Disentangling Bradykinesia and Rigidity in Parkinson's Disease: Evidence from Short- and Long-Term Subthalamic Nucleus Deep Brain Stimulation.

OBJECTIVE: Bradykinesia and rigidity are considered closely related motor signs in Parkinson disease (PD), but recent neurophysiological findings suggest distinct pathophysiological mechanisms. This study aims to examine and compare longitudinal changes in bradykinesia and rigidity in PD patients treated with bilateral subthalamic nucleus deep brain stimulation (STN-DBS). METHODS: In this retrospective cohort study, the clinical progression of appendicular and axial bradykinesia and rigidity was assessed up to 15 years after STN-DBS in the best treatment conditions (ON medication and ON stimulation). The severity of bradykinesia and rigidity was examined using ad hoc composite scores from specific subitems of the Unified Parkinson's Disease Rating Scale motor part (UPDRS-III). Short- and long-term predictors of bradykinesia and rigidity were analyzed through linear regression analysis, considering various preoperative demographic and clinical data, including disease duration and severity, phenotype, motor and cognitive scores (eg, frontal score), and medication. RESULTS: A total of 301 patients were examined before and 1 year after surgery. Among them, 101 and 56 individuals were also evaluated at 10-year and 15-year follow-ups, respectively. Bradykinesia significantly worsened after surgery, especially in appendicular segments (p < 0.001). Conversely, rigidity showed sustained benefit, with unchanged clinical scores compared to preoperative assessment (p > 0.05). Preoperative motor disability (eg, composite scores from the UPDRS-III) predicted short- and long-term outcomes for both bradykinesia and rigidity (p < 0.01). Executive dysfunction was specifically linked to bradykinesia but not to rigidity (p < 0.05). INTERPRETATION: Bradykinesia and rigidity show long-term divergent progression in PD following STN-DBS and are associated with independent clinical factors, supporting the hypothesis of partially distinct pathophysiology. ANN NEUROL 2024;96:234-246.

Focal cooling: An alternative treatment for drug-resistant epilepsy in a mesial temporal lobe epilepsy primate model-A preliminary study.

OBJECTIVE: Focal cooling is emerging as a relevant therapy for drug-resistant epilepsy (DRE). However, we lack data on its effectiveness in controlling seizures that originate in deep-seated areas like the hippocampus. We present a thermoelectric solution for focal brain cooling that specifically targets these brain structures. METHODS: A prototype implantable device was developed, including temperature sensors and a cannula for penicillin injection to create an epileptogenic zone (EZ) near the cooling tip in a non-human primate model of epilepsy. The mesial temporal lobe was targeted with repeated penicillin injections into the hippocampus. Signals were recorded from an sEEG (Stereoelectroencephalography) lead placed 2 mm from the EZ. Once the number of seizures had stabilized, focal cooling was applied, and temperature and electroclinical events were monitored using a customized detection algorithm. Tests were performed on two Macaca fascicularis monkeys at three temperatures. RESULTS: Hippocampal seizures were observed 40-120 min post-injection, their duration and frequency stabilized at around 120 min. Compared to the control condition, a reduction in the number of hippocampal seizures was observed with cooling to 21°C (Control: 4.34 seizures, SD 1.704 per 20 min vs Cooling to 21°C: 1.38 seizures, SD 1.004 per 20 min). The effect was more pronounced with cooling to 17°C, resulting in an almost 80% reduction in seizure frequency. Seizure duration and number of interictal discharges were unchanged following focal cooling. After several months of repeated penicillin injections, hippocampal sclerosis was observed, similar to that recorded in humans. In addition, seizures were identified by detecting temperature variations of 0.3°C in the EZ correlated with the start of the seizures. SIGNIFICANCE: In epilepsy therapy, the ultimate aim is total seizure control with minimal side effects. Focal cooling of the EZ could offer an alternative to surgery and to existing neuromodulation devices.

Advances in Technical Aspects of Deep Brain Stimulation Surgery.

