Search

Objective: Short-term outcomes of deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) were reported for people with drug-resistant focal epilepsy (PwE). Because long-term data are still scarce, the Medtronic Registry for Epilepsy (MORE) evaluated clinical routine application of ANT-DBS., Methods: In this multicenter registry, PwE with ANT-DBS were followed up for safety, efficacy, and battery longevity. Follow-up ended after 5 years or upon study closure. Clinical characteristics and stimulation settings were compared between PwE with no benefit, improvers, and responders, that is, PwE with average monthly seizure frequency reduction rates of ≥50%., Results: Of 170 eligible PwE, 104, 62, and 49 completed the 3-, 4-, and 5-year follow-up, respectively. Most discontinuations (68%) were due to planned study closure as follow-up beyond 2 years was optional. The 5-year follow-up cohort had a median seizure frequency reduction from 16 per month at baseline to 7.9 per month at 5-year follow-up (p < .001), with most-pronounced effects on focal-to-bilateral tonic-clonic seizures (n = 15, 77% reduction, p = .008). At last follow-up (median 3.5 years), 41% (69/170) of PwE were responders. Unifocal epilepsy (p = .035) and a negative history of epilepsy surgery (p = .002) were associated with larger average monthly seizure frequency reductions. Stimulation settings did not differ between response groups. In 179 implanted PwE, DBS-related adverse events (AEs, n = 225) and serious AEs (n = 75) included deterioration in epilepsy or seizure frequency/severity/type (33; 14 serious), memory/cognitive impairment (29; 3 serious), and depression (13; 4 serious). Five deaths occurred (none were ANT-DBS related). Most AEs (76.3%) manifested within the first 2 years after implantation. Activa PC depletion (n = 37) occurred on average after 45 months., Significance: MORE provides further evidence for the long-term application of ANT-DBS in clinical routine practice. Although clinical benefits increased over time, side effects occurred mainly during the first 2 years. Identified outcome modifiers can help inform PwE selection and management., (© 2024 Medtronic and The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction: There is a paucity of clinical studies examining the long-term effects of vagus nerve stimulation (VNS) on cognition, although a recent study of patients with drug-resistant epilepsy (DRE) treated with VNS therapy demonstrated significant improvement in executive functions as measured by the EpiTrack composite score. The present study aimed to investigate performance variability in three cognitive tests assessing executive functions and working memory in a cohort of DRE patients receiving VNS therapy during a follow-up duration of up to 5 years., Methods: The study included 46 DRE patients who were assessed with the Trail Making Test (TMT) (Parts A and B) and Digit Span Backward (DB) task prior to VNS implantation, 6 months and 12 months after implantation, and yearly thereafter as a part of the clinical VNS protocol. A linear mixed-effects (LME) model was used to analyze changes in test z scores over time, accounting for variations in follow-up duration when predicting changes over 5 years. Additionally, we conducted descriptive analyses to illustrate individual changes., Results: On average, TMT-A z scores improved by 0.024 units (95% confidence interval (CI): 0.006 to 0.042, p  = 0.009), TMT-B z scores by 0.034 units (95% CI: 0.012 to 0.057, p  = 0.003), and DB z scores by 0.019 units per month (95% CI: 0.011 to 0.028, p  < 0.001). Patients with psychiatric comorbidities achieved the greatest improvements in TMT-B and DB z scores among all groups (0.0058 units/month, p  = 0.036 and 0.028 units/month, p  = 0.003, respectively). TMT-A z scores improved the most in patients taking 1-2 ASMs as well as in patients with psychiatric comorbidities (0.042 units/month, p  = 0.002 and p  = 0.003, respectively)., Conclusion: Performance in all three tests improved at the group level during the follow-up period, with the most robust improvement observed in TMT-B, which requires inhibition control and set-switching in addition to the visuoperceptual processing speed that is crucial in TMT-A and working-memory performance that is essential in DB. Moreover, the improvement in TMT-B was further enhanced if the patient had psychiatric comorbidities., Competing Interests: NL has participated in a clinical trial for UCB; received speaker’s honoraria from LivaNova (OmaMedical). LK has received speaker’s honoraria from UCB, Merck, and Eisai; received support for travel to congress from UCB and Angelini Pharma. KL has received speaker’s honoraria from Medtronic. ER-O has received speaker’s honoraria from Novartis and Biogen. JP has participated in clinical trials for Eisai, UCB, and Bial; received research grants from Angelini Pharma, Eisai, Medtronic, UCB, and LivaNova; received speaker’s honoraria from LivaNova, Angelini Pharma, Eisai, Jazz Pharma, Medtronic, Orion Pharma, and UCB; received support for travel to congresses from LivaNova, Eisai, Medtronic, and UCB; and participated in advisory boards for LivaNova, Angelini Pharma, Jazz Pharma, Eisai, Medtronic, UCB, and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lähde, Basnyat, Raitanen, Kämppi, Lehtimäki, Rosti-Otajärvi and Peltola.)

