Targeting the centromedian thalamic nucleus for deep brain stimulation

Abstract

ObjectivesDeep brain stimulation (DBS) of the centromedian thalamic nucleus (CM) is an emerging treatment for multiple brain diseases, including the drug-resistant epilepsy Lennox-Gastaut syndrome (LGS). We aimed to improve neurosurgical targeting of the CM by: (1) developing a structural MRI approach for CM visualisation, (2) identifying the CM’s neurophysiological characteristics using microelectrode recordings (MERs) and (3) mapping connectivity from CM-DBS sites using functional MRI (fMRI).Methods19 patients with LGS (mean age=28 years) underwent presurgical 3T MRI using magnetisation-prepared 2 rapid acquisition gradient-echoes (MP2RAGE) and fMRI sequences; 16 patients proceeded to bilateral CM-DBS implantation and intraoperative thalamic MERs. CM visualisation was achieved by highlighting intrathalamic borders on MP2RAGE using Sobel edge detection. Mixed-effects analysis compared two MER features (spike firing rate and background noise) between ventrolateral, CM and parafasicular nuclei. Resting-state fMRI connectivity was assessed using implanted CM-DBS electrode positions as regions of interest.ResultsThe CM appeared as a hyperintense region bordering the comparatively hypointense pulvinar, mediodorsal and parafasicular nuclei. At the group level, reduced spike firing and background noise distinguished CM from the ventrolateral nucleus; however, these trends were not found in 20%–25% of individual MER trajectories. Areas of fMRI connectivity included basal ganglia, brainstem, cerebellum, sensorimotor/premotor and limbic cortex.ConclusionsIn the largest clinical trial of DBS undertaken in patients with LGS to date, we show that accurate targeting of the CM is achievable using 3T MP2RAGE MRI. Intraoperative MERs may provide additional localising features in some cases; however, their utility is limited by interpatient variability. Therapeutic effects of CM-DBS may be mediated via connectivity with brain networks that support diverse arousal, cognitive and sensorimotor processes.

Case Report: Responsive Neurostimulation of the Centromedian Thalamic Nucleus for the Detection and Treatment of Seizures in Pediatric Primary Generalized Epilepsy

“…RNS stimulation of the CM has been applied in adult patients for the treatment of drug-resistant regional neocortical epilepsy ( 37 ), generalized epilepsy ( 26 ), Lennox-Gastaut Syndrome ( 10 , 38 ), and drug-resistant focal onset-seizures ( 39 ). Seizure frequency of patients with implanted RNS systems often continues to improve over months to years, which implicates the role of neural plasticity induced by programmable closed-loop stimulation ( 16 , 23 ). Further research is needed to better understand the mechanisms underlying the clinical benefits of RNS CM stimulation for the treatment of CAE.…”

“…Electrophysiologic studies reveal that clinically relevant ictal discharges can be detected in the CM nucleus ( 16 , 26 ). Kokkinos et al ( 26 ), performed direct recording of the CM nucleus via RNS showing 3–5 Hz spike and wave activity consistent with their patient's preoperative EEG pattern.…”

“…Kokkinos et al ( 26 ), performed direct recording of the CM nucleus via RNS showing 3–5 Hz spike and wave activity consistent with their patient's preoperative EEG pattern. Warren et al ( 16 ), performed simultaneous EEG and CM recordings during DBS implantation to examine the relationship between generalized paroxysmal fast activity (GPFA) and slow spike wave (SSW) on EEG and from direct CM recordings. In this study, 86% of GPFA events were seen in both on both scalp EEG and CM, whereas 25% of SSW was observed from both recordings.…”

“…The CM was targeted in this report using indirect and direct technique as previously described ( 10 , 15 – 17 ). The CM remains difficult to demarcate on standard neuroimaging ( 36 ), however studies have shown that inverse MP2RAGE and quantitative susceptibility mapping (QSM) can be used to identify the nucleus with good reliability ( 16 , 41 ). Confirmation of electrode placement using intraoperative microelectrode recording (MER) evaluation of the CMN neurophysiological signature has shown mixed results, given the presence of low frequency firing rate while sedated, considerable interpatient variability, and subtle differences in neural signatures between adjacent thalamic nuclei ( 16 ).…”

Lead Repositioning Guided by Both Physiology and Atlas Based Targeting in Tourette Deep Brain Stimulation

“…Classical MRI image-based analysis must be coupled with a deformable atlas overlay, but even this approach may result in an ill-positioned CM nucleus DBS lead. Currently, no reliable functional mapping approach is available for targeting the CM nucleus, though this issue has become a potential area for research focus [23,31]. Furthermore, it has been recently shown that based on the DBS Registry and Database, there exists a large variability in the active DBS contact location within the CM thalamic region [11].…”