Centromedian Research Articles

High Frequency Stimulation of the Centromedian Thalamic Nucleus to Abort Seizures and Interictal Discharges During Stereoelectroencephalography Evaluation (P5-1.007)

<h3>Objective:</h3> To assess whether high frequency stimulation of the centromedian nucleus of the thalamus can disrupt seizures and/or interictal discharges. <h3>Background:</h3> There is growing evidence that subcortical structures, including the thalamus, are involved in seizure networks in patients with neocortical epilepsy. Responsive neurostimulation of the centromedian nucleus of the thalamus (CMT) has been shown to terminate seizures in case reports of patients with generalized and focal neocortical epilepsy [Burdette, et al. <i>Epilepsy and Behavior</i>, 2020]. However, to our knowledge, no prior reports have demonstrated the utility of stimulating the thalamus during a sEEG evaluation. We present two patients with refractory neocortical epilepsy who underwent sEEG evaluation including an electrode in the CMT. <h3>Design/Methods:</h3> Both patients underwent real-time high frequency stimulation (HFS) at CMT during runs of interictal discharges. Patient 1 was also stimulated during seizures. Stimulation settings for both patients were 50Hz, 0.3msec pulse duration, for 3 seconds. Patient 1 underwent stimulation at 2mA while Patient 2 was 1mA. For patient 1, seizure characteristics before and after stimulation were compared using a student’s t-test (duration) and Fisher exact test (apnea). <h3>Results:</h3> For Patient 1, HFS of the CMT successfully aborted 4 seizures. Compared to 11 seizures prior to stimulation, those with HFS were significantly shorter (9.5 vs. 20.5 seconds, p=0.018). The patient did not develop clinical apnea in any of the 4 seizures aborted with HFS, but did with all of the 11 seizures without stimulation (p=0.001). Stimulation during runs of interictal discharges was inconclusive. In Patient 2, HFS aborted runs of inter-ictal discharges in all 10 attempts. <h3>Conclusions:</h3> These cases demonstrate that stimulation of the CMT during sEEG evaluation can abort electroclinical seizures and potentially interictal discharges. This supports the idea that the CMT is involved in focal neocortical epilepsy networks. Stimulation during sEEG may be useful in predicting efficacy of thalamic neurostimulation. <b>Disclosure:</b> Dr. Nathan has nothing to disclose. Dr. Adney has received research support from NINDS. Joshua M Rosenow, MD, FAANS, FACS has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Boston Scientific Neuromodulation. Dr. Schuele has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Monteris. Dr. Schuele has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Neurelis. Dr. Schuele has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for SK Life Science. Dr. Schuele has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Jazz. Dr. Schuele has received personal compensation in the range of $50,000-$99,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Journal of Clinical Neurophysiology. Dr. Schuele has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Thomas Needham. Dr. Schuele has received research support from National Institute of Health. Dr. Gerard has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Greenwich Pharmaceuticals. The institution of Dr. Gerard has received research support from NIH/NINDS. The institution of Dr. Gerard has received research support from Xenon Pharmaceuticals. The institution of an immediate family member of Dr. Gerard has received research support from NIH. The institution of an immediate family member of Dr. Gerard has received research support from Novo Nordisk. The institution of Dr. Gerard has received research support from Eisai, Inc. (via Stanford University).

Thalamic neuromodulation outcomes in drug-resistant refractory epilepsy with Deep Brain Stimulation and Responsive Neurostimulation (P5-1.003)