Objective: To investigate executive functions and attention with repeated EpiTrack evaluations in a group of DR patients with drug-resistant epilepsy (DRE) receiving vagus nerve stimulation (VNS) during a follow-up duration of up to 5 years., Methods: The study involved 33 patients with DRE who were assessed with EpiTrack as a part of the clinical VNS protocol. Evaluations were scheduled prior to VNS implantation and then at 6 months, 12 months, and yearly thereafter. However, the COVID-19 pandemic disrupted follow-up. Therefore, changes in EpiTrack total scores over time were analyzed using a linear mixed-effects (LMEs) model to compensate for the variation in follow-up duration when predicting EpiTrack total score changes over 5 years., Results: The median follow-up time was 29 months. During each month, the EpiTrack total score was predicted to increase by 0.07 units (95% confidence interval [CI]: 0.01-0.12, P = 0.02), corresponding to a change from a baseline score of 27.3 (severe impairment) to a score of 28.9 (mild impairment) at 2 years and a score of 31.5 (almost normal) at 5 years. In the group of patients with psychiatric comorbidities, the EpiTrack total score increased by 0.14 units per month (P = 0.003), which was 3.5-fold higher than the increase of patients without psychiatric comorbidities. For the patients taking 1-2 antiseizure medications (ASMs), the EpiTrack total score increased by 0.11 units per month (P = 0.005), which was almost quadruple the rate of patients taking 3-4 ASMs., Significance: Based on EpiTrack total scores, the LME model predicted a four-point improvement in executive functions among patients with DRE at 5 years after the initiation of VNS, representing a clinically meaningful change. DRE patients with comorbid depression seemed to experience the most cognitive benefits. In addition, better cognitive outcomes were achieved if the patient took less than three ASMs., Plain Language Summary: Executive functions and attention may improve during vagus nerve stimulation therapy in patients with drug-resistant epilepsy. Epilepsy patients who have depression or use fewer than three antiseizure medications are likely to benefit cognitively more from the treatment., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: The objective of a musculoskeletal tissue bank is to collect, test, store, and provide musculoskeletal tissue allografts required in orthopedic procedures. Strict exclusion criteria are followed when selecting suitable cadaver musculoskeletal tissue donors, and the allografts are procured under sterile conditions to avoid bacterial contamination. Tissue banking in Turku, Finland, began in 1972, and tissue bank services were last reviewed in 2003. This study aimed to review the operation of the musculoskeletal tissue bank in Turku, Finland, between 2014 and 2020 and to analyze the number, types, and contamination rate of the allografts procured from the cadaver donors. Potential donor-related factors causing bacterial contamination of the allografts and whether potential musculoskeletal tissue donors were overlooked among multiorgan donors were also studied., Methods: A retrospective review of all cadaver musculoskeletal tissue donors used in the Hospital District of Southwest Finland Tyks Orto Musculoskeletal Tissue Bank during the study period was conducted, and data on the procured allograft was collected and presented. The donors were selected among patients treated in the intensive care unit (ICU) of Turku University Hospital (TYKS)., Results: A total of 28 cadaver donors were used, and 636 allografts were procured between 2014 and 2020. The bacterial contamination rate was 2.5%, which was lower than that in the previous international literature. The median treatment time in the ICU was significantly longer, and the median value of the highest C-reactive protein level was significantly higher in the group of donors with positive allograft bacterial cultures., Conclusions: The bacterial contamination rate in the tissue bank was low on an international scale. Some suitable musculoskeletal tissue donors were overlooked among multiorgan donors., Competing Interests: Declaration of Competing Interest The authors have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an emerging form of adjunctive therapy in focal refractory epilepsy. Unlike conventional DBS targets, the ANT is both encapsulated by white matter layers and located immediately adjacent to the cerebrospinal fluid (CSF) space. Owing to the location of the ANT, implantation has most commonly been performed using a transventricular trajectory. Previous studies suggest different electrical conductivity between gray matter, white matter, and CSF., Objectives: In this study, we asked whether therapeutic impedance values from a fully implanted DBS device could be used to deduce the actual location of the active contact to optimize the stimulation site. Secondly, we tested whether impedance values correlate with patient outcomes., Materials and Methods: A total of 16 patients with ANT-DBS for refractory epilepsy were evaluated in this prospective study. Therapeutic impedance values were recorded on regular outpatient clinic visits. Contact locations were analyzed using delayed contrast-enhanced postoperative computed tomography-3T magnetic resonance imaging short tau inversion recovery fusion images previously shown to demonstrate anatomical details around the ANT., Results: Transventricularly implanted contacts immediately below the CSF surface showed overall lower and slightly decreasing impedances over time compared with higher and more stable impedances in contacts with deeper parenchymal location. Impedance values in transventricularly implanted contacts in the ANT were significantly lower than those in transventricularly implanted contacts outside the ANT or extraventricularly implanted contacts that were typically at the posterior/inferior/lateral border of the ANT. Increasing contact distance from the CSF surface was associated with a linear increase in therapeutic impedance. We also found that therapeutic impedance values were significantly lower in contacts with favorable therapy response than in nonresponding contacts. Finally, we observed a significant correlation between the left- and right-side averaged impedance and the reduction of the total number of seizures., Conclusions: Valuable information can be obtained from the noninvasive measurement of therapeutic impedances. The selection of active contacts to target stimulation to the anterior nucleus may be guided by therapeutic impedance measurements to optimize outcome., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: The efficacy of deep brain stimulation of the anterior nucleus of the thalamus (ANT DBS) in patients with drug-resistant epilepsy (DRE) was demonstrated in the double-blind Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy randomized controlled trial. The Medtronic Registry for Epilepsy (MORE) aims to understand the safety and longer-term effectiveness of ANT DBS therapy in routine clinical practice., Methods: MORE is an observational registry collecting prospective and retrospective clinical data. Participants were at least 18 years old, with focal DRE recruited across 25 centers from 13 countries. They were followed for at least 2 years in terms of seizure frequency (SF), responder rate (RR), health-related quality of life (Quality of Life in Epilepsy Inventory 31), depression, and safety outcomes., Results: Of the 191 patients recruited, 170 (mean [SD] age of 35.6 [10.7] years, 43% female) were implanted with DBS therapy and met all eligibility criteria. At baseline, 38% of patients reported cognitive impairment. The median monthly SF decreased by 33.1% from 15.8 at baseline to 8.8 at 2 years ( p < 0.0001) with 32.3% RR. In the subgroup of 47 patients who completed 5 years of follow-up, the median monthly SF decreased by 55.1% from 16 at baseline to 7.9 at 5 years ( p < 0.0001) with 53.2% RR. High-volume centers (>10 implantations) had 42.8% reduction in median monthly SF by 2 years in comparison with 25.8% in low-volume center. In patients with cognitive impairment, the reduction in median monthly SF was 26.0% by 2 years compared with 36.1% in patients without cognitive impairment. The most frequently reported adverse events were changes (e.g., increased frequency/severity) in seizure (16%), memory impairment (patient-reported complaint, 15%), depressive mood (patient-reported complaint, 13%), and epilepsy (12%). One definite sudden unexpected death in epilepsy case was reported., Discussion: The MORE registry supports the effectiveness and safety of ANT DBS therapy in a real-world setting in the 2 years following implantation., Classification of Evidence: This study provides Class IV evidence that ANT DBS reduces the frequency of seizures in patients with drug-resistant focal epilepsy., Trial Registration Information: MORE ClinicalTrials.gov Identifier: NCT01521754, first posted on January 31, 2012., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: Deep Brain Stimulation (DBS) in the Anterior Nucleus of the Thalamus (ANT) has been shown to be a safe and efficacious treatment option for patients with Drug-Resitant focal Epilepsy (DRE). The ANT has been selected frequently in open and controlled studies for bilateral DBS. There is a substantial variability in ANT-DBS outcomes which is not fully understood. These outcomes might not be explained by the target location alone but potentially depend on the connectivity of the mere stimulation site with the epilepsy onset-associated brain regions. The likely sub-components of this anatomy are fiber pathways which penetrate or touch the ANT region and constitute a complex and dense fiber network which has not been described so far. A detailed characterization of this ANT associated fiber anatomy may therefore help to identify which areas are associated with positive or negative outcomes of ANT-DBS. Furthermore, prediction properties in individual ANT-DBS cases might be tested. In this work we aim to generate an anatomically detailed map of candidate fiber structures which might in the future lead to a holistic image of structural connectivity of the ANT region., Methods: To resolve the various components of the complex fiber network connected to the ANT we used a synthetic pathway reconstruction method that combines anatomical fiber tracking with dMRI-based tractography and iteratively created an anatomical high-resolution fiber map representing the most important bundles related to the ANT., Results: The anatomically detailed 3D representation of the fibers in the ANT region generated with the synthetic pathway reconstruction method incorporates multiple anatomically defined fiber bundles with their course, orientation, connectivity and relative strength. Distinctive positions within the ANT region have a different hierarchical profile with respect to the stimulation-activated fiber bundles. This detailed connectivity map, which is embedded into the topographic map of the MNI brain, provides novel opportunities to analyze the outcomes of the ANT-DBS studies., Conclusion: Our synthetic reconstruction method provides the first anatomically realistic fiber pathway map in the human ANT region incorporating histological and structural MRI data. We propose that this complex ANT fiber network can be used for detailed analysis of the outcomes of DBS studies and potentially for visualization during the stimulation planning procedures. The connectivity map might also facilitate surgical planning and will help to simulate the complex ANT connectivity. Possible activation patterns that may be elicited by electrodes in different positions in the ANT region will help to understand clinically diverse outcomes based on this new dense fiber network map. As a consequence this work might in the future help to improve individual outcomes in ANT-DBS., Competing Interests: Declaration of Competing Interest J.K.M is CEO of MRX-Brain GmbH, M.M. is data analyst and AI developer for MRX-Brain GmbH. M.M. F.G., K.L., J.K.M. have business relationships with Medtronics, which are makers of DBS devices, but none is related to the current work. V.A.C., has business relations with Medtronic, Boston Scientific and is advisor for Ceregate (Hamburg), Cortec (Freiburg) and InBrain (Spain). None of theses activities are related to the current work., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: Vascular endothelial growth factor (VEGF) has been related to the etiology of major depressive disorder (MDD). The findings involving the effects of electroconvulsive therapy (ECT) on the VEGF levels have been conflicting. The aim was to examine the possible changes in the VEGF levels and their associations with clinical outcome in patients with MDD during ECT., Methods: The study comprised 30 patients suffering from MDD. Their plasma VEGF levels were measured at baseline and 2 and 4 hr after the first, fifth, and last ECT session. The severity of depression was quantified by the Montgomery-Asberg Depression Rating Scale (MADRS)., Results: The VEGF levels increased between the 2-hr and 4-hr measurements during the first (p = .003) and the fifth (p = .017) sessions. The baseline VEGF levels between individual ECT sessions remained unchanged during the ECT series. No correlations were found between the increased VEGF levels and the clinical outcome., Conclusions: Electroconvulsive therapy increased the VEGF levels repeatedly at the same time point in two different ECT sessions. These increases had no association with the response to ECT. Consequently, VEGF may act as a mediator in the mechanism of action of ECT., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

