Centromedian Research Articles

Deep brain stimulation targets in drug-resistant epilepsy: Systematic review and meta-analysis of effectiveness and predictors of response

PurposeAnterior nucleus of the thalamus (ANT) is the only deep brain stimulation (DBS) target that is approved by the FDA for treatment of drug-resistant epilepsy (DRE). Hippocampus (HC) and centromedian nucleus (CMN) have been reported as potential DBS targets for DRE. This study aimed to assess the effectiveness and predictors of response among DRE patients treated with DBS in general and among ANT, HC and CMN DBS-targets. MethodsA systematic search was executed on PubMed, SCOPUS and the Cochrane Central Register of Controlled Trials (CENTRAL) electronic databases between Jan 1, 2000 and June 29, 2020. Patients with DRE who underwent DBS treatment with at least three months of follow-up were included. Individual patient data (IPD) meta-analysis was conducted on DBS studies with available IPD. Response was defined as ≥50 % reduction in seizures frequency. Responders group was compared with non-responders group in terms of demographics, epilepsy/seizure characteristics, MRI findings, and DBS targets and duration of use. Subsequently, predictors of response to different DBS targets were investigated. ResultsThirty-nine studies with a total of 296 patients (ANT: 69 %, HC: 11 %, CMN: 21 %) were included. The responders group constituted of 209 patients (70.6 %). The response was significantly higher in patients with generalized seizures compared to those with focal seizures (93.2% vs 63.9 %; p < 0.001). Response was significantly higher with CMN (83.9 %) and HC (77.4 %) compared with ANT (65.5 %) as DBS targets (p = 0.014). Response was also significantly associated with longer duration of DBS use (p = 0.008). The responder rate was higher among the patients with lesional MRIs (76.7 %) than those with non-lesional MRIs (66.7 %), but with no statistically significant difference (p = 0.134). Age, gender, epilepsy etiology, onset zone of focal seizures, and previous use of VNS had no significant differences between the responders and non-responders. A binary logistic regression including the seizure type, MRI findings, DBS targets, and DBS duration showed, after controlling for confounders, that the duration of DBS use was the only significant predictor of response (adjusted OR 1.061; 95 % CI 1.019–1.106; p = 0.005). Regarding DBS targets, the response rate in patients with symptomatic etiology was significantly higher with HC or CMN targets than the ANT (p = 0.003). In patients with non-lesional MRI, response rate was significantly higher with the CMN target compared to the other two targets (p = 0.008). ConclusionDBS proves to be effective in DRE, with progressive success upon longer treatment and possibility of improving quality of life. In addition to focal seizures, DBS has potential for treating generalized seizures as well. While the ANT stands as the most utilized and only approved DBS target for DRE, CMN and HC are alternative targets with high seizure control potential. Patients with symptomatic etiology showed significant seizure reduction when HC or CMN were targeted. Studies revealed noticeable effectiveness of CMN-DBS in treating patients with non-lesional MRI. Despite ANT prominence in research, our findings suggest promising outcomes with CMN and HC, emphasizing the need for future larger-scale comparative clinical trials to better understand the efficacy of different DBS targets.

Normative Modeling of Thalamic Nuclear Volumes and Characterization of Lateralized Volume Alterations in Alzheimer’s Disease Versus Schizophrenia

BackgroundThalamic nuclei facilitate a wide range of complex behaviors, emotions, and cognition and have been implicated in neuropsychiatric disorders including Alzheimer’s disease (AD) and schizophrenia (SCZ). The aim of this work was to establish novel normative models of thalamic nuclear volumes and their laterality indices and investigate their changes in SCZ and AD. MethodsVolumes of bilateral whole thalami and 10 thalamic nuclei were generated from T1 magnetic resonance imaging data using a state-of-the-art novel segmentation method in healthy control participants (n = 2374) and participants with early mild cognitive impairment (n = 211), late mild cognitive impairment (n = 113), AD (n = 88), and SCZ (n = 168). Normative models for each nucleus were generated from healthy control participants while controlling for sex, intracranial volume, and site. Extreme z-score deviations (|z| > 1.96) and z-score distributions were compared across phenotypes. z Scores were associated with clinical descriptors. ResultsIncreased infranormal and decreased supranormal z scores were observed in SCZ and AD. z Score shifts representing reduced volumes were observed in most nuclei in SCZ and AD, with strong overlap in the bilateral pulvinar, medial dorsal, and centromedian nuclei. Shifts were larger in AD, with evidence of a left-sided preference in early mild cognitive impairment while a predilection for right thalamic nuclei was observed in SCZ. The right medial dorsal nucleus was associated with disorganized thought and daily auditory verbal hallucinations. ConclusionsIn AD, thalamic nuclei are more severely and symmetrically affected while in SCZ, the right thalamic nuclei are more affected. We highlight the right medial dorsal nucleus, which may mediate multiple symptoms of SCZ and is affected early in the disease course.