<h3>Objective:</h3> We aim to compare effects of thalamic Deep Brain Stimulator (DBS) and responsive neurostimulator (RNS) device therapy on seizure burden in drug-resistant epilepsy patients. <h3>Background:</h3> Intractable epilepsy unamenable to cortical resection is often treated with a device, either RNS or DBS provides intracranial stimulation. The devices are thought to reduce seizure frequency by reducing synchronization of cortical activity. The RNS provides more localized stimulation while the DBS does this by stimulating the anterior nucleus of the thalamus. At our institution a small number of patients have also undergone thalamic stimulation by using the RNS. <h3>Design/Methods:</h3> We performed retrospective analysis on seizure frequency pre-implant and at most recent follow-up for our cohort, 12 DBS and 6 RNS patients. <h3>Results:</h3> Average age of RNS implantation was 30 years (range 19–41) vs 42 years (range 18–66) for DBS. Thirteen (9 DBS, 4 RNS) of the 18 patients had stereo-EEG (SEEG) evaluation before device placement, SEEG ictal onset was broad or multifocal in all (DBS: 7 – bilateral and 2 – unilateral, RNS: 3 bilateral, 1 unilateral). Three out of five patients who did not have invasive EEG evaluation before device placement had suspected (2) or confirmed (1) genetic etiology, all five had non-localizing, non-lateralizing scalp ictal EEG. The electrodes were placed to the anterior nucleus of thalamus bilaterally in all DBS and four RNS patients, two RNS patients had centromedian nucleus of thalamus sampling. Twelve of our 18 patients (8 out of 12 DBS and 4 out of 6 RNS) were shown to be responders, achieving 50% or greater reduction in seizure frequency. The average follow-up duration for RNS was 22 months (range 3–36), for DBS 13.5 months (range 2–29). <h3>Conclusions:</h3> This analysis demonstrates the potency of thalamic neuromodulation, both RNS and DBS, as therapies capable of seizure relief in wide breadths of epilepsy presentations. <b>Disclosure:</b> Dr. Das has received personal compensation for serving as an employee of Concentra. Dr. Das has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for janicek. The institution of an immediate family member of Dr. Das has received research support from NIH. irina podkorytova has nothing to disclose. Chijindu Iheanacho has nothing to disclose. Dr. Alick-Lindstrom has nothing to disclose. Dr. Agostini has nothing to disclose. Dr. Doyle has nothing to disclose. The institution of Dr. Ding has received research support from National Institute of Aging. The institution of Dr. Ding has received research support from NINDS. Dr. Hays has nothing to disclose. Dr. Perven has nothing to disclose. Dr. Dieppa has nothing to disclose. Dr. Zepeda Garcia has nothing to disclose.

Precision Mapping of Thalamic Deep Brain Stimulation Lead Positions Associated With the Microlesion Effect in Tourette Syndrome.

The microlesion effect refers to the improvement of clinical symptoms after deep brain stimulation (DBS) lead placement and is suggested to indicate optimal lead placement. Very few studies have reported its implications in neuropsychiatric disorders. To evaluate the magnitude of the microlesion effect in Tourette syndrome and the relationship between the microlesion effect and the anatomic location of implanted DBS leads. Six male patients were included. Their median age at surgery and follow-up period were 25 years (range, 18-47) and 12 months (range, 6-24), respectively. All patients were videotaped pre- and postoperatively, and tic frequencies were counted. We also analyzed the precision of lead placement and evaluated the normative connectome associated with the microlesion area. The microlesion effect was observed as an improvement in tic symptoms in all patients, and the long-term clinical outcomes were favorable. The median motor tic frequency was 20.2 tics/min (range, 9.7-60) at baseline and decreased to 3.2 tics/min (1.2-11.3) in patients on postoperative day 1 ( P = .043) and to 5.7 tics/min (range, 1.9-16.6) in patients on postoperative day 7 ( P = .028). Phonic tic tended to improve immediately after surgery although the changes were not significant. Image analyses revealed that the precise position of the electrode was directed toward the anteromedial centromedian nucleus. Normative connectome analysis demonstrated connections between improvement-related areas and wide areas of the prefrontal cortex. This study shows that the microlesion effect may seem as an immediate improvement after optimal DBS lead placement in patients with Tourette syndrome.

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

INTRODUCTION: One-third of patients with epilepsy experience seizures despite antiepileptic medications. Some of these refractory patients may not be candidates for surgical resection. The Responsive Neurostimulation System (RNS) is a closed-loop device that uses programmable detection and stimulation. METHODS: We 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. RESULTS: Twenty-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. Two patients (8.7%) developed infections: 1 improved with antibiotic treatments alone, and 1 required removal with eventual replacement of the system. Mean follow-up was 22.3 months. Based on overall reduction of seizure frequency, 2 patients (8.7%) had no- to &lt;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 foci located in the temporal lobe to achieve better outcomes after thalamic RNS compared to those with extratemporal foci. Seizure etiology was syndromic in 12 cases (52.2%). CONCLUSIONS: Thalamic 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.

