Anterior Thalamic Nuclei Research Articles

The anterior nucleus of the thalamus plays a role in the epileptic network.

We investigated both the metabolic differences and interictal/ictal discharges of the anterior nucleus of the thalamus (ANT) in patients with epilepsy to clarify the relationship between the ANT and the epileptic network. Nineteen patients with drug-resistant epilepsy who underwent stereoelectroencephalography were studied. Metabolic differences in ANT were analyzed using [18F] fluorodeoxyglucose-positron emission tomography with three-dimensional (3D) visual and quantitative analyses. Interictal and ictal discharges in the ANT were analyzed using visual and time-frequency analyses. The relationship between interictal discharge and metabolic differences was analyzed. We found that patients with temporal lobe epilepsy (TLE) showed significant metabolic differences in bilateral ANT compared with extratemporal lobe epilepsy in 3D visual and quantitative analyses. Four types of interictal activities were recorded from the ANT: spike, high-frequency oscillation (HFO), slow-wave, and α-rhythmic activity. Spike and HFO waveforms were recorded mainly in patients with TLE. Two spike patterns were recorded: synchronous and independent. In 83.3% of patients, ANT was involved during seizures. Three seizure onset types of ANT were recorded: low-voltage fast activity, rhythmic spikes, and theta band discharge. The time interval of seizure onset between the seizure onset zone and ANT showed two patterns: immediate and delayed. ANT can receive either interictal discharges or ictal discharges which propagate from the epileptogenic zones. Independent epileptic discharges can also be recorded from the ANT in some patients. Metabolic anomalies and epileptic discharges in the ANT indicate that the ANT plays a role in the epileptic network in most patients with epilepsy, especially TLE.

Invasive neuromodulation for epilepsy: Comparison of multiple approaches from a single center

BackgroundDrug-resistant epilepsy (DRE) patients not amenable to epilepsy surgery can benefit from neurostimulation. Few data compare different neuromodulation strategies. ObjectiveCompare five invasive neuromodulation strategies for the treatment of DRE: anterior thalamic nuclei deep brain stimulation (ANT-DBS), centromedian thalamic nuclei DBS (CM-DBS), responsive neurostimulation (RNS), chronic subthreshold stimulation (CSS), and vagus nerve stimulation (VNS). MethodsSingle center retrospective review and phone survey for patients implanted with invasive neuromodulation for 2004–2021. ResultsN = 159 (ANT-DBS = 38, CM-DBS = 19, RNS = 30, CSS = 32, VNS = 40). Total median seizure reduction (MSR) was 61 % for the entire cohort (IQR 5–90) and in descending order: CSS (85 %), CM-DBS (63 %), ANT-DBS (52 %), RNS (50 %), and VNS (50 %); p = 0.07. The responder rate was 60 % after a median follow-up time of 26 months. Seizure severity, life satisfaction, and quality of sleep were improved. Cortical stimulation (RNS and CSS) was associated with improved seizure reduction compared to subcortical stimulation (ANT-DBS, CM-DBS, and VNS) (67 % vs. 52 %). Effectiveness was similar for focal epilepsy vs. generalized epilepsy, closed-loop vs. open-loop stimulation, pediatric vs. adult cases, and high frequency (>100 Hz) vs. low frequency (<100 Hz) stimulation settings. Delivered charge per hour varied widely across approaches but was not correlated with improved seizure reduction. ConclusionsMultiple invasive neuromodulation approaches are available to treat DRE, but little evidence compares the approaches. This study used a uniform approach for single-center results and represents an effort to compare neuromodulation approaches.

Network localization of transient global amnesia beyond the hippocampus.