The aim of this study was to evaluate the effects of deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) on systemic inflammatory responses in patients with drug-resistant epilepsy (DRE). Twenty-two Finnish patients with ANT-DBS implantation were enrolled in this pilot study. Changes in plasma interleukin-6 (IL-6) and interleukin-10 (IL-10) levels were examined using generalized estimating equation models at seven time points (before DBS surgery and 1, 2, 3, 6, 9 and 12 months after implantation). In the whole group, the IL-6/IL-10 ratio decreased significantly over time following ANT-DBS, while the decrease in IL-6 levels and increase in IL-10 levels were not significant. In the responder and nonresponder groups, IL-6 levels remained unchanged during the follow-up. Responders had significantly lower pre-DBS IL-10 levels before the ANT-DBS treatment than nonresponders, but the levels significantly increased over time after the treatment. In addition, responders had a higher pre-DBS IL-6/IL-10 ratio than nonresponders, and the ratio decreased for both groups after treatment, but the decrease did not reach the level of statistical significance. The rate of decrease in the ratio per month tended to be higher in responders than in nonresponders. These results may highlight the anti-inflammatory properties of ANT-DBS treatment associated with its therapeutic effectiveness in patients with DRE. Additional studies are essential to evaluate the potential of the proinflammatory cytokine IL-6, the anti-inflammatory cytokine IL-10, and their ratio as biomarkers to evaluate the therapeutic response to DBS treatment, which could facilitate treatment optimization.