449 Stereoencephalography of Centromedian Thalamus Reveals Distinct Patterns of Thalamocortical Synchrony Across Seizure Onset Zones

INTRODUCTION: Thalamic nuclei are increasingly used targets for study and therapeutic modulation in drug-resistant epilepsy (DRE). Centromedian nucleus of thalamus (CMN) is relatively understudied despite known widespread connectivity and previous reports suggesting a role in both generalized and multifocal epilepsies. METHODS: The clinical and electrographic data of 13 consecutive patients who had at least one sEEG electrode sampling CMN were included. Electrographic seizures were visually analyzed for thalamic activity changes at seizure onset (SO), maintenance (SM), and end (SE) periods. Recordings were quantitatively assessed using a measure of sEEG signal interdependency (non-linear regression coefficient, h2) to compare thalamocortical synchrony at SO and SE periods. All analyses were performed using AnyWave software. RESULTS: Eighty focal-onset seizures (median 4, range 1-19 per patient) were captured and included in analysis. SOZs were mesial temporal (33%), neocortical temporal (23%), frontal (29%), and non-frontal extratemporal (15%). Median seizure length was 78 (IQR 25-133) seconds. In 74% of seizures, a change in thalamic activity was visually perceptible during the seizure with a median latency of 5 (IQR 2-9) seconds. A low voltage fast activity pattern predominantly in the alpha band was most commonly seen during SO. When thalamic activity changed during SM, a rhythmic spike-wave pattern was most often seen. Rhythmic waves predominantly in the delta band were the most common pattern of activity at SE. Average thalamocortical h2 values in the SE period were significantly higher than the SO period (Kruskal-Wallis p &lt; 0.0001). Mesial temporal, temporal, and frontal seizures demonstrated significant increases in thalamocortical synchronization while non-frontal extratemporal seizures did not. CONCLUSIONS: Consistent dynamic ictal patterns can be visualized within CMN thalamus using sEEG recordings. Bidirectional signal synchronization peaks during the SE period and may be involved in seizure termination.

453 Neuromodulation of the Centromedian Nucleus of the Thalamus for the Treatment of Generalized Drug-Resistant Epilepsy: Novel Insights Into the Targeting and the Anti-Seizure Mechanism From a Tractographic Study

INTRODUCTION: Neuromodulation of the centromedian nucleus (CM) has been investigated with promising results for the treatment of generalized drug-resistant epilepsy (gDRE). Recent evidence suggests a more clinically beneficial “sweet-spot” corresponding to the thalamic area between the antero-lateral CM and the posterior subdivision of the ventrolateral nucleus. However, it is unclear if this region can be considered a new target or still a subcomponent of CM. METHODS: We analyzed diffusion and structural MRI scans from 9 DRE patients, who underwent CM-stimulation surgery. CM masks from the THOMAS atlas and 2 spherical ROIs from the MNI coordinates of the sweet-spot and the cold-spot in Warren et al. 2022 were used as seed regions for probabilistic tractography (FSL software). 42 cortical and subcortical areas were selected as target regions and divided in 5 groups: sensorimotor, associative, basal ganglia, infratentorial and limbic structures. Mean structural connectivity was calculated using descriptive statistics and statistical significance was tested with a standard t-test. Statistical comparison among the 3 seed regions was conducted using ANOVA. RESULTS: For each seed, statistically significant (p &lt; 0.05) connections were found for all the 5 groups. When comparing the 3 seeds, the CM and the cold-spot had stronger connections with the postcentral and the superior temporal cortices, the brainstem, the caudate and the amygdala; the sweet-spot with the precentral and the superior frontal cortices, the cerebellum, the putamen and the nucleus accumbens. However, no statistically significant differences resulted among the 3 seeds. CONCLUSIONS: CM has widespread connections with both cortical and subcortical structures. The sweet-spot seems to correspond to the parvocellular part of CM on the border with the ventrolateral nucleus. CM connections with frontal and prefrontal areas and the cerebellum may underlie the beneficial effect against generalized seizures.

Post-ictal Rhythmic Thalamic Activity of the Centromedian Nucleus.

Deep brain stimulation of the centromedian nucleus of the thalamus (CMN) to treat drug-resistant epilepsy has been of interest for decades. However, little is known about the electrophysiological activity of the CMN during seizures. We describe a novel CMN EEG finding associated with seizure: post-ictal rhythmic thalamic activity. Five patients with drug-resistant epilepsy of unknown etiology with focal onset seizures underwent stereoelectroencephalography monitoring as part of evaluation for potential resective surgery or neuromodulation. Two patients had previously undergone complete corpus callosotomy and vagus nerve stimulation. A standardized plan for implantation included targets in the bilateral CMN. Each patient had frontal onset seizures, and two patients had additional insular, parietal, or mesial temporal onset seizures. Contacts of CMN were involved synchronously or rapidly after onset in most recorded seizures, particularly those with frontal onset. Focal onset hemiclonic and bilateral tonic-clonic seizures spread to involve cortical contacts with high-amplitude rhythmic spiking followed by abrupt offset with diffuse voltage attenuation. A post-ictal rhythmic 1.5 to 2.5 Hz delta frequency pattern, post-ictal rhythmic thalamic activity, emerged in CMN contacts amid the suppression of background activity in cortical contacts. In the two patients with corpus callosotomy, unilateral seizure spread and ipsilateral post-ictal rhythmic thalamic activity were observed. We observed post-ictal rhythmic thalamic activity in five patients with stereoelectroencephalography monitoring of the CMN with convulsive seizures. This rhythm appears late in ictal evolution and may signal an important role of the CMN in seizure termination. Furthermore, this rhythm may help identify CMN involvement in the epileptic network.