Transient global amnesia is common in the older adult, but the cause and mechanism remain unclear. Focal brain lesions allow for causal links between the lesion location and resulting symptoms, and we based on the reported TGA-causing lesions and used lesion network mapping to explore the causal neuroanatomical substrate of TGA. Fifty-one cases of transient global amnesias with DWI lesions from the literature were identified, and clinical data were extracted and analyzed. Next, we mapped each lesion volume onto a reference brain and computed the network of regions functionally connected to each lesion location using a large normative connectome dataset. Lesions primarily occurred in the hippocampus, and in addition to the hippocampus, there are also other locations of TGA-causing lesions such as the cingulate gyrus, anterior thalamic nucleus (ATN), putamen, caudate nucleus, corpus callosum, fornix. More than 90% of TGA-causing lesions inside the hippocampus were functionally connected with the default mode network (DMN). Structural abnormality in the hippocampus was the most consistently reported in TGA, and besides the hippocampus, lesions occurring at several other brain locations also could cause TGA. The DMN may also be involved in the pathophysiology of TGA. According to the clinical and neuroimaging characteristics, TGA may be a syndrome with multiple causes and cannot be treated simply as a subtype of TIA.

Total intravenous anesthesia with remimazolam in a patient with epilepsy who underwent deep brain stimulation: a case report

Drugs administered for anesthesia can trigger seizure attacks in patients with epilepsy. Benzodiazepines have been consistently reported to be anticonvulsants, and a novel benzodiazepine, remimazolam, was recently introduced. We report a case of total intravenous anesthesia maintained with remimazolam in a patient with epilepsy who underwent deep brain stimulation of both anterior thalamic nuclei. Despite the administration of multiple anti-epileptic drugs, no tolerance to remimazolam was observed. Perioperative seizures were also not observed. Remimazolam can be considered the anesthetic of choice in patients with epilepsy.

Mapping the neural circuits responding to deep brain stimulation of the anterior nucleus of the thalamus in the rat brain

Clinical studies have demonstrated that deep brain stimulation of the anterior nucleus of the thalamus (ANT) is a safe and effective treatment for focal epilepsy and drug-resistant epilepsy. However, the mechanism of action of ANT deep brain stimulation, especially in terms of neuromodulatory circuits, is not fully understood. In this study, we evaluated the anatomical and functional connectivity of the ANT in rats. For anatomical connectivity, herpes simplex virus (HSV) and pseudorabies virus (PRV; Bartha stain) were focally injected into the ANT of rats to label the connected brain structures in the retrograde and anterograde directions, respectively. For functional connectivity, we used c-Fos mapping in conjunction with electrical stimulation of the ANT to map the brain structures functionally connected to the ANT. Circuit connectivity mapping revealed that the ANT was connected to the hippocampus, the nucleus accumbens, the dorsal part of the lateral septal nucleus (LSD), the amygdala, the secondary motor cortex (M2), the cingulate cortex, the substantia nigra, the hypothalamus, and other regions. The ipsilateral connections were stronger than the contralateral connections. Deep brain stimulation of the ANT resulted in c-fos expression in the cortex, hippocampus, amygdala, striatum and hypothalamus, with the strongest activation in the hippocampus. These results suggest that the ANT has a wide range of structural and functional connections, which may underlie the effectiveness of deep brain stimulation in treating epilepsy. Data Availability StatementThe datasets generated for this study are available on request to the corresponding author.

Collateral rostral thalamic projections to prelimbic, infralimbic, anterior cingulate and retrosplenial cortices in the rat brain.