BACKGROUND: Deep brain stimulation has become an established technology for the treatment of patients with a wide variety of conditions, including movement disorders, psychiatric disorders, epilepsy, and pain. Surgery for implantation of DBS devices has enhanced our understanding of human physiology, which in turn has led to advances in DBS technology. Our group has previously published on these advances, proposed future developments, and examined evolving indications for DBS. SUMMARY: The crucial roles of structural MR imaging pre-, intra-, and post-DBS procedure in target visualization and confirmation of targeting are described, with discussion of new MR sequences and higher field strength MRI enabling direct visualization of brain targets. The incorporation of functional and connectivity imaging in procedural workup and their contribution to anatomical modelling is reviewed. Various tools for targeting and implanting electrodes, including frame-based, frameless, and robot-assisted, are surveyed, and their pros and cons are described. Updates on brain atlases and various software used for planning target coordinates and trajectories are presented. The pros and cons of asleep versus awake surgery are discussed. The role and value of microelectrode recording and local field potentials are described, as well as the role of intraoperative stimulation. Technical aspects of novel electrode designs and implantable pulse generators are presented and compared.

A Subpopulation of Spikes Predicts Successful Epilepsy Surgery Outcome.

OBJECTIVE: Epileptic spikes are the traditional interictal electroencephalographic (EEG) biomarker for epilepsy. Given their low specificity for identifying the epileptogenic zone (EZ), they are given only moderate attention in presurgical evaluation. This study aims to demonstrate that it is possible to identify specific spike features in intracranial EEG that optimally define the EZ and predict surgical outcome. METHODS: We analyzed spike features on stereo-EEG segments from 83 operated patients from 2 epilepsy centers (37 Engel IA) in wakefulness, non-rapid eye movement sleep, and rapid eye movement sleep. After automated spike detection, we investigated 135 spike features based on rate, morphology, propagation, and energy to determine the best feature or feature combination to discriminate the EZ in seizure-free and non-seizure-free patients by applying 4-fold cross-validation. RESULTS: The rate of spikes with preceding gamma activity in wakefulness performed better for surgical outcome classification (4-fold area under receiver operating characteristics curve [AUC] = 0.755 ± 0.07) than the seizure onset zone, the current gold standard (AUC = 0.563 ± 0.05, p = 0.015) and the ripple rate, an emerging seizure-independent biomarker (AUC = 0.537 ± 0.07, p = 0.006). Channels with a spike-gamma rate exceeding 1.9/min had an 80% probability of being in the EZ. Combining features did not improve the results. INTERPRETATION: Resection of brain regions with high spike-gamma rates in wakefulness is associated with a high probability of achieving seizure freedom. This rate could be applied to determine the minimal number of spiking channels requiring resection. In addition to quantitative analysis, this feature is easily accessible to visual analysis, which could aid clinicians during presurgical evaluation. ANN NEUROL 2023;93:522-535.

Lights for epilepsy: can photobiomodulation reduce seizures and offer neuroprotection?

Epilepsy is synonymous with individuals suffering repeated "fits" or seizures. The seizures are triggered by bursts of abnormal neuronal activity, across either the cerebral cortex and/or the hippocampus. In addition, the seizure sites are characterized by considerable neuronal death. Although the factors that generate this abnormal activity and death are not entirely clear, recent evidence indicates that mitochondrial dysfunction plays a central role. Current treatment options include drug therapy, which aims to suppress the abnormal neuronal activity, or surgical intervention, which involves the removal of the brain region generating the seizure activity. However, ~30% of patients are unresponsive to the drugs, while the surgery option is invasive and has a morbidity risk. Hence, there is a need for the development of an effective non-pharmacological and non-invasive treatment for this disorder, one that has few side effects. In this review, we consider the effectiveness of a potential new treatment for epilepsy, known as photobiomodulation, the use of red to near-infrared light on body tissues. Recent studies in animal models have shown that photobiomodulation reduces seizure-like activity and improves neuronal survival. Further, it has an excellent safety record, with little or no evidence of side effects, and it is non-invasive. Taken all together, this treatment appears to be an ideal treatment option for patients suffering from epilepsy, which is certainly worthy of further consideration.

Axial impairment and falls in Parkinson's disease: 15 years of subthalamic deep brain stimulation.

