One third of epilepsy patients do not achieve sufficient seizure freedom with current standard anti-seizure medications. Better understanding of the pathological mechanisms contributing to epileptogenesis is thus necessary to improve current therapies. SUR1-TRPM4 is a depolarizing ion channel minimally expressed in healthy brain that is upregulated de novo in neurons and glia after epileptogenic CNS injuries such as traumatic brain injury and stroke. However, its role in epilepsy is not well understood. Here, we demonstrate using immunofluorescent microscopy that SUR1-TRPM4 expression is elevated in neurons within electrographically sorted human epileptic brain compared to non-epileptic brain obtained after resection from six drug-resistant temporal lobe epilepsy patients. Additionally, we utilized immunofluorescence and co-immunoprecipitation to observe that SUR1-TRPM4 is upregulated within the hippocampus and temporal cortex in mice after PTZ kindling, a chronic model of rodent epilepsy. Pharmacologic inhibition of SUR1-TRPM4 using either the FDA-approved drug glyburide or 9-phenanthrol, as well as either constitutive or neuron-specific knock-out of this channel, attenuated chronic seizure development in this model. Exogenous overexpression of SUR1-TRPM4 by plasmid transfection in neurons in vitro increased neuronal hyperexcitability in response to low Mg2+ stimulation, while pharmacologic inhibition of endogenous TRPM4 attenuated neuronal population hyperexcitation. Collectively, our results reveal that elevated SUR1-TRPM4 expression found in human and rodent epileptic neurons promotes chronic seizures by increasing neuronal excitation. These findings directly support clinical investigation of SUR1-TRPM4 inhibitors as potential anti-seizure therapies in epilepsy patients and suggest further investigations into the contribution of SUR1-TRPM4 to seizures induced by specific epileptogenic insults, such as TBI, are warranted.

Pentylenetetrazol (PTZ) kindling is a widely used model for inducing epileptogenesis and evaluating long-term seizure susceptibility differences among animals. This model is typically performed by chronic, repetitive exposures to a constant subconvulsive PTZ dose. However, the effectiveness of the commonly used dose (35 mg/kg) varies among different animal groups due to factors such as species, age, sex, and genetic background. This study characterizes a novel kindling approach, the PTZ Dose Escalation (PTZ-DE) model, which assesses chronic seizure threshold with enhanced sensitivity by empirically determining the minimally effective dose to induce PTZ kindling for specific experimental conditions. The efficacy and validity of the PTZ-DE model were compared to the standard PTZ kindling approach. First, the characteristic increase in chronic seizure response was compared between PTZ-DE and the standard model across animal characteristics (strain, sex). Next, the PTZ-DE model’s validity was assessed by determining whether PTZ-DE could replicate the increased chronic seizure susceptibility previously reported using the standard approach after traumatic brain injury (TBI). Lastly, the PTZ-DE model’s effectiveness in detecting seizure differences was measured in a condition (glyburide treatment) where alterations to chronic seizure susceptibility were not detected with standard kindling. This study observed that, compared to the standard model, the PTZ-DE model corrects for background differences in PTZ susceptibility, replicates known alterations in chronic seizure thresholds, and uncovers changes in seizure threshold previously unidentified by the standard approach. The PTZ-DE model may be a superior approach for discovering new pathological mechanisms of epileptogenesis and for developing targeted therapies for seizure management.