As the functional properties of a cortical area partly reflect its thalamic inputs, the present study compared collateral projections arising from various rostral thalamic nuclei that terminate across prefrontal (including anterior cingulate) and retrosplenial areas in the rat brain. Two retrograde tracers, fast blue and cholera toxin B, were injected in pairs to different combinations of cortical areas. The research focused on the individual anterior thalamic nuclei, including the interanteromedial nucleus, nucleus reuniens and the laterodorsal nucleus. Of the principal anterior thalamic nuclei, only the anteromedial nucleus contained neurons reaching both the anterior cingulate cortex and adjacent cortical areas (prefrontal or retrosplenial), though the numbers were modest. For these same cortical pairings (medial prefrontal/anterior cingulate and anterior cingulate/retrosplenial), the interanteromedial nucleus and nucleus reuniens contained slightly higher proportions of bifurcating neurons (up to 11% of labelled cells). A contrasting picture was seen for collaterals reaching different areas within retrosplenial cortex. Here, the anterodorsal nucleus, typically provided the greatest proportion of bifurcating neurons (up to 15% of labelled cells). While individual neurons that terminate in different retrosplenial areas were also found in the other thalamic nuclei, they were infrequent. Consequently, these thalamo-cortical projections predominantly arise from separate populations of neurons with discrete cortical termination zones, consistent with the transmission of segregated information and influence. Overall, two contrasting medial-lateral patterns of collateral projections emerged, with more midline nuclei, for example, nucleus reuniens and the interoanteromedial nucleus innervating prefrontal areas, while more dorsal and lateral anterior thalamic collaterals innervated retrosplenial cortex.

Analysis of the extent of limbic system changes in multiple sclerosis using FreeSurfer and voxel-based morphometry approaches.

Background and purposeThe limbic brain is involved in diverse cognitive, emotional, and autonomic functions. Injury of the various parts of the limbic system have been correlated with clinical deficits in MS. The purpose of this study was to comprehensively examine different regions of the subcortical limbic system to assess the extent of damage within this entire system as it may be pertinent in correlating with specific aspects of cognitive and behavioral dysfunction in MS by using a fully automated, unbiased segmentation approach.MethodsSixty-seven subjects were included in this study, including 52 with multiple sclerosis (MS) and 15 healthy controls. Only patients with stable MS disease, without any relapses, MRI activity, or disability progression were included. Subcortical limbic system segmentation was performed using the FreeSurfer pipeline ScLimbic, which provides volumes for fornix, mammillary bodies, hypothalamus, septal nuclei, nucleus accumbens, and basal forebrain. Hippocampus and anterior thalamic nuclei were added as additional components of the limbic circuitry, also segmented through FreeSurfer. Whole limbic region mask was generated by combining these structures and used for Voxel-based morphometry (VBM) analysis.ResultsThe mean [95% confidence interval] of the total limbic system volume was lower (0.22% [0.21–0.23]) in MS compared to healthy controls (0.27%, [0.25–0.29], p < .001). Pairwise comparisons of individual limbic regions between MS and controls was significant in the nucleus accumbens (0.046%, [0.043–0.050] vs. 0.059%, [0.051–0.066], p = .005), hypothalamus (0.062%, [0.059–0.065] vs. 0.074%, [0.068–0.081], p = .001), basal forebrain (0.038%, [0.036–0.040] vs. 0.047%, [0.042–0.051], p = .001), hippocampus (0.47%, [0.45–0.49] vs. 0.53%, [0.49–0.57], p = .004), and anterior thalamus (0.077%, [0.072–0.082] vs. 0.093%, [0.084–0.10], p = .001) after Bonferroni correction. Volume of several limbic regions was significantly correlated with T2 lesion burden and brain parenchymal fraction (BPF). Multiple regression model showed minimal influence of BPF on limbic brain volume and no influence of other demographic and disease state variables. VBM analysis showed cluster differences in the fornix and anterior thalamic nuclei at threshold p < 0.05 after adjusting for covariates but the results were insignificant after family-wise error corrections.ConclusionsThe results show evidence that brain volume loss is fairly extensive in the limbic brain. Given the significance of the limbic system in many disease states including MS, such volumetric analyses can be expanded to studying cognitive and emotional disturbances in larger clinical trials. FreeSurfer ScLimbic pipeline provided an efficient and reliable methodology for examining many of the subcortical structures related to the limbic brain.