Frameless Robot-Assisted Asleep Centromedian Thalamic Nucleus Deep Brain Stimulation Surgery in Patients with Drug-Resistant Epilepsy: Technical Description and Short-Term Clinical Results.

This purpose of this work is to give a detailed description of a surgical technique for frameless robot-assisted asleep deep brain stimulation (DBS) of the centromedian thalamic nucleus (CMT) in drug-resistant epilepsy (DRE). Ten consecutively enrolled patients who underwent CMT-DBS were included in the study. The FreeSurfer "Thalamic Kernel Segmentation" module and experience target coordinates were used for locating the CMT, and quantitative susceptibility mapping (QSM) images were used to check the target. The patient's head was secured with a head clip, and electrode implantation was performed with the assistance of the neurosurgical robot Sinovation®. After opening the dura, the burr hole was continuously flushed with physiological saline to stop air from entering the skull. All procedures were performed under general anesthesia without intraoperative microelectrode recording (MER). The mean age of the patients at surgery and onset of seizures was 22years (range 11-41years) and 11years (range 1-21years), respectively. The median duration of seizures before CMT-DBS surgery was 10years (2-26years). CMT was successfully segmented, and its position was verified by experience target coordinates and QSM images in all ten patients. The mean surgical time for bilateral CMT-DBS in this cohort was 165 ± 18min. The mean pneumocephalus volume was 2 cm3. The median absolute errors in the x-, y-, and z-axes were 0.7mm, 0.5mm, and 0.9mm, respectively. The median Euclidean distance (ED) and radial error (RE) was 1.3 ± 0.5mm and 1.0 ± 0.3mm, respectively. No significant difference was found between right- and left-sided electrodes regarding the RE nor the ED. After a mean 12-month follow-up, the average reduction in seizures was 61%, and six patients experienced a ≥ 50% reduction in seizures, including one patient who had no seizures after the operation. All patients tolerated the anesthesia operation, and no permanent or serious complications were reported. Frameless robot-assisted asleep surgery is a precise and safe approach for placing CMT electrodes in patients with DRE, shortening the surgery time. The segmentation of the thalamic nuclei enables the precise location of the CMT, and the flow of physiological saline to seal the burr holes is a good way to reduce the influx of air. CMT-DBS is an effective method to reduce seizures.

Medial Pulvinar Stimulation in Temporal Lobe Epilepsy: A Literature Review and a Hypothesis Based on Neuroanatomical Findings.

While bilateral stimulation of the anterior thalamic nuclei remains the only approved deep brain stimulation (DBS) option for focal epilepsy, two additional thalamic targets have been proposed. Earlier work indicated the potential of centromedian thalamic nucleus stimulation with recent findings highlighting the medial pulvinar nucleus. The latter has been shown to exhibit electrophysiological and imaging alterations in patients with partial status epilepticus and temporal lobe epilepsy. On this basis, recent studies have begun assessing the feasibility and efficacy of pulvinar stimulation, with encouraging results on the reduction of seizure frequency and severity. Building on existing neuroanatomical knowledge, indicating that the medial pulvinar is connected to the temporal lobe via the temporopulvinar bundle of Arnold, we hypothesize that this is one of the routes through which medial pulvinar stimulation affects temporal lobe structures. We suggest that further anatomic, imaging, and electrophysiologic studies are warranted to deepen our understanding of the subject and guide future clinical applications.

Arousal and salience network connectivity alterations in surgical temporal lobe epilepsy.