Bilateral centromedian nucleus of thalamus responsive neurostimulation for pediatric-onset drug-resistant epilepsy.

Neuromodulation therapies offer an efficacious treatment alternative for patients with drug-resistant epilepsy (DRE), particularly those unlikely to benefit from surgical resection. Here we present our retrospective single-center case series of patients with pediatric-onset DRE who underwent responsive neurostimulation (RNS) depth electrode implantation targeting the bilateral centromedian nucleus (CM) of the thalamus between October 2020 and October 2022. Sixteen patients were identified; seizure outcomes, programming parameters, and complications at follow-up were reviewed. The median age at implantation was 13 years (range 3.6-22). Six patients (38%) were younger than 12 years of age at the time of implantation. Ictal electroencephalography (EEG) patterns during patients' most disabling seizures were reliably detected. Ten patients (62%) achieved 50% or greater reduction in seizure frequency at a median 1.3 years (range 0.6-2.6) of follow-up. Eight patients (50%) experienced sensorimotor side effects, and three patients (19%) had superficial pocket infection, prompting the removal of the RNS device. Side effects of stimulation were experienced mostly in monopolar-cathodal configuration and alleviated with programming change to bipolar configuration or low-frequency stimulation. Closed-loop neurostimulation using RNS targeting bilateral CM is a feasible and useful therapy for patients with pediatric-onset DRE.

Optimizing indirect targeting of the centromedian nucleus for deep brain stimulation by incorporating third ventricular anatomy.

Deep brain stimulation (DBS) of the centromedian nucleus (CM) is used to treat diverse brain diseases including epilepsy, Tourette syndrome, and disorders of consciousness. However, the CM is challenging to visualize on routine MRI. Many surgeons use an indirect targeting method based on established stereotactic coordinates. The authors aimed to quantify how often a DBS electrode's contacts were positioned within the CM using this approach, and to identify alternative indirect coordinates that are more accurate. Indirect targeting of the CM was performed on 100 MR images obtained in healthy adults, and the resulting coordinates were warped to a common brain template. To estimate positions of DBS contacts along this trajectory, the authors developed a probable electrode location (PEL) mask, modeled on trajectory angles obtained from prior clinical cases. Euclidean and x, y, and z distances between the centroids of the PEL mask and an atlas-based CM mask were measured and defined as error. The percentage of overlaps between the PEL mask and nearby thalamic nuclei was determined. To assess the clinical utility of this methodology, the analysis was validated using 20 MR images obtained in patients with generalized epilepsy, a common clinical indication for CM-DBS. Using standard indirect coordinates, the authors found the average Euclidean error to be 4.40 ± 1.05 mm, and the x, y, and z errors were 4.19 ± 0.97 mm, 0.73 ± 0.65 mm, and 0.66 ± 0.69 mm, respectively. The PEL mask overlap was 52% with the CM and 65% with the ventral posteromedial nucleus. Variation in third ventricular width was the dominant contributor to these errors (r = -0.71). To overcome this variation, the authors developed alternative indirect coordinates: 4.5 mm lateral to the posterolateral corner of the third ventricle at the level of the posterior commissure. With this refinement, the average Euclidean error was reduced to 1.24 ± 0.5 mm, with 84% of the PEL mask within the CM. The unavailability of advanced MRI for direct targeting limits access to CM-DBS in resource-constrained neurosurgical programs. Standard indirect coordinates do not provide optimal targeting of the CM, with most contacts laterally placed in the sensory thalamus. The proposed indirect approach may therefore increase the accuracy and availability of CM-DBS, while reducing side effects.