In this retrospective study, we longitudinally analyzed axial impairment and falls in people with Parkinson's disease (PD) and subthalamic nucleus deep brain stimulation (STN-DBS). Axial scores and falling frequency were examined at baseline, and 1, 10, and 15 years after surgery. Preoperative demographic and clinical data, including PD duration and severity, phenotype, motor and cognitive scales, medications, and vascular changes on neuroimaging were examined as possible risk factors through Kaplan-Meier and Cox regression analyses. Of 302 individuals examined before and at 1 year after surgery, 102 and 57 were available also at 10 and 15 years of follow-up, respectively. Axial scores were similar at baseline and at 1 year but worsened at 10 and 15 years. The prevalence rate of frequent fallers progressively increased from baseline to 15 years. Preoperative axial scores, frontal dysfunction and age at PD onset were risk factors for axial impairment progression after surgery. Axial scores, akinetic/rigid phenotype, age at disease onset and disease duration at surgery predicted frequent falls. Overall, axial signs progressively worsened over the long-term period following STN-DBS, likely related to the progression of PD, especially in a subgroup of subjects with specific risk factors.

Does Motor Symptoms Asymmetry Predict Motor Outcome of Subthalamic Deep Brain Stimulation in Parkinson's Disease Patients?

Background: In Parkinson's disease (PD), the side of motor symptoms onset may influence disease progression, with a faster motor symptom progression in patients with left side lateralization. Moreover, worse neuropsychological outcomes after subthalamic nucleus deep brain stimulation (STN-DBS) have been described in patients with predominantly left-sided motor symptoms. The objective of this study was to evaluate if the body side of motor symptoms onset may predict motor outcome of bilateral STN-DBS. Methods: This retrospective study included all consecutive PD patients treated with bilateral STN-DBS at Grenoble University Hospital from 1993 to 2015. Demographic, clinical and neuroimaging data were collected before (baseline condition) and 1 year after surgery (follow-up condition). The predictive factors of motor outcome at one-year follow-up, measured by the percentage change in the MDS-UPDRS-III score, were evaluated through univariate and multivariate linear regression analysis. Results: A total of 233 patients were included with one-year follow-up after surgery [143 males (61.40%); 121 (51.90 %) right body onset; 112 (48.10%) left body onset; mean age at surgery, 55.31 ± 8.44 years; mean disease duration, 11.61 ± 3.87]. Multivariate linear regression analysis showed that the left side of motor symptoms onset did not predict motor outcome (ß = 0.093, 95% CI = -1.967 to 11.497, p = 0.164). Conclusions: In this retrospective study, the body side of motor symptoms onset did not significantly influence the one-year motor outcome in a large cohort of PD patients treated with bilateral STN-DBS.

Agricultural activities and risk of central nervous system tumors among French farm managers: Results from the TRACTOR project.

The etiology of central nervous system (CNS) tumors is complex and involves many suspected risk factors. Scientific evidence remains insufficient, in particular in the agricultural field. The goal of our study was to investigate associations between agricultural activities and CNS tumors in the entire French farm manager workforce using data from the TRACTOR project. The TRACTOR project hold a large administrative health database covering the entire French agricultural workforce, over the period 2002-2016, on the whole French metropolitan territory. Associations were estimated for 26 activities and CNS tumors using Cox proportional hazards model, with time to first CNS tumor insurance declaration as the underlying timescale, adjusting for sex, age and geographical area. There were 1017 cases among 1 036 069 farm managers, including 317 meningiomas and 479 gliomas. Associations varied with tumor types, sex and types of crop and animal farming. Analyses showed several increased risks of CNS tumors, in particular for animal farming. The main increases in risk were observed for meningioma in mixed dairy and cow farming (hazard ratio [HR] = 1.75, 95% confidence interval [CI]: 1.09-2.81) and glioma in pig farming (HR = 2.28, 95% CI: 1.37-3.80). Our study brings new insights on the association of a wide range of agricultural activities and CNS tumor and subtype-specific risks in farm managers. Although these findings need to be corroborated in further studies and should be interpreted cautiously, they could have implications for enhancing CNS tumor surveillance in agriculture.

Long-term independence and quality of life after subthalamic stimulation in Parkinson disease.