It is poorly understood why patients with mesial temporal lobe epilepsy (TLE) have cognitive deficits and brain network changes that extend beyond the temporal lobe, including altered extratemporal intrinsic connectivity networks (ICNs). However, subcortical arousal structures project broadly to the neocortex, are affected by TLE, and thus may contribute to these widespread network effects. The authors' objective was to examine functional connectivity (FC) patterns between subcortical arousal structures and neocortical ICNs, possible neurocognitive relationships, and FC changes after epilepsy surgery. The authors obtained resting-state functional magnetic resonance imaging (fMRI) in 50 adults with TLE and 50 controls. They compared nondirected FC (correlation) and directed FC (Granger causality laterality index) within the salience network, default mode network, and central executive network, as well as between subcortical arousal structures; these 3 ICNs were also compared between patients and controls. They also used an fMRI-based vigilance index to relate alertness to arousal center FC. Finally, fMRI was repeated in 29 patients > 12 months after temporal lobe resection. Nondirected FC within the salience (p = 0.042) and default mode (p = 0.0008) networks, but not the central executive network (p = 0.79), was decreased in patients in comparison with controls (t-tests, corrected). Nondirected FC between the salience network and subcortical arousal structures (nucleus basalis of Meynert, thalamic centromedian nucleus, and brainstem pedunculopontine nucleus) was reduced in patients in comparison with controls (p = 0.0028-0.015, t-tests, corrected), and some of these connectivity abnormalities were associated with lower processing speed index, verbal comprehension, and full-scale IQ. Interestingly, directed connectivity measures suggested a loss of top-down influence from the salience network to the arousal nuclei in patients. After resection, certain FC patterns between the arousal nuclei and salience network moved toward control values in the patients, suggesting that some postoperative recovery may be possible. Although an fMRI-based vigilance measure suggested that patients exhibited reduced alertness over time, FC abnormalities between the salience network and arousal structures were not influenced by the alertness levels during the scans. FC abnormalities between subcortical arousal structures and ICNs, such as the salience network, may be related to certain neurocognitive deficits in TLE patients. Although TLE patients demonstrated vigilance abnormalities, baseline FC perturbations between the arousal and salience networks are unlikely to be driven solely by alertness level, and some may improve after surgery. Examination of the arousal network and ICN disturbances may improve our understanding of the downstream clinical effects of TLE.

Deep brain stimulation of thalamus for epilepsy

Neuromodulation (neurostimulation) is a relatively new and rapidly growing treatment for refractory epilepsy. Three varieties are approved in the US: vagus nerve stimulation (VNS), deep brain stimulation (DBS) and responsive neurostimulation (RNS). This article reviews thalamic DBS for epilepsy. Among many thalamic sub-nuclei, DBS for epilepsy has been targeted to the anterior nucleus (ANT), centromedian nucleus (CM), dorsomedial nucleus (DM) and pulvinar (PULV). Only ANT is FDA-approved, based upon a controlled clinical trial. Bilateral stimulation of ANT reduced seizures by 40.5% at three months in the controlled phase (p = .038) and 75% by 5 years in the uncontrolled phase. Side effects related to paresthesias, acute hemorrhage, infection, occasional increased seizures, and usually transient effects on mood and memory. Efficacy was best documented for focal onset seizures in temporal or frontal lobe. CM stimulation may be useful for generalized or multifocal seizures and PULV for posterior limbic seizures. Mechanisms of DBS for epilepsy are largely unknown, but animal work points to changes in receptors, channels, neurotransmitters, synapses, network connectivity and neurogenesis. Personalization of therapies, in terms of connectivity of the seizure onset zone to the thalamic sub- nucleus and individual characteristics of the seizures, might lead to improved efficacy. Many questions remain about DBS, including the best candidates for different types of neuromodulation, the best targets, the best stimulation parameters, how to minimize side effects and how to deliver current noninvasively. Despite the questions, neuromodulation provides useful new opportunities to treat people with refractory seizures not responding to medicines and not amenable to resective surgery.

Neurostimulation in generalized epilepsy: A systematic review and meta-analysis.

There are three neurostimulation devices available to treat generalized epilepsy: vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS). However, the choice between them is unclear due to lack of head-to-head comparisons. A systematic comparison of neurostimulation outcomes in generalized epilepsy has not been performed previously. The goal of this meta-analysis was to determine whether one of these devices is better than the others to treat generalized epilepsy. Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a systematic review of PubMed, Embase, and Web of Science was performed for studies reporting seizure outcomes following VNS, RNS, and DBS implantation in generalized drug-resistant epilepsy between the first pivotal trial study for each modality through August 2022. Specific search criteria were used for VNS ("vagus", "vagal", or "VNS" in the title and "epilepsy" or "seizure"), DBS ("deep brain stimulation", "DBS", "anterior thalamic nucleus", "centromedian nucleus", or "thalamic stimulation" in the title and "epilepsy" or "seizure"), and RNS ("responsive neurostimulation" or "RNS" in the title and "epilepsy" or "seizure"). From 4409 articles identified, 319 underwent full-text reviews, and 20 studies were included. Data were pooled using a random-effects model using the meta package in R. Sufficient data for meta-analysis were available from seven studies for VNS (n= 510) and nine studies for DBS (n= 87). Data from RNS (five studies, n= 18) were insufficient for meta-analysis. The mean (SD) follow-up durations were as follows: VNS, 39.1 (23.4) months; DBS, 23.1 (19.6) months; and RNS, 22.3 (10.6) months. Meta-analysis showed seizure reductions of 48.3% (95% confidence interval [CI] = 38.7%-57.9%) for VNS and 64.8% (95% CI=54.4%-75.2%) for DBS (p= .02). Our meta-analysis indicates that the use of DBS may lead to greater seizure reduction than VNS in generalized epilepsy. Results from RNS use are promising, but further research is required.