Centromedian region thalamic responsive neurostimulation mitigatesidiopathic generalized and multifocal epilepsy with focal to bilateral tonic-clonic seizures.

Although >30% of epilepsy patients have drug-resistant epilepsy (DRE), typically those with generalized or multifocal disease have not traditionally been considered surgical candidates. Responsive neurostimulation (RNS) of the centromedian (CM) region of the thalamus now appears to be a promising therapeutic option for this patient population. We present outcomes following CM RNS for 13 patients with idiopathic generalized epilepsy (IGE) and eight with multifocal onsets that rapidly generalize to bilateral tonic-clonic (focal to bilateral tonic-clonic [FBTC]) seizures. A retrospective review of all patients undergoing bilateral CM RNS by the senior author through July 2022 were reviewed. Electrodes were localized and volumes of tissue activation were modeled in Lead-DBS. Changes in patient seizure frequency were extracted from electronic medical records. Twenty-one patients with DRE underwent bilateral CM RNS implantation. For 17 patients with at least 1 year of postimplantation follow-up, average seizure reduction from preoperative baseline was 82.6% (SD = 19.0%, median = 91.7%), with 18% of patients Engel class 1, 29% Engel class 2, 53% Engel class 3, and 0% Engel class 4. There was a trend for average seizure reduction to be greater for patients with nonlesional FBTC seizures than for other patients. For patients achieving at least Engel class 3 outcome, median time to worthwhile seizure reduction was 203.5 days (interquartile range = 110.5-343.75 days). Patients with IGE with myoclonic seizures had a significantly shorter time to worthwhile seizure reduction than other patients. The surgical targeting strategy evolved after the first four subjects to achieve greater anatomic accuracy. Patients with both primary and rapidly generalized epilepsy who underwent CM RNS experienced substantial seizure relief. Subsets of these patient populations may particularly benefit from CM RNS. The refinement of lead targeting, tuning of RNS system parameters, and patient selection are ongoing areas of investigation.

Robot-assisted deep brain stimulation of the centromedian nucleus of the thalamus for generalized epilepsy: targeting and operative video.

The centromedian (CM) nucleus of the thalamus is a promising target for a range of brain diseases including drug-resistant generalized and multifocal epilepsy. CM is highly connected to cortical and subcortical regions including frontoparietal/sensorimotor cortex, striatum, brainstem, and cerebellum, which are involved in some generalized epilepsy syndromes like Lennox-Gastaut syndrome (LGS). In this video, the authors describe their methodology for targeting CM for deep brain stimulation (DBS). Delineation of an optimal and consistent target will expand the efficacy of neuromodulation of CM in intractable epilepsy. The video can be found here: https://stream.cadmore.media/r10.3171/2024.4.FOCVID245.

High-Frequency Stimulation of the Centromedian Thalamic Nucleus Aborts Seizures and Ictal Apnea.

A 32-year-old right-handed woman presented with medically and surgically refractory left temporal neocortical epilepsy secondary to focal cortical dysplasia who underwent stereoelectroencephalography involving the centromedian nucleus of the thalamus. With the use of real-time stereoelectroencephalography monitoring, four electroclinical seizures were aborted by administering high-frequency stimulation at the centromedian nucleus at seizure onset. Seizures before stimulation were all associated with ictal apnea, while those with stimulation had no ictal apnea. This case demonstrates how providing high-frequency stimulation to the centromedian nucleus of the thalamus can abort electroclinical seizures and ictal apnea.