OBJECTIVE:Continuous theta burst stimulation (cTBS), a form of repetitive transcranial magnetic stimulation (rTMS) known for its inhibitory effects, shows variable responses between individuals, potentially due to differences in neuroplasticity. This study explores whether motor evoked potential (MEP) input-output (IO) parameters measured prior to neuromodulation can predict responses to cTBS. METHODS:IO curves were sampled from healthy adults by recording MEPs over a range of single-pulse TMS intensities to obtain parameters including MEPmax and S50 (midpoint intensity). Subjects later received cTBS (80% AMT, low intensity) over the same location of motor cortex, and their MEPs before and after stimulation were compared. RESULTS:Both MEPmax and S50 predicted responses, significantly correlating (p < 0.05, R2 > 0.25) with individuals' MEP changes from 10 to 30 min after cTBS. We also validated an easily implementable biomarker not requiring time-consuming sampling of full IO curve: MEP130RMT (median of 10 MEPs at 130 % RMT), which strongly predicted cTBS response (p < 0.005, R2 > 0.3). Head-to-head comparison against a genetic biomarker of rTMS responses (BDNF polymorphism) showed that IO based predictors had superior performance in explaining response variability. CONCLUSION:IO curves derived prior to neuromodulation quickly, reliably predict cTBS-induced changes in cortical excitability. SIGNIFICANCE:This work provides an accessible strategy for stratifying responders in diagnostic and therapeutic applications of rTMS; potentially boosting response rates to brain stimulation.

Dysphagia at time of diagnosis suggests atypical parkinsonism instead Parkinson´s disease (PD). Our aim was to analyze the frequency of dysphagia in patients with early PD comparing with a control group and to identify related factors. Patients with early PD (≤ 2 years from symptoms onset) who were recruited from January/2016 to November/2017 (baseline visit; V0) and evaluated annually for 5 years from the Spanish cohort COPPADIS were included in this prospective study. Controls were assessed at baseline and at 2-, 4-, and 5-year follow-up. Dysphagia was defined as a score ≥ 1 in the item 20 of the Non-Motor Symptoms Scale (NMSS). Dysphagia was more frequent at baseline in PD patients (19.6

Level of Education (LoE) is widely used as an indicator of cognitive reserve and is associated with risk of dementia. The aim of the present study was to know the influence of the LoE on cognitive function (CF) in patients with Parkinson´s disease (PD). Controls and PD patients from the Spanish cohort COPPADIS with a disease duration from symptoms onset ≤ 5 years, who were recruited from January/2016 to November/2017 (baseline visit; V0) and evaluated at 2 (V2), 4 (V4) and 5 (V5) years of follow-up were included. Regarding LoE, patients were classified as with primary, secondary and university education. CF was assessed using the Parkinson´s Disease Cognitive Rating Scale (PD-CRS). General linear model (GLM) repeated measure was used to test for changes in the CF. A p value ≤ 0.005 was considered significant. Three hundred and ninety-nine PD patients (61.9 ± 8.9 years old; 58.4

Thirty percent of epilepsy patients have seizures despite best medical therapy. While epilepsy surgery has emerged as a promising treatment option for these patients, surgical outcomes vary considerably between patients and have not significantly improved over the years. These stagnant outcomes can be attributed to poor seizure onset zone and epileptic network localization with currently available tools. Lactate production is a well-known consequence of metabolic reprogramming and biomarker in epilepsy. Detection of lactate elevations using conventional magnetic resonance spectroscopy has been extensively studied as an effective tool to non-invasively detect epileptic brain tissue. However, this method suffers from poor spatial resolution, which limits its clinical utility in presurgical resection mapping. In this study, we explore the utility of a recently developed approach, magnetic resonance spectroscopy and spectroscopic imaging of hyperpolarized [1-13C]pyruvate, to identify epileptic tissues via detection of increased lactate production. We found that this approach accurately identifies elevated lactate production in an in vitro model of chronic hyperactivity and in the gold standard mouse epilepsy model, pentylenetetrazol kindling. These data suggest that magnetic resonance spectroscopic imaging of hyperpolarized [1-13C]pyruvate has the potential to effectively and non-invasively map epileptic foci and should be further explored as a clinical tool to guide epilepsy resection surgery by identifying epileptic tissue in patients.