BACKGROUND AND PURPOSE: Studies on long-term nonmotor outcomes of subthalamic nucleus stimulation in Parkinson disease (PD) are scarce. This study reports on very long-term non-motor and motor outcomes in one of the largest cohorts of people with advanced PD, treated for >10 years with subthalamic nucleus stimulation. The main outcome was to document the evolution of independence in activities of daily living. The secondary outcomes were to measure the change in quality of life, as well as non-motor and motor outcomes. METHODS: Patients were studied preoperatively, at 1 year, and beyond 10 years after subthalamic stimulation with an established protocol including motor, non-motor, and neuropsychological assessments. RESULTS: Eighty-five people with PD were included. Independence scores in the off-medication condition (measured with the Schwab & England Activities of Daily Living Scale) as well as quality of life (measured with the Parkinson's Disease Questionnaire [PDQ]-37) remained improved at longest follow-up compared to preoperatively (respectively, p < 0.001, p = 0.015). Cognitive scores, measured with the Mattis Dementia Rating Scale, significantly worsened compared to before and 1 year after surgery (p < 0.001), without significant change in depression, measured with the Beck Depression Inventory. Motor fluctuations, dyskinesias, and off dystonia remained improved at longest follow-up (p < 0.001), with a significant reduction in dopaminergic treatment (45%, p < 0.001). CONCLUSIONS: This study highlights the long-term improvement of subthalamic stimulation on independence and quality of life, despite the progression of disease and the occurrence of levodopa-resistant symptoms.

Surgical outcome of temporal plus epilepsy is improved by multilobar resection.

OBJECTIVE: Temporal plus epilepsy (TPE) represents a rare type of epilepsy characterized by a complex epileptogenic zone including the temporal lobe and the close neighboring structures. We investigated whether the complete resection of temporal plus epileptogenic zone as defined through stereoelectroencephalography (SEEG) might improve seizure outcome in 38 patients with TPE. METHODS: Inclusion criteria were as follows: epilepsy surgery performed between January 1990 and December 2001, SEEG defining a temporal plus epileptogenic zone, unilobar temporal operations ("temporal lobe epilepsy [TLE] surgery") or multilobar interventions including the temporal lobe ("TPE surgery"), magnetic resonance imaging either normal or showing signs of hippocampal sclerosis, and postoperative follow-up of at least 12 months. For each assessment of postoperative seizure outcome, at 1, 2, 5, and 10 years, we carried out descriptive analysis and classical tests of hypothesis, namely, Pearson χ2 test or Fisher exact test of independence on tables of frequency for each categorical variable of interest and Student t-test for each continuous variable of interest, when appropriate. RESULTS: Twenty-one patients underwent TPE surgery and 17 underwent TLE surgery with a follow-up of 12.4 ± 8.16 years. In the multivariate models, there was a significant effect of the time from surgery on Engel Class IA versus IB-IV outcome, with a steadily worsening trend from 5-year follow-up onward. TPE surgery was associated with better results than TLE surgery. SIGNIFICANCE: This study suggests that surgical outcome in patients with TPE can be improved by a tailored, multilobar resection and confirms that SEEG is mandatory when a TPE is suspected.

Correcting for physiological ripples improves epileptic focus identification and outcome prediction.

OBJECTIVE: The integration of high-frequency oscillations (HFOs; ripples [80-250 Hz], fast ripples [250-500 Hz]) in epilepsy evaluation is hampered by physiological HFOs, which cannot be reliably differentiated from pathological HFOs. We evaluated whether defining abnormal HFO rates by statistical comparison to region-specific physiological HFO rates observed in the healthy brain improves identification of the epileptic focus and surgical outcome prediction. METHODS: We detected HFOs in 151 consecutive patients who underwent stereo-electroencephalography and subsequent resective epilepsy surgery at two tertiary epilepsy centers. We compared how HFOs identified the resection cavity and predicted seizure-free outcome using two thresholds from the literature (HFO rate > 1/min; 50% of the total number of a patient's HFOs) and three thresholds based on normative rates from the Montreal Neurological Institute Open iEEG Atlas (https://mni-open-ieegatlas. RESEARCH: mcgill.ca/): global Atlas threshold, regional Atlas threshold, and regional + 10% threshold after regional Atlas correction. RESULTS: Using ripples, the regional + 10% threshold performed best for focus identification (77.3% accuracy, 27% sensitivity, 97.1% specificity, 80.6% positive predictive value [PPV], 78.2% negative predictive value [NPV]) and outcome prediction (69.5% accuracy, 58.6% sensitivity, 76.3% specificity, 60.7% PPV, 74.7% NPV). This was an improvement for focus identification (+1.1% accuracy, +17.0% PPV; p < .001) and outcome prediction (+12.0% sensitivity, +1.0% PPV; p = .05) compared to the 50% threshold. The improvement was particularly marked for foci in cortex, where physiological ripples are frequent (outcome: +35.3% sensitivity, +5.3% PPV; p = .014). In these cases, the regional + 10% threshold outperformed fast ripple rate > 1/min (+3.6% accuracy, +26.5% sensitivity, +21.6% PPV; p < .001) and seizure onset zone (+13.5% accuracy, +29.4% sensitivity, +17.0% PPV; p < .05-.01) for outcome prediction. Normalization did not improve the performance of fast ripples. SIGNIFICANCE: Defining abnormal HFO rates by statistical comparison to rates in healthy tissue overcomes an important weakness in the clinical use of ripples. It improves focus identification and outcome prediction compared to standard HFO measures, increasing their clinical applicability.

