Timo Möttönen

Deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) is an established therapy for drug-resistant epilepsy (DRE), yet the optimal stimulation targets and underlying network mechanisms remain unclear. This study employed high angular resolution diffusion weighted imaging (HARDI) and multi-shell multi-tissue constrained spherical deconvolution (MSMT-CSD) tractography in 13 healthy volunteers to map the structural connectivity of five anterior thalamic subregions: 1) anteromedial nucleus (AM), 2) anteroventral nucleus (AV), 3) dorsal superficial nucleus (DSF), 4) AV–mammillothalamic tract junction (AVmtt), and 5) external medullary lamina (EML) at the superolateral aspect of AV. Probabilistic tractography was used as the primary analytical approach due to its increased sensitivity to complex fiber configurations compared to deterministic methods. The results indicated that AM, AV, and DSF subnuclei connect inferiorly via inferior thalamic peduncle to the amygdala and posteriorly via temporopulvinar tract to the dorsal hippocampus, with AM also projecting to the orbitofrontal cortex via anterior thalamic radiation. AVmtt indicated a strong connection to the orbitofrontal cortex and dorsal hippocampus, while EML exhibited extensive connectivity via anterior and posterior thalamic radiations to orbitofrontal-, medial prefrontal-, cingulate-, parietal-, and occipital cortices in addition to the connection to the cingulum bundle but lacked inferior connections including amygdala. These findings demonstrate that anterior thalamic subregions possess distinct yet consistent connectivity patterns, supporting connectivity-informed, network-specific targeting strategies to optimize therapeutic outcomes in drug-resistant epilepsy.

The mediodorsal nucleus of the thalamus (MD), with its extensive connections to the lateral pFC, has been implicated in human working memory and executive functions. However, this understanding is based solely on indirect evidence from human lesion and imaging studies and animal studies. Direct, causal evidence from humans is missing. To obtain direct evidence for MD's role in humans, we studied patients treated with deep brain stimulation (DBS) for refractory epilepsy. This treatment is thought to prevent the generalization of a seizure by disrupting the functioning of the patient's anterior nuclei of the thalamus (ANT) with high-frequency electric stimulation. This structure is located superior and anterior to MD, and when the DBS lead is implanted in ANT, tip contacts of the lead typically penetrate through ANT into the adjoining MD. To study the role of MD in human executive functions and working memory, we periodically disrupted and recovered MD's function with high-frequency electric stimulation using DBS contacts reaching MD while participants performed a cognitive task engaging several aspects of executive functions. We hypothesized that the efficacy of executive functions, specifically working memory, is impaired when the functioning of MD is perturbed by high-frequency stimulation. Eight participants treated with ANT-DBS for refractory epilepsy performed a computer-based test of executive functions while DBS was repeatedly switched ON and OFF at MD and at the control location (ANT). In comparison to stimulation of the control location, when MD was stimulated, participants committed 2.26 times more errors in general (total errors; OR = 2.26, 95% CI [1.69, 3.01]) and 2.86 times more working memory-related errors specifically (incorrect button presses; OR = 2.88, CI [1.95, 4.24]). Similarly, participants committed 1.81 more errors in general (OR = 1.81, CI [1.45, 2.24]) and 2.08 times more working memory-related errors (OR = 2.08, CI [1.57, 2.75]) in comparison to no stimulation condition. “Total errors” is a composite score consisting of basic error types and was mostly driven by working memory-related errors. The facts that MD and a control location, ANT, are only few millimeters away from each other and that their stimulation produces very different results highlight the location-specific effect of DBS rather than regionally unspecific general effect. In conclusion, disrupting and recovering MD's function with high-frequency electric stimulation modulated participants' online working memory performance providing causal, in vivo evidence from humans for the role of MD in human working memory.

Super‐refractory status epilepticus is a condition characterized by recurrence of status epilepticus despite use of deep general anesthesia, and it has high morbidity and mortality rates. We report a case of a 17‐year‐old boy with a prolonged super‐refractory status epilepticus that eventually resolved after commencing deep brain stimulation of the centromedian nucleus of the thalamus. Later attempt to reduce stimulation parameters resulted in immediate relapse of status epilepticus, suggesting a pivotal role of deep brain stimulation in the treatment response. Deep brain stimulation may be a treatment option in super‐refractory status epilepticus when other treatment options have failed. ANN NEUROL 2017;81:142–146

Background: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus) (ANT) has been suggested as a treatment option in refractory epilepsy. The targeting of ANT is especially challenging due to its poor visualization in commonly used MRI sequences, lack of easily observable symptom relief during surgery and high degree of anatomical variation between individuals. Objectives: To study whether intraoperative microelectrode recording (MER), a method widely used in movement disorder surgery, provides clinically relevant information during the ANT-DBS implantation procedure. Methods: A total of 186 MER samples from 5 patients and 10 thalami obtained from ANT-DBS surgery for refractory epilepsy were analyzed with respect to the signal characteristics and location in 3-tesla (3T) MRI STIR (short T1 inversion recovery) images. The location of each MER sample was calculated relative to visible borders of the ANT after correction of the sample locations according to the position of the final DBS electrode in postoperative CT-MRI fusion images. Results: We found that the lateral aspect of the ANT lacked spiking activity consistent with the presence of white matter. The spike frequency in samples correlating with location at the ANT showed significantly lower spike frequency compared to samples correlating with location at the ventral anterior nucleus (median 3.0 and 7.0 spikes/2 s; p < 0.05), but spike bursts were morphologically similar in appearance. Trajectories entering the dorsomedial nucleus according to 3T MRI STIR images showed a yet different firing pattern with more low-amplitude regular activity. Conclusions: Our data suggest that MER provides clinically relevant information during implantation surgery by demonstrating both nucleus-specific neuronal firing patterns and white matter laminae between different nuclear groups.