The field of neuromodulation lacks predictors of individual differences in plasticity that influence responses to repetitive transcranial magnetic stimulation (rTMS). Continuous theta burst stimulation (cTBS), a form of rTMS known for its inhibitory effects, shows variable responses between individuals, potentially due to differences in neuroplasticity. Predicting individual cTBS effects could vastly enhance its clinical and experimental utility. This study explores whether motor evoked potential (MEP) input-output (IO) parameters measured prior to neuromodulation can predict motor cortex responses to cTBS. IO curves were sampled from healthy adults by recording MEPs over a range of single pulse TMS intensities to obtain parameters including MEP max and S 50 (midpoint intensity). Subjects later received cTBS over the same location of motor cortex and their MEPs before and after stimulation were compared. Both MEP max and S 50 predicted responses, significantly correlating (p<0.05, R 2 >0.25) with individuals' MEP changes at 10, 20, and 30 minutes after cTBS. Further, we introduced and validated an easily implementable biomarker that does not require the time-consuming sampling of full IO curve: MEP 130RMT (median of 10 MEPs at 130% RMT). MEP 130RMT was also a strong predictor of cTBS response (p<0.005, R 2 >0.3). Head-to-head comparison against a previously studied genetic biomarker of rTMS responses (BDNF polymorphism) showed that IO based predictors had a superior performance in explaining more response variability. Thus, IO curves derived prior to cTBS administration can reliably predict cTBS-induced changes in cortical excitability. This work points toward an accessible strategy for tailoring stimulation procedures in both diagnostic and therapeutic applications of rTMS, and potentially boosting response rate to other brain stimulation approaches. HIGHLIGHTS:Baseline TMS-MEP Input-Output (IO) Curve parameters significantly predict MEP responses to M1 cTBS. Higher MEP max at baseline predicts more robust inhibitory response to cTBS, while higher midpoint intensity (S 50 ) is associated with less response. D We developed and validated a new biomarker MEP 130RMT , which predicts cTBS response using just 10 baseline MEPs from single TMS pulses of 130% RMT intensity. Head to head comparison against BDNF genotyping shows superior performance of IO biomarkers.

Epilepsy is a common neurological disorder, affecting over 65 million people worldwide. Unfortunately, despite resective surgery, over 30% of patients with drug-resistant epilepsy continue to experience seizures. Retrospective studies considering connectivity using intracranial electrocorticography (ECoG) obtained during neuromonitoring have shown that treatment failure is likely driven by failure to consider critical components of the seizure network, an idea first formally introduced in 2002. However, current studies only capture snapshots in time, precluding the ability to consider seizure network development. Over the past few years, multiwell microelectrode arrays have been increasingly used to study neuronal networks in vitro. As such, we sought to develop a novel in vitro MEA seizure model to allow for study of seizure networks. Specifically, we used 4-aminopyridine (4-AP) to capture hyperexcitable activity, and then show increased network changes after 2 days of chronic treatment. We characterize network changes using functional connectivity measures and a novel technique using dimensionality reduction. We find that 4-AP successfully captures persistently elevated mean firing rate and significant changes in underlying connectivity patterns. We believe this affords a robust in vitro seizure model from which longitudinal network changes can be studied, laying groundwork for future studies exploring seizure network development.

ABSTRACTBackgroundLevodopa‐induced dyskinesias (LID) are frequent in Parkinson's disease (PD).ObjectiveTo analyze the change in the frequency of LID over time, identify LID related factors, and characterize how LID impact on patients’ quality of life (QoL).Patients and MethodsPD patients from the 5‐year follow‐up COPPADIS cohort were included. LID were defined as a non‐zero score in the item “Time spent with dyskinesia” of the Unified Parkinson's Disease Rating Scale—part IV (UPDRS‐IV). The UPDRS‐IV was applied at baseline (V0) and annually for 5 years. The 39‐item Parkinson's disease Questionnaire Summary Index (PQ‐39SI) was used to asses QoL.ResultsThe frequency of LID at V0 in 672 PD patients (62.4 ± 8.9 years old; 60.1% males) with a mean disease duration of 5.5 ± 4.3 years was 18.9% (127/672) and increased progressively to 42.6% (185/434) at 5‐year follow‐up (V5). The frequency of disabling LID, painful LID, and morning dystonia increased from 6.9%, 3.3%, and 10.6% at V0 to 17.3%, 5.5%, and 24% at V5, respectively. Significant independent factors associated with LID (P < 0.05) were a longer disease duration and time under levodopa treatment, a higher dose of levodopa, a lower weight and dose of dopamine agonist, pain severity and the presence of motor fluctuations. LID at V0 (β = 0.073; P = 0.027; R2 = 0.62) and to develop disabling LID at V5 (β = 0.088; P = 0.009; R2 = 0.73) were independently associated with a higher score on the PDQ‐39SI.ConclusionLID are frequent in PD patients. A higher dose of levodopa and lower weight were factors associated to LID. LID significantly impact QoL.