Microendoscopic transventricular deep brain stimulation of the anterior nucleus of the thalamus as a safe treatment in intractable epilepsy: A feasibility study

IntroductionDeep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is proposed in patients with severe intractable epilepsy. When used, the transventricular approach increases the risk of bleeding due the anatomy around the entry point in the thalamus. To avoid such a complication, we used a transventricular microendoscopic technique. MethodsWe performed a retrospective study of nine adult patients who were surgically treated for refractory epilepsy between 2010 and 2019 by DBS of the anterior thalamic nucleus. ResultsEndoscopy provides a direct visual control of the entry point of the lead in the thalamus through the ventricle by avoiding ependymal vessels. No hemorrhage was recorded and accuracy was systematically checked by intraoperative stereotactic MRI. We reported a responder rate improvement in 88.9% of patients at 1 year and in 87.5% at 2 years. We showed a significant decrease in global seizure count per month one year after DBS (68.1%; P=0.013) leading to an overall improvement in quality of life. No major adverse effect was recorded during the follow-up. ANT DBS showed a prominent significant effect with a decrease of the number of generalized seizures. ConclusionWe aimed at a better ANT/lead collimation using a vertical transventricular approach under microendoscopic monitoring. This technique permitted to demonstrate the safety and the accuracy of the procedure.

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.

Clinical outcome of imaging-based programming for anterior thalamic nucleus deep brain stimulation.

The authors hypothesized that the proximity of deep brain stimulator contacts to the anterior thalamic nucleus-mammillothalamic tract (ANT-MMT) junction determines responsiveness to treatment with ANT deep brain stimulation (DBS) in drug-resistant epilepsy and conducted this study to test that hypothesis. This retrospective study evaluated patients who had undergone ANT DBS electrode implantation and whose devices were programmed to stimulate nearest the ANT-MMT junction based on direct MRI visualization. The proximity of the active electrode to the ANT and the ANT-MMT junction was compared between responders (≥ 50% reduction in seizure frequency) and nonresponders. Linear regression was performed to assess the percentage of seizure reduction and distance to both the ANT and the ANT-MMT junction. Four (57.1%) of 7 patients had ≥ 50% reduction in seizures. All 4 responders had at least one contact within 1 mm of the ANT-MMT junction, whereas the 3 patients with < 50% seizure improvement did not have a contact within 1 mm of the ANT-MMT junction. Additionally, the 4 responders demonstrated contact positioning closer to the ANT-MMT junction than the 3 nonresponders (mean distance from MMT: 0.7 mm on the left and 0.6 mm on the right in responders vs 3.0 mm on the left and 2.3 mm on the right in nonresponders). However, proximity of the electrode contact to any point in the ANT nucleus did not correlate with seizure reduction. Greater seizure improvement was correlated with a contact position closer to the ANT-MMT junction (R2 = 0.62, p = 0.04). Seizure improvement was not significantly correlated with proximity of the contact to any ANT border (R2 = 0.24, p = 0.26). Obtained using a combination of direct visualization and targeted programming of the ANT-MMT junction, data in this study support the hypothesis that proximity to the ANT alone does not correlate with seizure reduction in ANT DBS, whereas proximity to the ANT-MMT junction does. These findings support the importance of direct targeting in ANT DBS, as well as imaging-informed programming. Additionally, the authors provide supportive evidence for future prospective trials using ANT-MMT junction for direct surgical targeting.

Anterior thalamic nuclei: A critical substrate for non-spatial paired-associate memory in rats.

Injury or dysfunction in the anterior thalamic nuclei (ATN) may be the key contributory factor in many instances of diencephalic amnesia. Experimental ATN lesions impair spatial memory and temporal discriminations, but there is only limited support for a more general role in non-spatial memory. To extend evidence on the effects of ATN lesions, we examined the acquisition of biconditional associations between odour and object pairings presented in a runway, either with or without a temporal gap between these items. Intact adult male rats acquired both the no-trace and 10-s trace versions of this non-spatial task. Intact rats trained in the trace version showed elevated Zif268 activation in the dorsal CA1 of the hippocampus, suggesting that the temporal component recruited additional neural processing. ATN lesions completely blocked acquisition on both versions of this association-memory task. This deficit was not due to poor inhibition to non-rewarded cues or impaired sensory processing, because rats with ATN lesions were unimpaired in the acquisition of simple odour discriminations and simple object discriminations using similar task demands in the same apparatus. This evidence challenges the view that impairments in arbitrary paired-associate learning after ATN lesions require the use of multimodal spatial stimuli. It suggests that diencephalic amnesia associated with the ATN stems from degraded attention to stimulus-stimulus associations and their representation across a distributed memory system.

