavioral outcome. ResultsNo significant cognitive declines or worsening of depression scores were observed through the blinded phase or in open-label at 7-years. Higher scores were observed at 7 years on measures of executive functions and attention. Depression and memory-related AEs were not associated with reliable change on objective measures or 7-year neurobehavioral outcome. The AEs were without significant impact on life quality. Memory and depression AEs were not related to demographic or seizure characteristics, change in seizure frequency, frequency of AE or depression report. ConclusionBilateral ANT DBS was associated with subjective depression and memory AEs during the blinded phase in a minority of patients that were not accompanied by objective, long-term neurobehavioral worsening. Monitoring and neuropsychological assessment of depression and memory are recommended from a theoretical standpoint and because more memory and depression AEs occurred in the active stimulation than control group.

Relationship between Postoperative EEG Driving Response and Lead Location in Deep Brain Stimulation of the Anterior Nucleus of the Thalamus for Refractory Epilepsy

Objectives: Interpreting the postoperative electroencephalographic (EEG) driving response (DR) as an indicator of electrode placement within the thalamic nucleus in deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) for refractory epilepsy is controversial. Materials and Methods: We retrospectively investigated the relationship between postoperative EEG DR and the location of 11 electrodes in 6 patients who underwent ANT DBS for refractory epilepsy. Results: Cerebral synchronizing EEG DR was observed in 10 electrodes. However, 9 of the 11 electrodes were located within the ANT. For the 2 electrodes that missed the ANT, DR was observed in 1 misplaced electrode facing the anterior surface of the ANT within the third ventricle. The other misplaced electrode without DR elicitation showed a DR after electrode repositioning. Conclusions: The diagnostic significance of DR as indirect evidence of electrodes being within thalamic nuclei is limited. If DR is not elicited, it should be regarded as a misplacement. Even if DR is elicited, it may not be interpreted as a sound indicator of proper electrode placement within the thalamus. A sophisticated, postoperative imaging study is warranted in every case of ANT DBS.

EP 71. Single cell firing patterns in the anterior nucleus of the thalamus relate to therapy response in deep brain stimulation for refractory epilepsy

Introduction: Patients with medically refractory epilepsy treated with deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) vary highly in their therapy response. Proper positioning of the DBS lead is crucial to maximize efficacy and minimize side effects. For a correct implantation, the ANT is anatomically located using pre-operative 3T MRI and perioperative microelectrode recordings (MER). Neurons in the ANT have highly variable, yet characteristic patterns of firing in bursts. During DBS lead implantation, we noted differences among patients’ characteristic burst patterns along the electrode trajectory. In this study, we investigate whether electrophysiological characteristics of the target region could predict therapy response to DBS and could thus be used to improve ANT targeting during DBS surgery. Objectives: To determine whether perioperative neurophysiological characteristics relate to therapy response in DBS for patients with medically refractory epilepsy. Patients and methods: We included ten consecutive epilepsy patients planned for DBS surgery at Maastricht University Medical Center. All patients were diagnosed with medically refractory epilepsy and had incapacitating seizures. Patients failed trials of at least two reasonably tolerated and adequately chosen antiepileptic drug schedules. Using pre-operative 3T MRI, we planned an extraventricular approach to target. The ANT was defined as a grey matter structure at the top of the mamillothalamic tract. Along this trajectory, we performed stereotactic single cell MERs. The anatomical location of the recordings were verified using preoperative 3T MR images. We compared characteristics of the neural signals at different depths along the trajectory between DBS responders and non-responders. Responders were defined as patients with a seizure frequency reduction of more than 50% at one year follow-up. Results: Using MER data from 19 electrode trajectories of ten patients (one unilateral and nine bilateral trajectories), we found high-amplitude neuronal bursts around the target area or ANT. Responders to DBS (n = 5) had higher normalized mean firing rates and mean burst rates near the target area compared to non-responders (n = 5), with a clearer delineation between the target region and surroundings. Electrode trajectories and lead localization did not differ between responders and non-responders. Conclusion: Single cell firing patterns in the ANT relate to therapy response in DBS for patients with medically refractory epilepsy. Analysis of single cell firing patterns using MER may guide targeting or contribute to predicting therapy response to ANT DBS. Further exploration into the use of electrophysiological recordings is warranted to improve targeting or predict outcome in DBS for epilepsy patients.

Neuroprotective effects of electrical stimulation of the anterior nucleus of the thalamus for hippocampus neurons in intractable epilepsy

Epilepsy and Parkinson’s disease (PD) are common neurological disorders. Both epilepsy and PD are potentially progressive disabling diseases that can be treated with the established therapy of deep brain stimulation (DBS). The difference in therapy is target selection and stimulation parameter modulation. The anterior nucleus of the thalamus (ANT) is chosen for intractable epilepsy and the subthalamic nucleus (STN) is chosen for PD. Long-term stable symptom control of STN–DBS can be seen in PD patients while the positive effect of ANT-DBS can be observed in epilepsy patients. Experimental data and clinical evidence have been reported that indicate the neuroprotective property of STN–DBS could be found in PD patients. Therefore, we hypothesize that the neuroprotective benefits of ANT–DBS may be present in epilepsy patients.