Background: Transcranial alternating current stimulation (tACS)-a noninvasive brain stimulation technique that modulates cortical oscillations in the brain-has shown the capacity to enhance working memory (WM) abilities in healthy individuals. The efficacy of tACS in the improvement of WM performance in healthy individuals is not yet fully understood.Objective/Hypothesis: This meta-analysis aimed to systematically evaluate the efficacy of tACS in the enhancement of WM in healthy individuals and to assess moderators of response to stimulation. We hypothesized that active tACS would significantly enhance WM compared with sham. We further hypothesized that it would do so in a task-dependent manner and that differing stimulation parameters would affect response to tACS.Materials and Methods: Ten tACS studies met the inclusion criteria and provided 32 effects in the overall analysis. Random -effect models assessed mean change scores on WM tasks from baseline to poststimulation. The included studies involved varied in stimulation parameters, between-subject and within-subject study designs, and online vs offline tACS.Results: We observed a significant, heterogeneous, and moderate effect size for active tACS in the enhancement of WM per-formance over sham (Cohen's d = 0.5). Cognitive load, task domain, session number, and stimulation region showed a significant relationship between active tACS and enhanced WM behavior over sham. Conclusions: Our findings indicate that active tACS enhances WM performance in healthy individuals compared with sham. Future randomized controlled trials are needed to further explore key parameters, including personalized stimulation vs stan-dardized electroencephalography frequencies and maintenance of tACS effects, and whether tACS-induced effects translate to populations with WM impairments.

Background: Although many studies have analyzed what factors contribute to caregiver burden in Parkinson's disease (PD), there is currently no knowledge about how the status of the caregiver could impact the patient. Objective: The aim of this study was to analyze how the change in the caregiver's status influences PD patients. Methods: PD patients and their caregivers who were recruited from January/2016 to November/2017 from 35 centers in Spain from the COPPADIS cohort were included in the study (V0). They were evaluated again at 2-year follow-up (V2). Caregivers completed the Zarit Caregiver Burden Inventory (ZCBI), Caregiver Strain Index (CSI), Beck Depression Inventory-II (BDI-II), and EUROHIS-QOL 8-item index (EUROHIS-QOL8) at V0 and V2. Multivariate models were used to analyze the impact of the change from V0 to V2 ( similar to) on the caregiver's status over the change in the patient's status. Results: similar to BDI-II and similar to EUROHIS-QOL8 in the caregiver predicted similar to BDI-II (similar to = 0.32; p < 0.0001; R2 = 0.71) and similar to EUROHIS-QOL8 (similar to = 0.39; p < 0.0001; R2 = 0.68) in the patient, respectively. Variables related to the caregiver were not associated with changes in the patient ' s health-related QoL ( similar to PDQ-39 [39-item Parkinson's disease Questionnaire]) or autonomy for activities of daily-living ( similar to ADLS [Schwab & England Activities of Daily Living Scale]). Conclusion: The change in the caregiver's mood and global QoL was associated with the change in the patient's mood and global QoL, respectively, independently of other variables of the disease influencing both patient ' s aspects. Based on this finding, it could be of great importance to detect depression in the principal caregiver of a patient and act on it as earlier as possible.