Role of anterior thalamic circuitry during sleep

Increased attention has been paid to the structure and function of anterior nucleus of the thalamus (ANT), since deep brain stimulation (DBS) treatment for epilepsy launched a decade ago. The efficacy of the treatment on seizure count varies patient from patient and we have limited information on the predictors of better outcomes. While the thalamus is considered the key brain region responsible for maintaining sleep, ANT was traditionally not involved in this function. Recent experimental and human data point to a possible role of ANT in sleep processes, although the underlying mechanisms are still ambiguous. Beside evaluating the current knowledge on sleep disturbances experienced during ANT-DBS treatment, the search for valid biomarkers primarily resides on a better understanding of sleep circuits implicating ANT and its subnuclei. Hypothetically better selectivity within the target may increase seizure outcomes and reduce psychiatric and cognitive side effects. Hence, the main scope of this review is to summarize the evidence on the activity measured in the ANT during non-REM and REM sleep. Furthermore, we aim to find shared properties of sleep processes and ANT-related functions examined more thoroughly during wakefulness, such as selective attention and memory.

Structural connectivity of the ANT region based on human ex-vivo and HCP data. Relevance for DBS in ANT for epilepsy

ObjectiveDeep Brain Stimulation (DBS) in the Anterior Nucleus of the Thalamus (ANT) has been shown to be a safe and efficacious treatment option for patients with Drug-Resitant focal Epilepsy (DRE). The ANT has been selected frequently in open and controlled studies for bilateral DBS. There is a substantial variability in ANT-DBS outcomes which is not fully understood. These outcomes might not be explained by the target location alone but potentially depend on the connectivity of the mere stimulation site with the epilepsy onset-associated brain regions. The likely sub-components of this anatomy are fiber pathways which penetrate or touch the ANT region and constitute a complex and dense fiber network which has not been described so far. A detailed characterization of this ANT associated fiber anatomy may therefore help to identify which areas are associated with positive or negative outcomes of ANT-DBS. Furthermore, prediction properties in individual ANT-DBS cases might be tested. In this work we aim to generate an anatomically detailed map of candidate fiber structures which might in the future lead to a holistic image of structural connectivity of the ANT region. MethodsTo resolve the various components of the complex fiber network connected to the ANT we used a synthetic pathway reconstruction method that combines anatomical fiber tracking with dMRI-based tractography and iteratively created an anatomical high-resolution fiber map representing the most important bundles related to the ANT. ResultsThe anatomically detailed 3D representation of the fibers in the ANT region generated with the synthetic pathway reconstruction method incorporates multiple anatomically defined fiber bundles with their course, orientation, connectivity and relative strength. Distinctive positions within the ANT region have a different hierarchical profile with respect to the stimulation-activated fiber bundles. This detailed connectivity map, which is embedded into the topographic map of the MNI brain, provides novel opportunities to analyze the outcomes of the ANT-DBS studies. ConclusionOur synthetic reconstruction method provides the first anatomically realistic fiber pathway map in the human ANT region incorporating histological and structural MRI data. We propose that this complex ANT fiber network can be used for detailed analysis of the outcomes of DBS studies and potentially for visualization during the stimulation planning procedures. The connectivity map might also facilitate surgical planning and will help to simulate the complex ANT connectivity. Possible activation patterns that may be elicited by electrodes in different positions in the ANT region will help to understand clinically diverse outcomes based on this new dense fiber network map. As a consequence this work might in the future help to improve individual outcomes in ANT-DBS.

Responsive Neurostimulation of the Thalamus for the Treatment of Refractory Epilepsy.