Long-term stability of the chronic epidural wireless recorder WIMAGINE in tetraplegic patients.

Objective.The evaluation of the long-term stability of ElectroCorticoGram (ECoG) signals is an important scientific question as new implantable recording devices can be used for medical purposes such as Brain-Computer Interface (BCI) or brain monitoring.Approach.The long-term clinical validation of wireless implantable multi-channel acquisition system for generic interface with neurons (WIMAGINE), a wireless 64-channel epidural ECoG recorder was investigated. The WIMAGINE device was implanted in two quadriplegic patients within the context of a BCI protocol. This study focused on the ECoG signal stability in two patients bilaterally implanted in June 2017 (P1) and in November 2019 (P2).Methods. The ECoG signal was recorded at rest prior to each BCI session resulting in a 32 month and in a 14 month follow-up for P1 and P2 respectively. State-of-the-art signal evaluation metrics such as root mean square (RMS), the band power (BP), the signal to noise ratio (SNR), the effective bandwidth (EBW) and the spectral edge frequency (SEF) were used to evaluate stability of signal over the implantation time course. The time-frequency maps obtained from task-related motor activations were also studied to investigate the long-term selectivity of the electrodes.Mainresults.Based on temporal linear regressions, we report a limited decrease of the signal average level (RMS), spectral distribution (BP) and SNR, and a remarkable steadiness of the EBW and SEF. Time-frequency maps obtained during motor imagery, showed a high level of discrimination 1 month after surgery and also after 2 years.Conclusions.The WIMAGINE epidural device showed high stability over time. The signal evaluation metrics of two quadriplegic patients during 32 months and 14 months respectively provide strong evidence that this wireless implant is well-suited for long-term ECoG recording.Significance.These findings are relevant for the future of implantable BCIs, and could benefit other patients with spinal cord injury, amyotrophic lateral sclerosis, neuromuscular diseases or drug-resistant epilepsy.

Long-term Outcomes (15 Years) After Subthalamic Nucleus Deep Brain Stimulation in Patients With Parkinson Disease.

OBJECTIVE: To evaluate the effects of deep brain stimulation of the subthalamic nucleus (STN-DBS) in Parkinson disease (PD) patients on motor complications beyond 15 years after surgery. METHODS: Data about motor complications, quality of life (QoL), activities of daily living, the UPDRS motor scores, dopaminergic treatment, stimulation parameters, and side effects of STN-DBS were retrospectively retrieved and compared between before surgery, at 1 year and beyond 15 years after bilateral STN-DBS. RESULTS: Fifty-one patients with 17.06 ± 2.18 years STN-DBS follow-up were recruited. Compared to baseline, the time spent with dyskinesia and the time spent in the off state were reduced by 75% (p<0.001) and by 58.7% (p<0.001), respectively. Moreover, dopaminergic drugs were reduced by 50.6% (p<0.001). The PDQL total score, and the emotional function and social function domains improved of 13.8% (p=0.005), 13.6% (p=0.01) and 29.9% (p<0.001), respectively. Few and mostly manageable device-related adverse events were observed during the follow-up. CONCLUSIONS: STN-DBS is still effective beyond 15 years from the intervention, notably with significant improvement in motor complications and stable reduction of dopaminergic drugs. Furthermore, despite the natural continuous progression of PD with worsening of levodopa-resistant motor and non-motor symptoms over the years, STN-DBS patients could maintain an improvement in QoL. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, for patients with PD, STN-DBS remains effective at treating motor complications 15 years after surgery.