Background: The range of motion (ROM) in reverse shoulder arthroplasty (RSA), is mechanically limited by the surrounding bony obstacles especially in abduction and rotation planes. However, the clinical effect of implant positioning, prosthesis design, and individual differences in bone morphology, on ROM is obscure. The aim of this study was to investigate the correlation between radiographic geometry and clinical glenohumeral (GH) ROM after RSA., Methods: RSA patients operated at Turku University Hospital during 2007-2013 were called for radiological and clinical follow-up. Pre- and postoperative true anteroposterior radiographs were obtained and the positioning of the center of rotation (COR) in relation to the surrounding bony structures was measured. Active and passive shoulder and GH abduction, flexion, internal and external rotation ROM were measured with goniometer. The Constant score (CS) and pain visual analogue scale (VAS) were recorded. The correlation between the radiographically measured parameters and the active and passive ROM and clinical outcome was statistically analyzed., Results: 91 shoulders were available for analyses with a mean follow-up of 38.7 months ± SD 20 (range 12-83) months. 77% of the patients were female, the mean age was 73 (SD 9) years. The mean angle between the line of supraspinatus fossa, and the line between COR and lateral edge of the acromion (α-angle) was 127° (SD 14) and the mean angle between the lines from lateral edge of the acromion to COR, and from there to the superior edge of the greater tubercle (β-angle) was 54° (SD 11). The mean active shoulder flexion at follow-up was 118° (SD 26), abduction 104° (SD 32), external rotation 41° (SD 22), internal rotation 77° (SD 21). The mean passive GH flexion was 80° (SD 19), abduction 67° (SD 15), external rotation 31° (SD 16) and internal rotation 34° (SD 14). The mean Constant score at follow-up was 53 (SD 18) and pain VAS 2 (SD 3). The positioning of the radiographically measured COR did not statistically significantly correlate with the ROM or clinical outcome scores., Conclusions: Postoperative radiographically measured two-dimensional geometry and positioning of the COR does not significantly correlate with the glenohumeral range of motion or clinical results after RSA., Level of Evidence: Level 3, retrospective cohort study., (© 2021 The Authors. Published by Elsevier B.V. on behalf of Professor P K Surendran Memorial Education Foundation.)

Background: Responsive vagus nerve stimulation (rVNS) utilizes an electrocardiograph (ECG)-based algorithm to detect rapid sympathetic activations associated with the onset of a seizure. Abrupt sympathetic activation may also be associated with nocturnal arousals between sleep cycles or transitioning from sleep to wakefulness, a period in which many patients with epilepsy experience seizures. Because of circadian changes in autonomic function, we hypothesized that the autostimulation feature might also behave in a circadian fashion., Objective: The aim of this study was to assess the circadian rhythmicity of autostimulations in rVNS treatment in patients with drug-resistant epilepsy (DRE)., Materials and Methods: We performed a retrospective follow-up study of 30 patients with DRE treated with rVNS including 17 new implantations and 13 battery replacements at a single center in Finland. After initiation of autostimulation mode, the exact rVNS stimulation parameters and the timestamps of all individual autostimulations delivered were registered. A clustered autostimulation was defined as any autostimulation that occurred within the duration of the therapeutic cycle during the therapy "OFF" time compared with both the previous autostimulation and the following autostimulation., Results: Autostimulations and especially autostimulation clusters show a higher probability of occurring in the morning and less at night. This trend appeared to follow the circadian rhythm of cortisol concentration., Conclusions: Early morning peaks of autostimulations at low thresholds may reflect awakening-induced activation of the cardiovascular system, which is associated with a shift towards the dominance of the sympathetic branch of the autonomic nervous system. Cortisol release occurs in parallel driven by wakening-induced activation of the hypothalamic-pituitary-adrenal axis, which is fine-tuned by direct sympathetic input to the adrenal gland. This is of interest considering the known sympathetic hyperactivity in patients with epilepsy., Competing Interests: Declaration of competing interest Toni Kulju has received grants from Maire Taponen's Foundation, Finnish Epilepsy Research Foundation, and City of Tampere Grant Committee. Ryan Verner is an employee of LivaNova PLC and holds stock options. Maxine Dibué-Adjei is an employee of LivaNova PLC and holds stock options. Sirpa Rainesalo has received speaker honoraria from Fenno Medical, Orion Pharma, and UCB. Kai Lehtimäki has received consultation fees and speaker honoraria from Medtronic and Abbott (former St. Jude Medical). Joonas Haapasalo has received support for travel to congresses from Medtronic and Stryker. Jukka Peltola has participated in clinical trials for Eisai, UCB, and Bial; received research grants from Eisai, Medtronic, UCB, and LivaNova; received speaker honoraria from LivaNova, Eisai, Medtronic, Orion Pharma, and UCB; received support for travel to congresses from LivaNova, Eisai, Medtronic, and UCB; and participated in advisory boards for LivaNova, Eisai, Medtronic, UCB, and Pfizer. The remaining authors have no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Deep brain stimulation of the ANT is a novel treatment option in refractory epilepsy with an established efficacy at the group level. However, data on the effect of individualized programming are currently lacking. We report the effect of programming changes on outcome in deep brain stimulation of anterior nucleus of thalamus (ANT DBS). Secondly, we investigated whether the effect differs between seizure types. Thirdly, we compared the response status between patients with stimulation contacts verified inside the ANT with patients with contacts located outside of ANT., Methods: The participants were 27 consecutive patients with ANT DBS implantation with at least two-year follow-up. Seizures were subdivided into focal aware (FAS), focal impaired awareness (FIAS), and focal to bilateral tonic-clonic seizures (FBTCS). The patients' seizure diaries were analyzed retrospectively to assess changes in different seizure types. Active contact locations for each patient were verified from preoperative MRI and postoperative CT fusion images using SureTune III (Medtronic Inc, Minneapolis, MN) software., Results: A significant reduction in monthly mean seizure frequency occurred in FIAS: 56% at two-year and 65% at five-year follow-up. The effects on FAS and FBTCS were less pronounced. Patients with contacts inside the ANT or on the anterolateral border of ANT experienced a greater reduction in seizure frequency than patients with outside-ANT contacts. Ultimately, seven patients became responders due to changes in DBS programming or repositioning of contacts, increasing our responder rate from 44% to 70% as measured by a seizure reduction of at least 50%., Significance: ANT DBS appears to be especially effective in reducing FIAS, when the appropriately chosen contacts are activated., Competing Interests: SJ has received study grants from Maire Taponen Foundation, Finnish Epilepsy Research Foundation, Finnish Medical Foundation and Instrumentarium Science Foundation. JP has received speaker and consultation fees from Medtronic. KL has received speaker honoraria and travel grant from Medtronic, and Abbot. KL has received lecture fees from Medtronic, Otsuka Pharmaceutical, and Lundbeck and has been sponsored to travel and attend to a medical congress by Medtronic. SR declares no conflict of interest. TM has received study grants from Finnish Epilepsy Research Foundation, Maire Taponen Foundation, and Finnish Medical Foundation and has been sponsored to travel and attend medical congresses by Medtronic and Boston Scientific. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (© 2020 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: In vagal nerve stimulation (VNS) therapy, the release of VNS model 106 (AspireSR) allowed for responsive VNS (rVNS). rVNS utilizes a cardiac-based seizure detection algorithm to detect seizure-induced tachycardia to trigger additional stimulation. There are some studies suggesting clinical benefits of rVNS over traditional VNS, but the performance and significance of autostimulation mode in clinical practice are poorly understood., Objectives: To assess the effect of initiation of rVNS therapy and altered stimulation settings on the number of daily stimulations and energy consumption in VNS therapy and to compare autostimulation performance in different epilepsy types., Materials and Methods: Retrospective follow-up of 30 patients with drug-resistant epilepsy treated with rVNS including 17 new implantations and 13 battery replaces at a single center in Finland. Our data consist of 208 different stimulation periods, that is, episodes with defined stimulation settings and both autostimulation and total stimulation performance-related data along with clinical follow-up., Results: The variation in autostimulation frequency was highly dependent on the duration of the OFF-time and autostimulation threshold (p < 0.05). There was a large additional effect of autostimulation mode on therapy time and energy consumption with longer OFF-times, but a minor effect with shorter OFF-times. Significantly more autostimulations were triggered in the temporal lobe and multifocal epilepsies than in extratemporal lobe epilepsies., Conclusions: The initiation of autostimulation mode in VNS therapy increased the total number of stimulations. Shortening the OFF-time leads to a decreased number and share of automatic activations. Epilepsy type may affect autostimulation activity., (© 2020 International Neuromodulation Society.)