IntroductionOne-third of patients with epilepsy continue to have seizures despite antiepileptic medications. Some of these refractory patients may not be candidates for surgical resection primarily because the seizure onset zones (SOZs) involve both hemispheres or are located in eloquent areas. The NeuroPace Responsive Neurostimulation System (RNS) is a closed-loop device that uses programmable detection and stimulation to tailor therapy to a patient's individual neurophysiology. Here, we present our single-center experience with the use of RNS in thalamic nuclei to provide long-term seizure control in patients with refractory epilepsy.MethodsWe performed a prospective single-center study of consecutive refractory epilepsy patients who underwent RNS system implantation in the anterior (ANT) and centromedian (CM) thalamic nuclei from September 2015 to December 2020. Patients were followed postoperatively to evaluate seizure freedom and complications.ResultsTwenty-three patients underwent placement of 36 RNS thalamic leads (CM = 27 leads, ANT = 9 leads). Mean age at implant was 18.8 ± 11.2 years (range 7.8–62 years-old). Two patients (8.7%) developed infections: 1 improved with antibiotic treatments alone, and 1 required removal with eventual replacement of the system to recover the therapeutic benefit. Mean time from RNS implantation to last follow-up was 22.3 months. Based on overall reduction of seizure frequency, 2 patients (8.7%) had no- to <25% improvement, 6 patients (26.1%) had 25–49% improvement, 14 patients (60.9%) had 50–99% improvement, and 1 patient (4.3%) became seizure-free. All patients reported significant improvement in seizure duration and severity, and 17 patients (74%) reported improved post-ictal state. There was a trend for subjects with SOZs located in the temporal lobe to achieve better outcomes after thalamic RNS compared to those with extratemporal SOZs. Of note, seizure etiology was syndromic in 12 cases (52.2%), and 7 patients (30.4%) had undergone resection/disconnection surgery prior to thalamic RNS therapy.ConclusionThalamic RNS achieved ≥50% seizure control in ~65% of patients. Infections were the most common complication. This therapeutic modality may be particularly useful for patients affected by aggressive epilepsy syndromes since a young age, those whose seizure foci are located in the mesial temporal lobe, and those who have failed prior surgical interventions.

Involvement of the Anterior Nucleus of the Thalamus during Focal Automatisms in Epileptic Seizures: A First Evidence Study.

The Anterior Nucleus of Thalamus (ANT) Deep Brain Stimulation (DBS) has long been touted as the most effective DBS-target for interrupting seizures in focal refractory epilepsy patients. The ANT is primarily involved in cognitive tasks but has extensive reciprocal connections with motor-related regions, suggesting that it is also involved in motor-cognitive tasks. In this work, we aimed to assess the involvement of the ANT during voluntary upper limbs movements. For this purpose, we analyzed Local Field Potentials (LFPs) signals recorded during a movement protocol from one of the first epilepsy patients implanted with a Percept™ PC system, who performed a 5-day period of simultaneous video electroencephalography (vEEG) and Percept PC-LFPs recordings. We estimated time-frequency maps and performed event-related desynchronization (ERD) or synchronization (ERS) analysis and we found that synchronizations found in left hemisphere 7-17 Hz map corresponded to maximum hand rotations. Positive peaks on the ERD/ERS curve occurred at a similar frequency of the hand movements ([Formula: see text] against [Formula: see text]). These results suggested that the ANT may be involved in the execution of automatisms. Moreover, we found that ERD/ERS appeared approximately 2 seconds before the movement onset, as it was found on the EEG of healthy subjects performing the same protocol.

Anterior nucleus of the thalamus deep brain stimulation vs temporal lobe responsive neurostimulation for temporal lobe epilepsy.