Adjuvant therapeutic potential of moderate hypothermia for glioblastoma.

PURPOSE: Glioblastoma is the most common malignant brain tumor, currently treated by surgery followed by concomitant radiotherapy and temozolomide-based chemotherapy. Despite these treatments, median survival is only 15 months as a result of tumor recurrence in the resection margins. Here, we propose therapeutic hypothermia - known to have neuroprotective effects - as an adjuvant treatment to maintain residual glioblastoma cells in a dormant state, and thus prevent tumor recurrence. METHODS: In vitro experiments were performed on healthy tissue with primary human astrocytes, and four human glioblastoma cell lines: A172, U251, U87, and T98G. We explored the adjuvant potential of moderate hypothermia (28 °C) by studying the reversibility of its inhibitory effects on cell proliferation and comparing them to currently used temozolomide. RESULTS: Moderate hypothermia reduced healthy cell growth, but also inhibited glioblastoma cell proliferation even after rewarming. Indeed, hypothermic preconditioning duration strongly enhanced inhibitory effects from 35% after 3 days to 100% after 30 days. In contrast, moderate (28 °C) and severe (23 °C) preconditioning induced similar results. Finally, moderate hypothermia had more uniform inhibitory effects than temozolomide, which reduced proliferation by between 15% and 95%, and also potentiated the effects of the latter. CONCLUSION: Moderate hypothermia shows promise as an adjuvant therapy for glioblastoma through its inhibition of cell proliferation beyond direct conditioning and potentiation of the effects of chemotherapy. If in vivo preclinical results corroborate our findings, therapeutic hypothermia applied at the resection margins could probably inhibit tumor growth, delay tumor recurrence and reduce inter-patient variability.

Long-Term Efficacy of Occipital Nerve Stimulation for Medically Intractable Cluster Headache.

BACKGROUND: Occipital nerve stimulation (ONS) has been proposed to treat refractory chronic cluster headache (rCCH) but its efficacy has only been showed in small short-term series. OBJECTIVE: To evaluate ONS long-term efficacy in rCCH. METHODS: We studied 105 patients with rCCH, treated by ONS within a multicenter ONS prospective registry. Efficacy was evaluated by frequency, intensity of pain attacks, quality of life (QoL) EuroQol 5 dimensions (EQ5D), functional (Headache Impact Test-6, Migraine Disability Assessment) and emotional (Hospital Anxiety Depression Scale [HAD]) impacts, and medication consumption. RESULTS: At last follow-up (mean 43.8 mo), attack frequency was reduced >50% in 69% of the patients. Mean weekly attack frequency decreased from 22.5 at baseline to 9.9 (P < .001) after ONS. Preventive and abortive medications were significantly decreased. Functional impact, anxiety, and QoL significantly improved after ONS. In excellent responders (59% of the patients), attack frequency decreased by 80% and QoL (EQ5D visual analog scale) dramatically improved from 37.8/100 to 73.2/100. When comparing baseline and 1-yr and last follow-up outcomes, efficacy was sustained over time. In multivariable analysis, low preoperative HAD-depression score was correlated to a higher risk of ONS failure. During the follow-up, 67 patients experienced at least one complication, 29 requiring an additional surgery: infection (6%), lead migration (12%) or fracture (4.5%), hardware dysfunction (8.2%), and local pain (20%). CONCLUSION: Our results showed that long-term efficacy of ONS in CCH was maintained over time. In responders, ONS induced a major reduction of functional and emotional headache-related impacts and a dramatic improvement of QoL. These results obtained in real-life conditions support its use and dissemination in rCCH patients.

Predictors of Long-Term Outcome of Subthalamic Stimulation in Parkinson Disease.