Modulation of neuronal activity in human centromedian nucleus during an auditory attention and working memory task

Centromedian nucleus (CM) is one of several intralaminar nuclei of the thalamus and is thought to be involved in consciousness, arousal, and attention. CM has been suggested to play a key role in the control of attention, by regulating the flow of information to different brain regions such as the ascending reticular system, basal ganglia, and cortex. While the neurophysiology of attention in visual and auditory systems has been studied in animal models, combined single unit and LFP recordings in human have not, to our knowledge, been reported. Here, we recorded neuronal activity in the CM nucleus in 11 patients prior to insertion of deep brain stimulation electrodes for the treatment of epilepsy while subjects performed an auditory attention task. Patients were requested to attend and count the infrequent (p = 0.2) odd or "deviant" tones, ignore the frequent standard tones and report the total number of deviant tones at trial completion. Spikes were discriminated, and LFPs were band pass filtered (5–45 Hz). Average peri‑stimulus time histograms and spectra were constructed by aligning on tone onsets and statistically compared. The firing rate of CM neurons showed selective, multi-phasic responses to deviant tones in 81% of the tested neurons. Local field potential analysis showed selective beta and low gamma (13–45 Hz) modulations in response to deviant tones, also in a multi-phasic pattern. The current study demonstrates that CM neurons are under top-down control and participate in the selective processing during auditory attention and working memory. These results, taken together, implicate the CM in selective auditory attention and working memory and support a role of beta and low gamma oscillatory activity in cognitive processes. It also has potential implications for DBS therapy for epilepsy and non-motor symptoms of PD, such as apathy and other disorders of attention.

Deep brain stimulation of anterior nucleus and centromedian nucleus of thalamus in treatment for drug-resistant epilepsy.

Drug-resistant epilepsy (DRE) remains poorly-controlled in c.33% of patients, and up to 50% of patients suffering from DRE are deemed not to be suitable candidates for resective surgery. For these patients, deep brain stimulation (DBS) may constitute the last resort in the treatment of DRE. We undertook a systematic review of the current literature on DBS efficacy and the safety of two thalamic nuclei-anterior nucleus of the thalamus (ANT) and the centromedian nucleus of the thalamus in the management of patients with DRE. A search using two electronic databases, the Medical Literature, Analysis, and Retrieval System on-line (MEDLINE) and the Cochrane Central Register of Controlled Trials (CEN-TRAL) was conducted. We found 30 articles related to ANT DBS and 13 articles related to CMN DBS which were further analysed. Based on the clinical research articles, we found a mean seizure frequency reduction for both thalamic nuclei. For ANT DBS, the mean seizure frequency reduction ranged from 48% to 75%, and for CMN DBS from 46.7% to 91%. The responder rate (defined as at least 50% reduction in seizure frequency) was reported to be 53.2-75% for patients after ANT DBS and 50-90% for patients after CMN DBS. ANT and CMN DBS appear to be safe and efficacious treatments, particularly in patients with refractory partial seizures and primary generalised seizures. ANT DBS reduces most effectively seizures originating in the temporal and frontal lobes. CMN DBS reduces mostly primary generalised tonic-clonic and atypical absences and atonic seizures. Seizures related to Lennox-Gastaut syndrome respond very favourably to CMN DBS.

Regional structural abnormalities in thalamus in idiopathic cervical dystonia

BackgroundThe thalamus has a central role in the pathophysiology of idiopathic cervical dystonia (iCD); however, the nature of alterations occurring within this structure remain largely elusive. Using a structural magnetic resonance imaging (MRI) approach, we examined whether abnormalities differ across thalamic subregions/nuclei in patients with iCD.MethodsStructural MRI data were collected from 37 patients with iCD and 37 healthy controls (HCs). Automatic parcellation of 25 thalamic nuclei in each hemisphere was performed based on the FreeSurfer program. Differences in thalamic nuclei volumes between groups and their relationships with clinical information were analysed in patients with iCD.ResultsCompared to HCs, a significant reduction in thalamic nuclei volume primarily in central medial, centromedian, lateral geniculate, medial geniculate, medial ventral, paracentral, parafascicular, paratenial, and ventromedial nuclei was found in patients with iCD (P < 0.05, false discovery rate corrected). However, no statistically significant correlations were observed between altered thalamic nuclei volumes and clinical characteristics in iCD group.ConclusionThis study highlights the neurobiological mechanisms of iCD related to thalamic volume changes.

Negative family and interpersonal relationship are associated with centromedial amygdala functional connectivity alterations in adolescent depression.