Thalamic nuclei changes in early and late onset Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Increasing evidence points to the thalamus as an important hub in the clinical symptomatology of the disease, with the 'limbic thalamus' been described as especially vulnerable. In this work, we examined thalamic atrophy in early-onset AD (EOAD) and late-onset AD (LOAD) compared to young and old healthy controls (YHC and OHC, respectively) using a recently developed cutting-edge thalamic nuclei segmentation method. A deep learning variant of Thalamus Optimized Multi Atlas Segmentation (THOMAS) was used to parcellate 11 thalamic nuclei per hemisphere from T1-weighted MRI in 88 biomarker-confirmed AD patients (49 EOAD and 39 LOAD) and 58 healthy controls (41 YHC and 17 OHC) with normal AD biomarkers. Nuclei volumes were compared among groups using MANCOVA. Further, Pearson's correlation coefficient was computed between thalamic nuclear volume and cortical-subcortical regions, CSF tau levels, and neuropsychological scores. The results showed widespread thalamic nuclei atrophy in EOAD and LOAD compared to their respective healthy control groups, with EOAD showing additional atrophy in the centromedian and ventral lateral posterior nuclei compared to YHC. In EOAD, increased thalamic nuclei atrophy was associated with posterior parietal atrophy and worse visuospatial abilities, while LOAD thalamic nuclei atrophy was preferentially associated with medial temporal atrophy and worse episodic memory and executive function. Our findings suggest that thalamic nuclei may be differentially affected in AD according to the age at symptoms onset, associated with specific cortical-subcortical regions, CSF total tau and cognition.

Structural connections of the centromedian nucleus of thalamus and their relevance for neuromodulation in generalized drug-resistant epilepsy: insight from a tractography study.

Epilepsy is a widespread neurologic disorder and almost one-third of patients suffer from drug-resistant epilepsy (DRE). Neuromodulation targeting the centromediannucleus of the thalamus (CM) has been showing promising results for patients with generalized DRE who are not surgical candidates. Recently, the effect of CM- deep brain stimulation (DBS) in DRE patients was investigated in the Electrical Stimulation of Thalamus for Epilepsy of Lennox-Gastaut phenotype (ESTEL) trial, a monocentric randomized-controlled study. The same authors described a 'cold-spot' and a 'sweet-spot', which are defined as the volume of stimulation in the thalamus yielding the least and the best clinical response, respectively. However, it remains unclear which structural connections may contribute to the anti-seizure effect of the stimulation. We investigated the differences in structural connectivity among CM, the sweet-spot and the cold-spot. Furthermore, we tried to validate our results in a cohort of DRE patients who underwent CM-DBS or CM-RNS (responsive neurostimulation). We hypothesized that the sweet-spot would share similar structural connectivity with responder patients. By using the software FMRIB Software Library (FSL), probabilistic tractography was performed on 100 subjects from the Human Connectome Project to calculate the probability of connectivity of the whole CM, the sweet-spot and the cold-spot to 45 cortical and subcortical areas. Results among the three seeds were compared with multivariate analysis of variance (MANOVA). Similarly, the structural connectivity of volumes of tissue activated (VTAs) from eight DRE patients was investigated. Patients were divided into responders and non-responders based on the degree of reduction in seizure frequency, and the mean probabilities of connectivity were similarly compared between the two groups. The sweet-spot demonstrated a significantly higher probability of connectivity (p < 0.001) with the precentral gyrus, superior frontal gyrus, and the cerebellum than the whole CM and the cold-spot. Responder patients displayed a higher probability of connectivity with both ipsilateral (p = 0.011) and contralateral cerebellum (p = 0.04) than the non-responders. Cerebellar connections seem to contribute to the beneficial effects of CM-neuromodulation in patients with drug-resistant generalized epilepsy.

Centromedian thalamic deep brain stimulation for drug-resistant epilepsy: single-center experience.