OBJECTIVE: This study was undertaken to identify preoperative predictive factors of long-term motor outcome in a large cohort of consecutive Parkinson disease (PD) patients with bilateral subthalamic nucleus deep brain stimulation (STN-DBS). METHODS: All consecutive PD patients who underwent bilateral STN-DBS at the Grenoble University Hospital (France) from 1993 to 2015 were evaluated before surgery, at 1 year (short-term), and in the long term after surgery. All available demographic variables, neuroimaging data, and clinical characteristics were collected. Preoperative predictors of long-term motor outcome were investigated by performing survival and univariate/multivariate Cox regression analyses. Loss of motor benefit from stimulation in the long term was defined as a reduction of less than 25% in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III scores compared to the baseline off-medication scores. As a secondary objective, potential predictors of short-term motor outcome after STN-DBS were assessed by performing univariate and multivariate linear regression analyses. RESULTS: In the long-term analyses (mean follow-up = 8.4 ± 6.26 years, median = 10 years, range = 1-17 years), 138 patients were included. Preoperative higher frontal score and off-medication MDS-UPDRS part III scores predicted a better long-term motor response to stimulation, whereas the presence of vascular changes on neuroimaging predicted a worse motor outcome. In 357 patients with available 1-year follow-up, preoperative levodopa response, tremor dominant phenotype, baseline frontal score, and off-medication MDS-UPDRS part III scores predicted the short-term motor outcome. INTERPRETATION: Frontal lobe dysfunction, disease severity in the off-medication condition, and the presence of vascular changes on neuroimaging represent the main preoperative clinical predictors of long-term motor STN-DBS effects. ANN NEUROL 2021;89:587-597.

Indications, Techniques, and Outcomes of Robot-Assisted Insular Stereo-Electro-Encephalography: A Review.

Stereo-electro-encephalography (SEEG) is an invasive, surgical, and electrophysiological method for three-dimensional registration and mapping of seizure activity in drug-resistant epilepsy. It allows the accurate analysis of spatio-temporal seizure activity by multiple intraparenchymal depth electrodes. The technique requires rigorous non-invasive pre-SEEG evaluation (clinical, video-EEG, and neuroimaging investigations) in order to plan the insertion of the SEEG electrodes with minimal risk and maximal recording accuracy. The resulting recordings are used to precisely define the surgical limits of resection of the epileptogenic zone in relation to adjacent eloquent structures. Since the initial description of the technique by Talairach and Bancaud in the 1950's, several techniques of electrode insertion have been used with accuracy and relatively few complications. In the last decade, robot-assisted surgery has emerged as a safe, accurate, and time-saving electrode insertion technique due to its unparalleled potential for orthogonal and oblique insertion trajectories, guided by rigorous computer-assisted planning. SEEG exploration of the insular cortex remains difficult due to its anatomical location, hidden by the temporal and frontoparietal opercula. Furthermore, the close vicinity of Sylvian vessels makes surgical electrode insertion challenging. Some epilepsy surgery teams remain cautious about insular exploration due to the potential of neurovascular injury. However, several authors have published encouraging results regarding the technique's accuracy and safety in both children and adults. We will review the indications, techniques, and outcomes of insular SEEG exploration with emphasis on robot-assisted implantation.

Coherence between the hippocampus and anterior thalamic nucleus as a tool to improve the effect of neurostimulation in temporal lobe epilepsy: An experimental study.

BACKGROUND: Although the mechanisms by which deep brain stimulation (DBS) modifies the activity of the ictal network are mostly undefined, recent studies have suggested that DBS of the anterior nucleus of the thalamus (ANT) can be an effective treatment for mesial temporal lobe epilepsy (MTLE) when resective surgery cannot be performed. In a nonhuman primate (NHP) model of MTL seizures, we showed that the ANT was actively involved during interictal and ictal periods through different patterns and that the hippocampus (HPC) and ANT synchronously oscillate in the high beta-band during seizures. OBJECTIVE: Based on those findings, we evaluated whether the frequency of stimulation is an important parameter that interferes with seizures and how to adapt stimulation protocols to it. METHODS: We investigated the effects of low-frequency (40 Hz - determined as the ictal frequency of correlation between structures) and high-frequency (130 Hz - as commonly used in clinic) ANT stimulation in three monkeys in which MTLE seizures were initiated. RESULTS: Low-frequency stimulation had a strong effect on the number of seizures and the total time spent in seizure, whereas high-frequency stimulation had no effect. The coherence of oscillations between the HPC and the ANT was significantly correlated with the success of low-frequency stimulation: the greater the coherence was, the greater the antiepileptic effect of ANT-DBS. CONCLUSION: Our results suggest that low-frequency stimulation is efficient in treating seizures in a nonhuman primate model. More importantly, the study of the coherence between the ANT and HPC during seizures can help to predict the anti-epileptic effects of ANT stimulation. Furthermore, the DBS paradigm could be customized in frequency for each patient on the basis of the coherence spectral pattern.