Objectives: Deep brain stimulation (DBS) of the anterior thalamic nucleus (ANT) may be used against refractory focal epilepsy, but only two randomized double-blinded trials have been performed. The Oslo study was discontinued prematurely since reduction in seizure frequency was less than expected. The aim of the present study was to review the targeting used in the Oslo study and to identify the actual positions of the contacts used for stimulation., Material and Methods: BrainLab MRI data were available from 12 Oslo study patients. Based on MRI the coordinates of the center of the ANT were identified. The coordinates were considered as the visually identified preferred target and were compared with the target originally used for ANT electrode implantation and with the actual electrode positions estimated from post-operative CT scans., Results: We found considerable differences between the visually identified preferred target, the originally planned target, and the actual electrode position. The total distance between the active electrode position and the visually identified preferred target was on average 3.3 mm on the right and 2.9 mm on the left side., Conclusion: Indirect targeting based on preset coordinates may contribute to explain the modest effect of ANT-DBS on seizure frequency seen in the Oslo study. Observed differences between the center of the ANT and the actual electrode position may at least in part be explained by variations in position and size of the ANT. Direct identification of the target using better MRI imaging protocols is recommended for future ANT-DBS surgery., (© 2020 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

Background: An arthroscopic Bankart operation is the most common operative procedure to treat shoulder instability. In case of recurrence, both Bankart and Latarjet procedures are used as revision procedures. The purpose of this study was to compare the re-recurrence rate of instability and clinical results after arthroscopic revision Bankart and open revision Latarjet procedures following failed primary arthroscopic Bankart operations., Methods: Consecutive patients operatively treated for shoulder instability at Turku University Hospital between 2002 and 2013 were analyzed. Patients who underwent a primary arthroscopic Bankart operation followed by a recurrence of instability and underwent a subsequent arthroscopic Bankart or open Latarjet revision operation with a minimum of 1 year of follow-up were called in for a follow-up evaluation. The re-recurrence of instability, Subjective Shoulder Value, and Western Ontario Shoulder Instability index were assessed., Results: Of 69 patients, 48 (dropout rate, 30%) were available for follow-up. Recurrent instability symptoms occurred in 13 patients (43%) after the revision Bankart procedure and none after the revision Latarjet procedure. A statistically and clinically significant difference in the Western Ontario Shoulder Instability index was found between the patients after the revision Bankart and revision Latarjet operations (68% and 88%, respectively; P  = .0166)., Conclusions: The redislocation rate after an arthroscopic revision Bankart operation is high. Furthermore, patient-reported outcomes remain poor after a revision Bankart procedure compared with a revision Latarjet operation. We propose that in cases of recurring instability after a failed primary Bankart operation, an open Latarjet revision should be considered., (© 2020 The Authors.)

Duchenne muscular dystrophy (DMD) is a severe childhood muscle disease primarily caused by the lack of functional dystrophin at the muscle fiber membranes. Multiple therapeutic approaches are currently in (pre)clinical development, aimed at restoring expression of (truncated) dystrophin. Key questions in this phase relate to route of drug administration, dose regimen, and levels of dystrophin required to improve muscle function. A series of studies applying antisense oligonucleotides (AONs) in the mdx mouse model for DMD has been reported over the last two decades, claiming a variable range of exon skipping and increased dystrophin levels correlated to some functional improvement. The aim of this study was to compare the efficacy of subcutaneous (SC) versus intravenous (IV) dosing routes of an mdx -specific AON at both the molecular and functional level, using state-of-the-art quantitative technologies, including digital droplet polymerase chain reaction, capillary Western immunoassay, magnetic resonance imaging, and automated kinematic analysis. The majority of all readouts we quantified, both molecular and functional, showed that IV dosing of the AON had a more pronounced beneficial effect than SC dosing in mdx mice. Last, but not least, the more quantitative molecular and functional data obtained in this study suggest that low levels of dystrophin protein of at least 2.5% of wild type may already have a beneficial effect on muscle leakiness and may improve motor performance of mdx mice.