Based on the promising results of randomized controlled trials, deep brain stimulation (DBS) and responsive neurostimulation (RNS) are used increasingly in the treatment of patients with drug-resistant epilepsy. Drug-resistant temporal lobe epilepsy (TLE) is an indication for either DBS of the anterior nucleus of the thalamus (ANT) or temporal lobe (TL) RNS, but there are no studies that directly compare the seizure benefits and adverse effects associated with these therapies in this patient population. We, therefore, examined all patients who underwent ANT-DBS or TL-RNS for drug-resistant TLE at our center. We performed a retrospective review of patients who were treated with either ANT-DBS or TL-RNS for drug-resistant TLE with at least 12 months of follow-up. Along with the clinical characteristics of each patient's epilepsy, seizure frequency was recorded throughout each patient's postoperative clinical course. Twenty-six patients underwent ANT-DBS implantation and 32 patients underwent TL-RNS for drug-resistant TLE. The epilepsy characteristics of both groups were similar. Patients who underwent ANT-DBS demonstrated a median seizure reduction of 58% at 12-15 months, compared to a median seizure reduction of 70% at 12-15 months in patients treated with TL-RNS (p > .05). The responder rate (percentage of patients with a 50% decrease or more in seizure frequency) was 54% for ANT-DBS and 56% for TL-RNS (p > .05). The incidence of complications and stimulation-related side effects did not significantly differ between therapies. We demonstrate in our single-center experience that patients with drug-resistant TLE benefit similarly from either ANT-DBS or TL-RNS. Selection of either ANT-DBS or TL-RNS may, therefore, depend more heavily on patient and provider preference, as each has unique capabilities and configurations. Future studies will consider subgroup analyses to determine if specific patients have greater seizure frequency reduction from one form of neuromodulation strategy over another.

Responsive Thalamic Neurostimulation: A Systematic Review of a Promising Approach for Refractory Epilepsy.

IntroductionResponsive neurostimulation is an evolving therapeutic option for patients with treatment-refractory epilepsy. Open-loop, continuous stimulation of the anterior thalamic nuclei is the only approved modality, yet chronic stimulation rarely induces complete seizure remission and is associated with neuropsychiatric adverse effects. Accounts of off-label responsive stimulation in thalamic nuclei describe significant improvements in patients who have failed multiple drug regimens, vagal nerve stimulation, and other invasive measures. This systematic review surveys the currently available data supporting the use of responsive thalamic neurostimulation in primary and secondary generalized, treatment-refractory epilepsy.Materials and MethodsA systematic review was performed using the following combination of keywords and controlled vocabulary: (“Seizures”[Mesh] AND “Thalamus”[Mesh] AND “Deep Brain Stimulation”[Mesh]) OR (responsive neurostim* AND (thalamus[MeSH])) OR [responsive neurostimulation AND thalamus AND (epilepsy OR seizures)]. In addition, a search of the publications listed under the PubMed “cited by” tab was performed for all publications that passed title/abstract screening in addition to manually searching their reference lists.ResultsTen publications were identified describing a total of 29 subjects with a broad range of epilepsy disorders treated with closed-loop thalamic neurostimulation. The median age of subjects was 31 years old (range 10–65 years). Of the 29 subjects, 15 were stimulated in the anterior, 11 in the centromedian, and 3 in the pulvinar nuclei. Excluding 5 subjects who were treated for 1 month or less, median time on stimulation was 19 months (range 2.4–54 months). Of these subjects, 17/24 experienced greater than or equal to 50%, 11/24 least 75%, and 9/24 at least 90% reduction in seizures. Although a minority of patients did not exhibit significant clinical improvement by follow-up, there was a general trend of increasing treatment efficacy with longer periods on closed-loop thalamic stimulation.ConclusionThe data supporting off-label closed-loop thalamic stimulation for refractory epilepsy is limited to 29 adult and pediatric patients, many of whom experienced significant improvement in seizure duration and frequency. This encouraging progress must be verified in larger studies.

Neuromodulation of the anterior thalamic nucleus as a therapeutic option for difficult-to-control epilepsy.