The amygdala, known for its functional heterogeneity, plays a critical role in the neural mechanism of adolescent major depressive disorder (aMDD). However, changes in its subregional functional networks in relation to stressful factors remain unclear. We recruited 78 comorbidity-free, medication-naive aMDD patients and 40 matched healthy controls (HC) to explore changes in resting-state functional connectivity (FC) across four amygdala subregions: the centromedial nucleus (CM), the basolateral nucleus (LB), the superficial nucleus (SF), and the amygdalostriatal transition area (Astr). Then, we performed partial correlation analysis to investigate the relationship between amygdala subregional FC and stressful factors as measured by the Chinese Version of Family Environment Scale (FES-CV) and the Adolescent Self-Rated Life Events Scale (ASLEC). Compared to HC, aMDD patients demonstrated significantly decreased functional connectivity between the left CM and left precentral gyrus, as well as between left SF and left precentral gyrus, and between left LB and posterior cingulate gyrus (PCC)/precuneus. In aMDD group, left CM-precentral gyrus FC exhibited negative correlation with interpersonal relationship and punishment, and positive correlation with family cohesion and expressiveness. This study reveals distinct patterns of abnormal functional connectivity among amygdala subregions in aMDD. Our findings suggest that the CM network, in particular, may be involved in stress-related factors in aMDD, which provide a potential target for the prevention and treatment of adolescent depression.

Perinatal stress modulates glutamatergic functional connectivity: A post-synaptic density immediate early gene-based network analysis

Early life stress may induce synaptic changes within brain regions associated with behavioral disorders. Here, we investigated glutamatergic functional connectivity by a postsynaptic density immediate-early gene-based network analysis. Pregnant female Sprague–Dawley rats were randomly divided into two experimental groups: one exposed to stress sessions and the other serving as a stress-free control group. Homer1 expression was evaluated by in situ hybridization technique in eighty-eight brain regions of interest of male rat offspring. Differences between the perinatal stress exposed group (PRS) (n = 5) and the control group (CTR) (n = 5) were assessed by performing the Student's t-test via SPSS 28.0.1.0 with Bonferroni correction. Additionally, all possible pairwise Spearman's correlations were computed as well as correlation matrices and networks for each experimental group were generated via RStudio and Cytoscape. Perinatal stress exposure was associated with Homer1a reduction in several cortical, thalamic, and striatal regions. Furthermore, it was found to affect functional connectivity between: the lateral septal nucleus, the central medial thalamic nucleus, the anterior part of the paraventricular thalamic nucleus, and both retrosplenial granular b cortex and hippocampal regions; the orbitofrontal cortex, amygdaloid nuclei, and hippocampal regions; and lastly, among regions involved in limbic system. Finally, the PRS networks showed a significant reduction in multiple connections for the ventrolateral part of the anteroventral thalamic nucleus after perinatal stress exposure, as well as a decrease in the centrality of ventral anterior thalamic and amygdaloid nuclei suggestive of putative reduced cortical control over these regions.Within the present preclinical setting, perinatal stress exposure is a modifier of glutamatergic early gene-based functional connectivity in neuronal circuits involved in behaviors relevant to model neurodevelopmental disorders.

Uncovering spatiotemporal dynamics of the corticothalamic network at ictal onset.

Although the clinical efficacy of deep brain stimulation targeting the anterior nucleus (AN) and centromedian nucleus (CM) of the thalamus has been actively investigated for the treatment of medication-resistant epilepsy, few studies have investigated dynamic ictal changes in corticothalamic connectivity in human electroencephalographic (EEG) recording. This study aims to establish the complex spatiotemporal dynamics of the ictal corticothalamic network associated with various seizure foci. We analyzed 10 patients (aged 2.7-28.1 years) with medication-resistant focal epilepsy who underwent stereotactic EEG evaluation with thalamic sampling. We examined both undirected and directed connectivity, incorporating coherence and spectral Granger causality analysis (GCA) between the diverse seizure foci and thalamic nuclei (AN and CM) at ictal onset. In our analysis of 36 seizures, coherence between seizure onset and thalamic nuclei increased across all frequencies, especially in slower bands (delta, theta, alpha). GCA showed increased information flow from seizure onset to the thalamus across all frequency bands, but outflows from the thalamus were mainly in slower frequencies, particularly delta. In the subgroup analysis based on various seizure foci, the delta coherence showed a more pronounced increase at CM than at AN during frontal lobe seizures. Conversely, in limbic seizures, the delta coherence increase was greater at AN compared to CM. It appears that the delta frequency plays a pivotal role in modulating the corticothalamic network during seizures. Our results underscore the significance of comprehending the spatiotemporal dynamics of the corticothalamic network at ictal onset, and this knowledge could guide personalized responsive neuromodulation treatment strategies.