Background: Reverse shoulder arthroplasty (RSA) has gained popularity in the treatment of proximal humeral fractures (PHFs), especially in elderly patients. The purpose of this study was to investigate the use of RSA implants for acute PHFs and risk of revision, as well as risk factors for revision., Methods: RSA implants for acute PHFs were identified from the Nordic Arthroplasty Register Association registry data from 2004 to 2016. Kaplan-Meier survival analysis was used to calculate implant survival. Cox multiple regression analysis was used to calculate the adjusted revision rate for sex, age, country of operation, and year of surgery., Results: The study included 1523 RSA implants for PHFs (84% women; average age, 77 years; average follow-up time, 2.5 years). The 5-year cumulative implant survival rate was 97% (confidence limits, 95.5% and 98%). Revision was performed for 33 implants (2%). The most common reason for revision was instability, occurring in 11 cases (0.7%), followed by fracture, occurring in 6 (0.4%), and infection, occurring in 5 (0.3%). Four different arthroplasty brands were used in this cohort, with the Delta Xtend in two-thirds of cases (n = 1025). Age younger than 60 years and male sex were associated with slightly higher rates of revision; however, these differences did not reach statistical significance (hazard ratio of 2.02 with P  = .075 and hazard ratio of 3.23 with P  = .057, respectively)., Conclusion: The use of RSA for acute PHFs is increasing in the Nordic countries. The short-term risk of revision is low. The main reason for revision of RSA for this indication is instability., (© 2019 The Author(s).)

Purpose: Dopamine receptors are involved in pathophysiology of neuropsychiatric diseases, including Huntington's disease (HD). PET imaging of dopamine D2 receptors (D2R) in HD patients has demonstrated 40% decrease in D2R binding in striatum, and D2R could be a reliable quantitative target to monitor disease progression. A D2/3R antagonist, [ 18 F] fallypride, is a high-affinity radioligand that has been clinically used to study receptor density and occupancy in neuropsychiatric disorders. Here we report an improved synthesis method for [ 18 F]fallypride. In addition, high molar activity of the ligand has allowed us to apply PET imaging to characterize D2/D3 receptor density in striatum of the recently developed zQ175DN knock-in (KI) mouse model of HD., Methods: We longitudinally characterized in vivo [ 18 F] fallypride -PET imaging of D2/D3 receptor densities in striatum of 9 and 12 month old wild type (WT) and heterozygous (HET) zQ175DN KI mouse. Furthermore, we verified the D2/D3 receptor density in striatum with [ 3 H] fallypride autoradiography at 12 months of age., Results: We implemented an improved synthesis method for [ 18 F] fallypride to yield high molar activity (MA, 298-360 GBq/μmol) and good reproducibility. In the HET zQ175DN KI mice, we observed a significant longitudinal decrease in binding potential (BP ND ) (30.2%, p < 0.001, 9 months of age and 51.6%, p < 0.001, 12 months of age) compared to WT littermates. No mass effect was observed when the MA of [ 18 F] fallypride was > 100 GBq/μmol at the time of injection. Furthermore, the decrease of D2/D3 receptor density in striatum in HET zQ175DN KI was consistent using [ 3 H] fallypride autoradiography., Conclusions: We observed a significant decrease in D2/D3R receptor densities in the striatum of HET zQ175DN KI mice compared to WT mice at 9 and 12 months of age. These results are in line with clinical findings in HD patients, suggesting [ 18 F] fallypride PET imaging has potential as a quantitative translational approach to monitor disease progression in preclinical studies.

Objectives: Until now, the vagus nerve stimulation (VNS) treatment in epilepsy has consisted of two different modes: normal and magnet stimulation. A new vagus nerve stimulator model (106 AspireSR®, LivaNova, Houston, TX, USA) also allows automatic stimulation (AutoStim). The purpose of this study is to examine the effect of autostimulation on seizure frequencies together with energy consumption., Materials and Methods: The study material consisted of 14 patients whose former stimulator model (102/103) was replaced with model 106. We calculated the theoretical charge (Q) in Coulombs for one day in both of those groups. We evaluated the follow-up data of the patients' seizure counts, with a mean follow-up time of 18.1 months (SD 8.1)., Results: The total charge, "VNS dose," was reduced with model 106 in comparison with models 102 or 103 (p = 0.001, Mann-Whitney test). The average charge (Q total ) for one day with AutoStim was 142.56 mC; without AutoStim, it was 321.09 mC. We were able to assess seizure diaries in 11 out of 14 patients. Four patients (36%) had >50% seizure reduction and two patients (18%) experienced a reduction in seizure severity with VNS with autostimulation. Five patients (46%) remained unchanged. In three out of four patients with improved seizure control, the duty cycle was maintained at the original level. The patients whose duty cycle was modified for a more prolonged OFF-time had unchanged seizure frequencies., Conclusion: VNS with AutoStim achieves maintenance of prior-established seizure control with markedly less energy consumption and can also improve seizure control as compared to former stimulator model., (© 2018 International Neuromodulation Society.)

Background: The Medtronic Registry for Epilepsy (MORE; Medtronic Inc, Dublin, Ireland) is an open label observational study evaluating the long-term effectiveness, safety, and performance of deep brain stimulation (DBS) of the anterior nucleus of thalamus (ANT) for the treatment of refractory epilepsy., Objective: To compare the difference in success rate of placing contacts at ANT-target region (ANT-TR) between transventricular (TV) and extraventricular (EV) lead trajectories in 73 ANT-DBS implants in 17 European centers participating in the MORE registry., Methods: The success rate of placing contacts at ANT-TR was evaluated using a screening method combining both individual patient imaging information and stereotactic atlas information to identify contacts at ANT-TR., Results: EV lead trajectory was used in 53% of the trajectories. Approximately, 90% of the TV lead trajectories had at least 1 contact at ANT-TR, vs only 71% of the EV lead trajectories. The success rate for placing at least 1 contact at ANT-TR bilaterally was 84% for TV implants and 58% for EV implants (P < .05; Fisher's exact). No intracranial bleedings were observed, but 1 cortical infarct was reported following EV lead trajectory., Conclusion: The results of this registry support the use of TV lead trajectories for ANT-DBS as they have a higher probability in placing contacts at ANT-TR, without appearing to compromise procedural safety. Follow-up data collection is continuing in the MORE registry. These data will provide outcomes associated with TV and EV trajectories.