Neuromodulation of the centromedian nucleus of the thalamus (CM) has unclear effectiveness in the treatment of drug-resistant epilepsy. Prior reports suggest that it may be more effective in the generalized epilepsies such as Lennox-Gastaut syndrome (LGS). The objective of this study was to determine the outcome of CM deep brain stimulation (DBS) at the authors' institution. Retrospective chart review was performed for all patients who underwent CM DBS at Emory University, which occurred between December 2018 and May 2021. CM DBS electrodes were implanted using three different surgical methods, including frame-based, robot-assisted, and direct MRI-guided. Seizure frequency, stimulation parameters, and adverse events were recorded from subsequent clinical follow-up visits. Fourteen patients underwent CM DBS: 9 had symptomatic generalized epilepsy (including 5 with LGS), 3 had primary or idiopathic generalized epilepsy, and 2 had bifrontal focal epilepsy. At last follow-up (mean [± SEM] 19 ± 5 months, range 4.1-33 months, ≥ 6 months in 11 patients), the median seizure frequency reduction was 91%. Twelve patients (86%) were considered responders (≥ 50% decrease in seizure frequency), including 10 of 12 with generalized epilepsy and both patients with bifrontal epilepsy. Surgical adverse events were rare and included 1 patient with hardware breakage, 1 with a postoperative aspiration event, and 1 with a nonclinically significant intracranial hemorrhage. CM DBS was an effective treatment for drug-resistant generalized and bifrontal epilepsies. Additional studies and analyses may investigate whether CM DBS is best suited for specific epilepsy types, and the relationship of lead location to outcome in different epilepsies.

Thalamic stereoelectroencephalography in epilepsy surgery: a scoping literature review.

Stereoelectroencephalography (sEEG) is a well-established surgical method for defining the epileptogenic network. Traditionally reserved for identifying discrete cortical regions for resection or ablation, sEEG in current practice is also used for identifying more broadly involved subcortical epileptic network components, driven by the availability of brain-based neuromodulation strategies. In particular, sEEG investigations including thalamic nuclei are becoming more frequent in parallel with the increase in therapeutic strategies involving thalamic targets such as deep brain stimulation (DBS) and responsive neurostimulation (RNS). The objective to this study was to evaluate existing evidence and trends regarding the purpose, techniques, and relevant electrographic findings of thalamic sEEG. MEDLINE and Embase databases were systematically queried for eligible peer-reviewed studies involving sEEG electrode implantation into thalamic nuclei of patients with epilepsy. Available data were abstracted concerning preoperative workup and purpose for implanting the thalamus, thalamic targets and trajectories, and electrophysiological methodology and findings. sEEG investigations have included thalamic targets for both basic and clinical research purposes. Medial pulvinar, dorsomedial, anterior, and centromedian nuclei have been the most frequently studied. Few studies have reported any complications with thalamic sEEG implantation, and no studies have reported long-term complications. Various methods have been utilized to characterize thalamic activity in epileptic disorders including evoked potentials, power spectrograms, synchronization indices, and the epileptogenicity index. Thalamic intracranial recordings are beginning to be used to guide neuromodulation strategies including RNS and DBS, as well as to understand complex, network-dependent seizure disorders. Inclusion of thalamic coverage during sEEG evaluation in drug-resistant epilepsy is a growing practice and is amenable to various methods of electrographic data analysis. Further study is required to establish well-defined criteria for thalamic implantation during invasive investigations as well as safety and ethical considerations.

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.

Corticotropin Releasing Factor (CRF) Coexpression in GABAergic, Glutamatergic, and GABA/Glutamatergic Subpopulations in the Central Extended Amygdala and Ventral Pallidum of Young Male Primates.