Frameless ROSA® Robot-Assisted Lead Implantation for Deep Brain Stimulation: Technique and Accuracy.

BACKGROUND: Frameless robotic-assisted surgery is an innovative technique for deep brain stimulation (DBS) that has not been assessed in a large cohort of patients. OBJECTIVE: To evaluate accuracy of DBS lead placement using the ROSA® robot (Zimmer Biomet) and a frameless registration. METHODS: All patients undergoing DBS surgery in our institution between 2012 and 2016 were prospectively included in an open label single-center study. Accuracy was evaluated by measuring the radial error (RE) of the first stylet implanted on each side and the RE of the final lead position at the target level. RE was measured on intraoperative telemetric X-rays (group 1), on intraoperative O-Arm® (Medtronic) computed tomography (CT) scans (group 2), and on postoperative CT scans or magnetic resonance imaging (MRI) in both groups. RESULTS: Of 144 consecutive patients, 119 were eligible for final analysis (123 DBS; 186 stylets; 192 leads). In group 1 (76 patients), the mean RE of the stylet was 0.57 ± 0.02 mm, 0.72 ± 0.03 mm for DBS lead measured intraoperatively, and 0.88 ± 0.04 mm for DBS lead measured postoperatively on CT scans. In group 2 (43 patients), the mean RE of the stylet was 0.68 ± 0.05 mm, 0.75 ± 0.04 mm for DBS lead measured intraoperatively; 0.86 ± 0.05 mm and 1.10 ± 0.08 mm for lead measured postoperatively on CT scans and on MRI, respectively No statistical difference regarding the RE of the final lead position was found between the different intraoperative imaging modalities and postoperative CT scans in both groups. CONCLUSION: Frameless ROSA® robot-assisted technique for DBS reached submillimeter accuracy. Intraoperative CT scans appeared to be reliable and sufficient to evaluate the final lead position.

Epileptogenicity Maps of Intracerebral Fast Activities (60-100 Hz) at Seizure Onset in Epilepsy Surgery Candidates.

Fast activities (FA) at seizure onset have been increasingly described as a useful signature of the epileptogenic zone (EZ) in patients undergoing intracranial EEG recordings. Different computer-based signal analysis methods have thus been developed for objectively quantifying ictal FA. Whether these methods detect FA in all forms of focal epilepsies, whether they provide similar information than visual analysis (VA), and whether they might help for the surgical decision remain crucial issues. We thus conducted a retrospective study in 21 consecutive patients suffering from drug-resistant seizures studied by SEEG recordings. Ictal FA were quantified using the Epileptogenicity Maps (EM) method that we recently developed and which generates, by adopting a neuroimaging approach, statistical parametric maps of FA ranging from 60 to 100 Hz (FA60-100). Ictal FA were analyzed blindly using VA and EM, and the prognostic significance of removing areas exhibiting FA60-100 at seizure onset was evaluated. A significant ictal FA60-100 activation was found in all patients, and in 92.6% of all the 68 seizures recorded, whatever the epilepsy type. The overlap ratio (OR) between VA and EM was significantly better for defining the regions spared at seizure onset than those from which seizure arose (p < 0.001), especially in temporal or temporal "plus" epilepsies. EM and VA were much more discordant to define the EZ, with a mean number of electrode contacts involved at seizure onset significantly higher with EM than with VA (p = <0.0001). Seizure outcome correlated with the resection ratio for FA60-100, which was significantly higher in seizure-free (Engel's class Ia) than in non seizure-free patients (class Ic-IV) (p = 0.048). The quantification of FA at seizure onset can bring information additional to clinical expertise that might contribute to define accurately the cortical region to be resected.