Objectives: Brain-derived neurotrophic factor (BDNF) has been associated with depression and its treatment response. The aim of the present study was to explore the effect of electroconvulsive therapy (ECT) on serum and plasma BDNF levels and change of Montgomery-Asberg Depression Rating Scale (MADRS) and their associations in patients with major depressive disorder (MDD)., Methods: The study included thirty patients suffering from MDD. Their serum and plasma BDNF levels were examined before ECT (baseline) and after the first, fifth, and last ECT session. The severity of the depression and the response to ECT were measured with MADRS., Results: Electroconvulsive therapy caused no significant changes in serum BDNF levels. Plasma BDNF levels decreased during the fifth ECT session between the baseline and the 2-hr samples (p = 0.019). No associations were found between serum or plasma BDNF levels and remission. The correlations between plasma and serum BDNF levels in each measurement varied between 0.187 and 0.636., Conclusions: Neither serum nor plasma BDNF levels were systematically associated with the clinical remission. However, the plasma BDNF levels somewhat varied during the ECT series. Therefore, the predictive value of BDNF for effects of ECT appears to be at least modest., (© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Objective: Anterior nucleus of thalamus (ANT) deep brain stimulation (DBS) is becoming a more common treatment for drug-resistant epilepsy. Epilepsy and depression display a bidirectional association. Anterior nucleus of thalamus has connections to anterior cingulate cortex and orbitomedial prefrontal cortex, hence, a possible role in emotional and executive functions, and thus, ANT DBS might exert psychiatric adverse effects. Our aim was to evaluate previous and current psychiatric symptoms in patients with epilepsy undergoing ANT DBS surgery and assess the predictability of psychiatric adverse effects. Programming-related psychiatric adverse effects are also reported., Method: Twenty-two patients with ANT DBS for retractable epilepsy were examined, and a psychiatric evaluation of depressive and other psychiatric symptoms was performed with Montgomery and Åsberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), and Symptom Checklist prior to surgery, concentrating on former and current psychiatric symptoms and medications. The follow-up visit was one year after surgery., Results: At the group level, no changes on mood were observed during ANT DBS treatment. Two patients with former histories of depression experienced sudden depressive symptoms related to DBS programming settings; these were quickly alleviated after changing the stimulation parameters. In addition, two patients with no previous histories of psychosis gradually developed clear paranoid and anxiety symptoms that also relieved slowly after changing the programming settings., Conclusion: The majority of our ANT DBS patients did not experience psychiatric adverse effects. Certain DBS parameters might predispose to sudden depressive or slowly manifesting paranoid symptoms that are reversible via programming changes., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Reverse shoulder arthroplasty (RSA) has gained increasing popularity in the treatment of rotator cuff tear arthropathy (CTA). The purpose of this study was to evaluate the survival of RSA and the risk factors for revision following RSA., Methods: RSA patients with CTA or osteoarthritis were identified from the Nordic Arthroplasty Register Association registry data (2004-2013). Kaplan-Meier survival analysis was used to calculate survival probabilities. Cox multiple regression analysis was used to calculate revision rates adjusted for sex, arthroplasty brand, age (<70 years), and year of surgery., Results: The study included 1904 patients with RSA (1904 RSAs) (69% women; mean age, 74 years; age range, 35-97 years). Revision was performed in 95 patients (5%), with a 10-year cumulative revision rate of 0.91. The most common reason for revision was infection (n = 42), followed by loosening (n = 16) and instability (n = 12). Most revisions occurred less than 6 months after the primary operation. Men had a significantly increased risk of revision compared with women (risk ratio, 3.8; 95% confidence interval, 2.4-6.1). The most common implants were the Delta Xtend (n = 1366) and Delta Mark III (n = 246). The risk of revision of the Delta Mark III was 2.1 (95% confidence interval, 1.1-4.3) compared with the Delta Xtend. Age and year of surgery were not statistically significantly associated with risk of revision., Conclusion: The overall midterm risk of revision after RSA for CTA was low (5%). The most common reason for early revision was infection. Male sex was associated with a significantly increased risk of revision., (Copyright © 2018 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Objectives: Neurostimulation has offered new treatment options in refractory epilepsy, first with vagus nerve stimulation (VNS) and more recently with deep brain stimulation (DBS). There is a lack of previous detailed data assessing the relationship between VNS and ANT-DBS. The aim of this study was to investigate the potential correlation between therapeutic responses to VNS and ANT-DBS., Materials and Methods: A total of 11 patients with previous VNS therapy underwent ANT-DBS implantation. Monthly seizure counts starting from baseline before VNS extending to long-term DBS treatment were analyzed. The reasons for VNS discontinuation were assessed., Results: Altogether in 10 of 11 patients, the response to VNS seemed to be similar to the response to DBS therapy. Progressive response to VNS was likely to correlate with a progressive response to DBS in three of three patients. Partial response to VNS was associated with a fluctuating response pattern to DBS in two patients. Five of six nonresponders to VNS were also nonresponders to DBS. One of the VNS nonresponders obtained progressive response to DBS., Conclusions: This is the first study to evaluate in detail the effect of both VNS and ANT-DBS in refractory epilepsy patients. There is a putative association between VNS and DBS responses suggesting the need for further studies., (© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Background: Deep brain stimulation (DBS) of the anterior nucleus of thalamus (ANT) is an emerging treatment option for patients suffering from refractory epilepsy. ANT has extensive connections with hippocampus and retrosplenial cingulum, areas associated mainly with spatial memory and with anterior cingulum which is important in executive functions. As refractory epilepsy is often associated with cognitive decline and neuronal damage, the decreased connectivity between ANT and remote structures might impact on the effects of DBS., Objective: We hypothesized that the neuropsychological profile could reflect the connectivity of ANT and further predict the efficacy of ANT DBS. We evaluated the cognitive performance of patients with refractory epilepsy with DBS to evaluate whether neuropsychological profiles could reflect the connectivity of ANT and further predict the efficacy of ANT DBS., Method: Sixteen patients with refractory epilepsy treated with ANT DBS with at least 2 years of follow-up were included in the study. Patients underwent a neuropsychological evaluation as a part of the protocol and their clinical outcome was determined by seizure frequency in the last 6 months compared to baseline. The patients were classified as responders if there was a ≥50% reduction in the frequency of the predominant seizure type, otherwise as nonresponders., Results: There were 12 responders and 4 nonresponders for ANT DBS treatment in the study population. Nonresponders performed worse than responders in neuropsychological tasks measuring executive functions and attention, such as the Trail-Making Test., Conclusion: Better executive functions and attention seemed to predict improved clinical outcome after the ANT DBS surgery. Based on our preliminary descriptive findings and the anatomical connectivity hypothesis, we suggest that deficits in executive functions may relate to an inferior outcome. This finding might offer new tools for refining the selection of patients with refractory epilepsy scheduled to undergo ANT DBS surgery. Moreover, it highlights the need for further investigations of neural connectivity in epilepsy.