Thalamic stereoelectroencephalography for neuromodulation target selection: Proof of concept and review of literature of pulvinar direct electrical stimulation.

In patients with drug-resistant epilepsy (DRE) who are not candidates for resective surgery, various thalamic nuclei, including the anterior, centromedian, and pulvinar nuclei, have been extensively investigated as targets for neuromodulation. However, the therapeutic effects of different targets for thalamic neuromodulation on various types of epilepsy are not well understood. Here, we present a 32-year-old patient with multifocal bilateral temporoparieto-occipital epilepsy and bilateral malformations of cortical development (MCDs) who underwent bilateral stereoelectroencephalographic (SEEG) recordings of the aforementioned three thalamic nuclei bilaterally. The change in the rate of interictal epileptiform discharges (IEDs) from baseline were compared in temporal, central, parietal, and occipital regions after direct electrical stimulation (DES) of each thalamic nucleus. A significant decrease in the rate of IEDs (33% from baseline) in the posterior quadrant regions was noted in the ipsilateral as well as contralateral hemisphere following DES of the pulvinar. A scoping review was also performed to better understand the current standpoint of pulvinar thalamic stimulation in the treatment of DRE. The therapeutic effect of neuromodulation can differ among thalamic nuclei targets and epileptogenic zones (EZs). In patients with multifocal EZs with extensive MCDs, personalized thalamic targeting could be achieved through DES with thalamic SEEG electrodes.

Sudden unexpected death in epilepsy in a patient with a brain‐responsive neurostimulation device

AbstractBackgroundSudden unexpected death in epilepsy (SUDEP) is the most common cause of epilepsy‐related mortality. Although most witnessed SUDEPs follow seizures, mechanisms are uncertain. Investigations into the pathophysiology of SUDEP have relied on models and rare recordings of brain function at the time of the event. The brain‐responsive neurostimulation (RNS) device from Neuropace offers a therapeutic option for drug‐refractory epilepsy (DRE), enabling the recording of brain activity and the preemptive termination of seizures. Therefore, patients who experience SUDEP while being treated with an RNS device can provide insights into neural activity at the moment of this event.ObjectiveWe report the history and electrocorticographic (ECoG) recordings of a patient with DRE who experienced SUDEP years after RNS placement.Patient HistoryA girl with Phelan–McDermid syndrome and Lennox–Gastaut syndrome had an RNS device implanted at the age of 14 to treat DRE. Initially, electrodes were positioned in the right orbitofrontal (OF) and right premotor frontal regions, with the OF lead later changed to the centromedian thalamic nucleus. At age 19, the patient was found unconscious and in cardiac arrest by her parents. Although spontaneous circulation returned en route to the hospital, the patient did not regain consciousness and died. Subsequent analysis of ECoGs from RNS recordings at the time of death indicated seizure onset in the right premotor frontal cortex, which persisted despite seizure termination attempts by the RNS.ConclusionsWe present a patient with SUDEP associated with the onset of RNS‐refractory seizures. The significance of this report is highlighted by the rarity of literature on neuronal function at the time of SUDEP. Moreover, it underscores the potential for devices capable of monitoring ECoG activity to shed light on the mechanisms underlying SUDEP and to inform interventions.