Deep brain stimulation (DBS) consists of the electrical stimulation of the subcortical structures by implanting electrodes connected to a pulse generator. The thalamus, being a structure that has multiple connections with various parts of the central nervous system, is a suitable target for DBS. The anterior thalamic nucleus (ANT) serves as an important relay site for the limbic system by receiving input from the hippocampus and mammillary bodies, and sending input to the cingulate gyrus; thus forming the Papez circuit. Due to these connections, the ANT constitutes an ideal route for the propagation of epileptogenic activity. ANT-DBS has excellent results in the control of complex partial seizures. The vast majority of patients with ANT-DBS have shown a significant reduction in the frequency of their seizures of more than 50%.

Investigating Fractal Analysis as a Diagnostic Tool That Probes the Connectivity of Hippocampal Neurons.

Many of nature’s fractal objects benefit from the favorable functionality that results from their pattern repetition at multiple scales. Our recent research focused on the importance of fractal scaling in establishing connectivity between neurons. Fractal dimension D A of the neuron arbors was shown to relate to the optimization of competing functional constraints—the ability of dendrites to connect to other neurons versus the costs associated with building the dendrites. Here, we consider whether pathological states of neurons might affect this fractal optimization and if changes in D A might therefore be used as a diagnostic tool in parallel with traditional measures like Sholl analyses. We use confocal microscopy to obtain images of CA1 pyramidal neurons in the coronal plane of the dorsal rat hippocampus and construct 3-dimensional models of the dendritic arbors using Neurolucida software. We examine six rodent groups which vary in brain condition (whether they had lesions in the anterior thalamic nuclei, ATN) and experience (their housing environment and experience in a spatial task). Previously, we showed ATN lesions reduced spine density in hippocampal CA1 neurons, whereas enriched housing increased spine density in both ATN lesion and sham rats. Here, we investigate whether ATN lesions and experience also effect the complexity and connectivity of CA1 dendritic arbors. We show that sham rats exposed to enriched housing and spatial memory training exhibited higher complexity (as measured by D A ) and connectivity compared to other groups. When we categorize the rodent groups into those with or without lesions, we find that both categories achieve an optimal balance of connectivity with respect to material cost. However, the D A value used to achieve this optimization does not change between these two categories, suggesting any morphological differences induced by the lesions are too small to influence the optimization process. Accordingly, we highlight considerations associated with applying our technique to publicly accessible repositories of neuron images with a broader range of pathological conditions.

Long Term Performance of a Bi-Directional Neural Interface for Deep Brain Stimulation and Recording.

Background: In prior reports, we described the design and initial performance of a fully implantable, bi-directional neural interface system for use in deep brain and other neurostimulation applications. Here we provide an update on the chronic, long-term neural sensing performance of the system using traditional 4-contact leads and extend those results to include directional 8-contact leads.Methods: Seven ovine subjects were implanted with deep brain stimulation (DBS) leads at different nodes within the Circuit of Papez: four with unilateral leads in the anterior nucleus of the thalamus and hippocampus; two with bilateral fornix leads, and one with bilateral hippocampal leads. The leads were connected to either an Activa PC+S® (Medtronic) or Percept PC°ledR (Medtronic) deep brain stimulation and recording device. Spontaneous local field potentials (LFPs), evoked potentials (EPs), LFP response to stimulation, and electrode impedances were monitored chronically for periods of up to five years in these subjects.Results: The morphology, amplitude, and latencies of chronic hippocampal EPs evoked by thalamic stimulation remained stable over the duration of the study. Similarly, LFPs showed consistent spectral peaks with expected variation in absolute magnitude dependent upon behavioral state and other factors, but no systematic degradation of signal quality over time. Electrode impedances remained within expected ranges with little variation following an initial stabilization period. Coupled neural activity between the two nodes within the Papez circuit could be observed in synchronized recordings up to 5 years post-implant. The magnitude of passive LFP power recorded from directional electrode segments was indicative of the contacts that produced the greatest stimulation-induced changes in LFP power within the Papez network.Conclusion: The implanted device performed as designed, providing the ability to chronically stimulate and record neural activity within this network for up to 5 years of follow-up.