Experimental and clinical reports highlight the role of cytokines in pathophysiological processes in underpinning epilepsy, but the clinical data remains somewhat limited. The levels of Interleukin (IL)-6 were measured in serum from 49 patients with refractory epilepsy [temporal lobe epilepsy (TLE, n=23), extratemporal lobe epilepsy (XLE, n=22), and idiopathic generalized epilepsy (IGE, n=4)] before and after the first verified seizure (IS; index seizure) during inpatient video-electroencephalographic (VEEG) monitoring. The levels of IL-6 increased significantly at all time points between 3h and 24h after the IS compared to the baseline. IL-6 concentrations were significantly higher at the 3h and 6h time point after tonic-clonic seizures (TCS) compared to the situation with simple partial and complex partial seizures. An IS duration longer than 100s, low baseline IL-6 level and <10 seizures/month in patients with TLE were associated with an increase in IL-6 concentrations during the 24h after the IS. In patients with TLE, the maximum change in IL-6 levels after IS was significantly higher than in XLE. If the baseline level of IL-6 was low (under 5pg/ml), seizures induced a significant elevation in both absolute and relative values in TLE patients but not in XLE. In patients with ≤10 seizures per month during the last year, the maximum change was higher than in patients with >10 seizures. If the total seizure burden during registration was ≥100s, the IL-6 increase was significantly higher than if it were under 100s. The results of this study highlight the complexity of factors involved in the seizure induced production of the inflammatory cytokine, IL-6. The major factor is the epilepsy type i.e. increased production of IL-6 in TLE compared to XLE. The response to a single seizure in TLE is dependent on the previous seizure frequency and the baseline IL-6 concentration., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Ibuprofen, a nonsteroidal anti-inflammatory drug, and nitric oxide (NO) donors have been reported to reduce the severity of muscular dystrophies in mice associated with the absence of dystrophin or α -sarcoglycan, but their effects on mice that are dystrophic due to the absence of dysferlin have not been examined. We have tested ibuprofen, as well as isosorbide dinitrate (ISDN), a NO donor, to learn whether used alone or together they protect dysferlin-null muscle in A/J mice from large strain injury (LSI) induced by a series of high strain lengthening contractions. Mice were maintained on chow containing ibuprofen and ISDN for 4 weeks. They were then subjected to LSI and maintained on the drugs for 3 additional days. We measured loss of torque immediately following injury and at day 3 postinjury, fiber necrosis, and macrophage infiltration at day 3 postinjury, and serum levels of the drugs at the time of euthanasia. Loss of torque immediately after injury was not altered by the drugs. However, the torque on day 3 postinjury significantly decreased as a function of ibuprofen concentration in the serum (range, 0.67-8.2 µ g/ml), independent of ISDN. The effects of ISDN on torque loss at day 3 postinjury were not significant. In long-term studies of dysferlinopathic BlAJ mice, lower doses of ibuprofen had no effects on muscle morphology, but reduced treadmill running by 40%. Our results indicate that ibuprofen can have deleterious effects on dysferlin-null muscle and suggest that its use at pharmacological doses should be avoided by individuals with dysferlinopathies., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

Objective: Changes in the tumor necrosis factor-α (TNFα) have been associated with major depressive disorder (MDD). Findings concerning the effects of electroconvulsive therapy (ECT) on the TNFα level have been contradictory. The aim was to examine the immediate and long-term changes in the TNFα level and their associations with symptom reduction in patients with MDD during ECT., Method: The study included 30 patients with MDD. Their TNFα levels were measured at baseline and 2 and 4 hr after the first, fifth and last ECT session. Depressive symptoms were assessed with the Montgomery-Asberg Depression Rating Scale (MADRS)., Results: The TNFα level decreased from baseline to the 2- and 4-hr measurements. There was a correlation between the first ECT session TNFα levels and the relative symptom reduction according to the MADRS score after the ECT series. Both the first (baseline) ECT and 4-hr TNFα levels were lower in responders than in nonresponders., Conclusion: ECT consistently induced a decrease in the TNFα level after each studied session. A low TNFα level at the first ECT appeared to predict a symptom reduction. These findings suggest that TNFα might have a role in the pathogenesis in MDD and in the mechanism of action of ECT.

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.

Vagus nerve stimulation (VNS) is used for treating refractory epilepsy and major depression. While the impact of this treatment on seizures has been established, its impact on human cognition remains equivocal. The goal of this study is to elucidate the immediate effects of vagus nerve stimulation on attention, cognition, and emotional reactivity in patients with epilepsy. Twenty patients (12 male and 8 female; 45 ± 13 years old) treated with VNS due to refractory epilepsy participated in the study. Subjects performed a computer-based test of executive functions embedded with emotional distractors while their brain activity was recorded with electroencephalography. Subjects' cognitive performance, early visual event-related potential N1, and frontal alpha asymmetry were studied when cyclic vagus nerve stimulation was on and when it was off. We found that vagus nerve stimulation improved working memory performance as seen in reduced errors on a subtask that relied on working memory, odds ratio (OR) = 0.63 (95% confidence interval, CI [0.47, 0.85]) and increased N1 amplitude, F(1, 15) = 10.17, p = .006. In addition, vagus nerve stimulation resulted in longer reaction time, F(1, 16) = 8.23, p = .019, and greater frontal alpha asymmetry, F(1, 16) = 11.79, p = .003, in response to threat-related distractors. This is the first study to show immediate improvement in working memory performance in humans with clinically relevant vagus nerve stimulation. Furthermore, vagus nerve stimulation had immediate effects on emotional reactivity evidenced in behavior and brain physiology.