Extrasynaptic GABAA receptors in central medial thalamus mediate anesthesia in rats

Neuronal depression in the thalamus underlies anesthetic-induced loss of consciousness, while the precise sub-thalamus nuclei and molecular targets involved remain to be elucidated. The present study investigated the role of extrasynaptic GABAA receptors in the central medial thalamic nucleus (CM) in anesthesia induced by gaboxadol (THIP) and diazepam (DZP) in rats. Local lesion of the CM led to a decrease in the duration of loss of righting reflex induced by THIP and DZP. CM microinjection of THIP but not DZP induced anesthesia. The absence of righting reflex in THIP-treated rats was consistent with the increase of low frequency oscillations in the delta band in the medial prefrontal cortex. CM microinjection of GABAA receptor antagonist SR95531 significantly attenuated the anesthesia induced by systemically-administered THIP, but not DZP. Moreover, the rats with declined expression of GABAA receptor δ-subunit in the CM were less responsive to THIP or DZP. These findings explained a novel mechanism of THIP-induced loss of consciousness and highlighted the role of CM extrasynaptic GABAA receptors in mediating anesthesia.

483 Network Analysis of the Thalamic RNS in Patients With Drug Resistant Epilepsy: Insights to Improve Surgical Targeting

INTRODUCTION: Approximately 30% of epilepsy patients are refractory to pharmacotherapy. Patients with drug-resistant epilepsy (DRE) with seizure foci located bilaterally or in the eloquent cortex may be ineligible for resective surgery. For such cases, responsive neurostimulation (RNS) is a viable treatment strategy. METHODS: Retrospective analysis of 23 patients treated with thalamic RNS of the centromedian (CM) and anterior nuclei of the thalamus (ANT) from 2015-2022. Clinical features and seizure outcomes were recorded. RNS electrodes were used to model the electrical field using the parameters at last follow up. Patient-specific probabilistic tractography was used to define the network of the seizure onset zone (SOZ) and its thalamic involvement. Each patient’s probabilistic map was used to define the area of highest connectivity of the thalamus with the seizure network. Each of these patient-specific thalamic areas demonstrating highest connectivity with the seizure network were correlated with electrode position, stimulation modeling, and seizure outcomes. RESULTS: Seizure network from neocortical areas were highly connected to the CM and from limbic cortical areas to the ANT, MD, and parafascicularis nuclei. Results of the correlation analysis between connectivity, stimulation modelling of the RNS electrode, and seizure outcomes will be presented along with illustrative cases of patient-specific targeting using tractography for RNS placement. CONCLUSIONS: Probabilistic tractography is useful to define the networks associated with improved seizure control in thalamic RNS. The identification of these networks prior to surgery could help to identify specific corticothalamic connections and their anatomical trajectories to optimize the implantation of the leads for better and more predictable seizure control.

439 Optimal Targets, Connectivity, and Tissue Integrity for Deep Brain Stimulation in Patients With Disorders of Consciousness

INTRODUCTION: Disorders of consciousness (DOC) are characterized by alterations in arousal and/or awareness resulting from brain injuries. Deep brain stimulation (DBS) is an emerging treatment to restore arousal/awareness in DOC. However, little is known about optimal targets and whether outcomes depend on brain connectivity, tissue integrity, or reorganization potential. METHODS: Retrospective analysis of 38 patients with DOC who underwent unilateral DBS targeting thalamic centromedian nucleus (ages = 12-65 years). DOC resulted from anoxic (n = 26) or traumatic (n = 12) injuries. Patients were classified as ‘responders’ or ‘non-responders’ using Coma/Near Coma and Coma Recovery Scales. Volumes of tissue activated (VTAs) assessed DBS locations associated with favorable response. Correlations were also performed with age, regional brain volumes from pre-operative MRI, and structural connectivity calculated from patients’ VTAs using normative diffusion MRI. RESULTS: 8/38 patients were responders and 24/38 non-responders; outcomes are pending in 6/38 patients due to &lt;3 months follow-up. Favorable response was associated with younger age (median age = 19 years in responders, 42 years in non-responders) and greater volumes of whole-brain grey matter and subcortical regions including putamen, pallidum, caudate, and cerebellum. Responders also tended to have deeper and more medial implantations, with VTAs engaging parafascicular nucleus, reticular nucleus, and peri-midbrain red nucleus. In responders, VTA connectivity was higher with superior frontal gyrus, caudate, pallidum, and cerebellum, and lower with sensorimotor and occipital cortex. CONCLUSIONS: Efficacious DBS for DOC is linked to younger age, greater preservation of whole-brain grey-matter, greater volumes of and connectivity with select subcortical areas (pallidum, caudate, cerebellum), stronger connectivity with superior frontal gyrus, and stimulation of locations inferomedial to the centromedian nucleus. Findings may assist with optimizing patient selection, DBS targeting, and post-implantation programming.