The central extended amygdala (CEA) and ventral pallidum (VP) are involved in diverse motivated behaviors based on rodent models. These structures are conserved, but expanded, in higher primates, including human. Corticotropin releasing factor (CRF), a canonical "stress molecule" associated with the CEA and VP circuitry across species, is dynamically regulated by stress and drugs of abuse and misuse. CRF's effects on circuits critically depend on its colocation with primary "fast" transmitters, making this crucial for understanding circuit effects. We surveyed the distribution and colocalization of CRF-, VGluT2- (vesicular glutamate transporter 2), and VGAT- (vesicular GABA transporter) mRNA in specific subregions of the CEA and VP in young male monkeys. Although CRF-containing neurons were clustered in the lateral central bed nucleus (BSTLcn), the majority were broadly dispersed throughout other CEA subregions, and the VP. CRF/VGAT-only neurons were highest in the BSTLcn, lateral central amygdala nucleus (CeLcn), and medial central amygdala nucleus (CeM) (74%, 73%, and 85%, respectively). In contrast, lower percentages of CRF/VGAT only neurons populated the sublenticular extended amygdala (SLEAc), ventrolateral bed nucleus (BSTLP), and VP (53%, 54%, 17%, respectively), which had higher complements of CRF/VGAT/VGluT2-labeled neurons (33%, 29%, 67%, respectively). Thus, the majority of CRF-neurons at the "poles" (BSTLcn and CeLcn/CeM) of the CEA are inhibitory, while the "extended" BSTLP and SLEAc subregions, and neighboring VP, have a more complex profile with admixtures of "multiplexed" excitatory CRF neurons. CRF's colocalization with its various fast transmitters is likely circuit-specific, and relevant for understanding CRF actions on specific target sites.SIGNIFICANCE STATEMENT The central extended amygdala (CEA) and ventral pallidum (VP) regulate multiple motivated behaviors through differential downstream projections. The stress neuropeptide corticotropin releasing factor (CRF) is enriched in the CEA, and is thought to "set the gain" through modulatory effects on coexpressed primary transmitters. Using protein and transcript assays in monkey, we found that CRF neurons are broadly and diffusely distributed in CEA and VP. CRF mRNA+ neurons colocalize with VGAT (GABA) and VGluT2 (glutamate) mRNAs in different proportions depending on subregion. CRF mRNA was also coexpressed in a subpopulation of VGAT/VGluT2 mRNA ("multiplexed") cells, which were most prominent in the VP and "pallidal"-like parts of the CEA. Heterogeneous CRF and fast transmitter coexpression across CEA/VP subregions implies circuit-specific effects.

Projections from the five divisions of the orbital cortex to the thalamus in the rat.

The orbital cortex (ORB) of the rat consists of five divisions: the medial (MO), ventral (VO), ventrolateral (VLO), lateral (LO), and dorsolateral (DLO) orbital cortices. No previous report has comprehensively examined and compared projections from each division of the ORB to the thalamus. Using the anterograde anatomical tracer, Phaseolus vulgaris leucoagglutinin, we describe the efferent projections from the five divisions of the ORB to the thalamus in the rat. We demonstrated that, with some overlap, each division of the ORB distributed in a distinct (and unique) manner to nuclei of the thalamus. Overall, ORB projected to a relatively restricted number of sites in the thalamus, and strikingly distributed entirely to structures of the medial/midline thalamus, while completely avoiding lateral regions or principal nuclei of the thalamus. The main termination sites in the thalamus were the paratenial nucleus (PT) and nucleus reuniens (RE) of the midline thalamus, the medial (MDm) and central (MDc) divisions of the mediodorsal nucleus, the intermediodorsal nucleus, the central lateral, paracentral, and central medial nuclei of the rostral intralaminar complex and the submedial nucleus (SM). With some exceptions, medial divisions of the ORB (MO, VO) mainly targeted "limbic-associated" nuclei such as PT, RE, and MDm, whereas lateral division (VLO, LO, DLO) primarily distributed to "sensorimotor-associated" nuclei including MDc, SM, and the rostral intralaminar complex. As discussed herein, the medial/midline thalamus may represent an important link (or bridge) between the orbital cortex and the hippocampus and between the ORB and medial prefrontal cortex. In summary, the present results demonstrate that each division of the orbital cortex projects in a distinct manner to nuclei of the thalamus which suggests unique functions for each division of the orbital cortex.

Management of Lennox-Gastaut syndrome with deep brain stimulation: A systematic literature review.

To review the current literature regarding the efficacy and safety of deep brain stimulation (DBS) in Lennox-Gastaut syndrome (LGS). The authors conducted a systematic review of PubMed databases using keywords relevant to the objective of this research. Titles and abstracts were reviewed, after which studies that met the inclusion criteria were selected. Findings were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Thirteen studies were identified, and only 3 studies that reported 50 patients (age range from 3 to 65 years) met the inclusion criteria of DBS for LGS. Radiological imaging findings and neurophysiological findings were described in all studies. The thalamus nuclei, particularly the centromedian thalamic nucleus (CMN), were found to be highly active in LGS. By targeting this brain region, patients showed favorable outcomes. Overall, the mean seizure reduction was more than 50% in all patients (among whom 2 were seizure free) at a mean follow-up of 15 (12-18) months. According to this systemic review, DBS for LGS showed satisfactory outcomes, indicating that DBS should be considered a valid treatment option. However, more studies are needed to ensure the role of DBS in LGS by establishing accurate targeting of the CMN using proper lead positioning and radiological imaging, a standard DBS intervention, and long-term outcomes.