194 Responsive Neurostimulation Targeting the Centromedian Nucleus of the Thalamus Improves Seizure Control in Idiopathic Generalized Epilepsy and Select Multifocal Disease

INTRODUCTION: Although more than 30% of epilepsy patients are drug resistant, many have not traditionally been considered surgical candidates due to generalized or multifocal disease. However, responsive neurostimulation (RNS) of the centromedian nucleus (CM) of the thalamus appears promising for this patient population. We present outcomes following CM RNS for patients with idiopathic generalized epilepsy (IGE) or multifocal disease, with subgroup analyses of patients’ seizure types and targeting methodology. METHODS: 21 patients with drug resistant epilepsy underwent bilateral CM RNS implantation. Electrodes were localized and volumes of tissue activation (VTAs) were modeled in Lead-DBS. Outcome measures were extracted from electronic medical records. Clinical outcomes over time were compared between patients’ seizure types and RNS recorded long-episodes, and VTA overlap with thalamic nuclei was compared between patients with direct and indirect targeting methodologies. RESULTS: For patients with at least 1-year of follow up, average seizure reduction from pre-operative baseline was 81.3%, with 3 Engel class 1 patients, 5 Engel class 2, 8 Engel class 3, and 0 Engel class 4. Average seizure reduction was greatest for non-lesional multifocal patients. Average time to worthwhile seizure reduction was 217 days, and was shortest for myoclonic IGE patients. Long-episodes were associated with seizure reduction in IGE patients only. Direct targeting led to more anterior and medial electrodes with greater VTA overlap with CM. CONCLUSIONS: CM RNS may provide significant relief for IGE and multifocal epilepsy patients. Subsets of these patient populations may particularly benefit from CM RNS. Direct targeting may facilitate more selective stimulation of the CM. The refinement of stimulation targeting, tuning of RNS system parameters, and deliberate patient selection are ongoing areas of investigation.

486 Responsive Neurostimulation of the Centromedian Nucleus of the Thalamus in Adult Epilepsy: Multi-center Case Series

INTRODUCTION: Responsive neurostimulation (RNS) is an FDA-approved therapy for focal drug-resistant epilepsy (DRE). Emerging evidence supports a role for RNS in DRE with regional, multifocal, or non-resectable seizure onset zones. The centromedian nucleus of the thalamus (CMT) is a promising target, although descriptions of predictors of longer-term response are lacking. METHODS: We retrospectively reviewed patients who underwent RNS implantation with at least one CMT electrode at Baylor College of Medicine (BCM) and the University of Utah (UoU) from 2019-2023. Patients with = 6 months of follow-up were assessed for changes in clinical seizure frequency following surgery, as well as changes in seizure severity and subjective quality-of-life (QoL). RESULTS: Sixteen patients underwent CMT RNS (n = 12 BCM, n = 4 UoU) at a median age of 30 years [range 20-51] with a median 19-year history of epilepsy. All patients were evaluated by a multidisciplinary team that recommended thalamic RNS. Thirteen underwent bilateral CMT implantation and 7 had a documented lesional effect (&gt;50% reduction in seizures in the months following implantation). Thirteen patients had = 6-month follow-up with which to do subsequent seizure outcome analysis. In these patients, with a median follow-up of 18 months [6-40], median clinical seizure reduction was 80% [0-100%], 2 patients were seizure free for 6 months, and 1 was seizure free for 40 months. Patients with a lesional effect had a median 87% seizure reduction at last follow-up while those without a lesional effect had a 51% seizure reduction (two-tailed, two-sample t-test, p = 0.04). Subjective reduced seizure severity and increased QoL was documented in 92% of patients. CONCLUSIONS: RNS of the CMT can result in robust seizure frequency, severity, and QoL improvements in patients with DRE. Post-implantation lesional effect may be associated with longer-term improved response.