BACKGROUND AND OBJECTIVE:Sex plays a role in Parkinson's disease (PD) mechanisms. We analyzed sex difference manifestations among Spanish patients with PD.PATIENTS AND METHODS:PD patients who were recruited from the Spanish cohort COPPADIS from January 2016 to November 2017 were included. A cross-sectional and a two-year follow-up analysis were conducted. Univariate analyses and general linear model repeated measure were used.RESULTS:At baseline, data from 681 PD patients (mean age 62.54 ± 8.93) fit the criteria for analysis. Of them, 410 (60.2%) were males and 271 (39.8%) females. There were no differences between the groups in mean age (62.36 ± 8.73 vs. 62.8 ± 9.24; p = 0.297) or in the time from symptoms onset (5.66 ± 4.65 vs. 5.21 ± 4.11; p = 0.259). Symptoms such as depression (p < 0.0001), fatigue (p < 0.0001), and pain (p < 0.00001) were more frequent and/or severe in females, whereas other symptoms such as hypomimia (p < 0.0001), speech problems (p < 0.0001), rigidity (p < 0.0001), and hypersexuality (p < 0.0001) were more noted in males. Women received a lower levodopa equivalent daily dose (p = 0.002). Perception of quality of life was generally worse in females (PDQ-39, p = 0.002; EUROHIS-QOL8, p = 0.009). After the two-year follow-up, the NMS burden (Non-Motor Symptoms Scale total score) increased more significantly in males (p = 0.012) but the functional capacity (Schwab and England Activities of Daily Living Scale) was more impaired in females (p = 0.001).CONCLUSION:The present study demonstrates that there are important sex differences in PD. Long-term prospective comparative studies are needed.

BACKGROUND AND OBJECTIVE:Recently, we demonstrated that staging Parkinson's disease (PD) with a novel simple classification called MNCD, based on four axes (motor, non-motor, cognition, and dependency) and five stages, correlated with disease severity and patients' quality of life. Here, we analyzed the correlation of MNCD staging with PD caregiver's status.PATIENTS AND METHODS:Data from the baseline visit of PD patients and their principal caregiver recruited from 35 centers in Spain from the COPPADIS cohort from January 2016 to November 2017 were used to apply the MNCD total score (from 0 to 12) and MNCD stages (from 1 to 5) in this cross-sectional analysis. Caregivers completed the Zarit Caregiver Burden Inventory (ZCBI), Caregiver Strain Index (CSI), Beck Depression Inventory-II (BDI-II), PQ-10, and EUROHIS-QOL 8-item index (EUROHIS-QOL8).RESULTS:Two hundred and twenty-four PD patients (63 ± 9.6 years old; 61.2% males) and their caregivers (58.5 ± 12.1 years old; 67.9% females) were included. The frequency of MNCD stages was 1, 7.6%; 2, 58.9%; 3, 31.3%; and 4-5, 2.2%. A more advanced MNCD stage was associated with a higher score on the ZCBI (p < .0001) and CSI (p < .0001), and a lower score on the PQ-10 (p = .001), but no significant differences were observed in the BDI-II (p = .310) and EUROHIS-QOL8 (p = .133). Moderate correlations were observed between the MNCD total score and the ZCBI (r = .496; p < .0001), CSI (r = .433; p < .0001), and BDI-II (r = .306; p < .0001) in caregivers.CONCLUSION:Staging PD according to the MNCD classification is correlated with caregivers' strain and burden.

Patients with young-onset Parkinson’s disease (YOPD) have a slower progression. Our aim was to analyze the change in cognitive function in YOPD compared to patients with a later onset and controls. Patients with Parkinson’s disease (PD) and controls from the COPPADIS cohort were included. Cognitive function was assessed with the Parkinson’s Disease Cognitive Rating Scale (PD-CRS) at baseline (V0), 2-year ± 1 month (V2y), and 4-year ± 3 months follow-up (V4y). Regarding age from symptoms onset, patients were classified as YOPD (< 50 years) or non-YOPD (≥ 50). A score in the PD-CRS < 81 was defined as cognitive impairment (CI): ≤ 64 dementia; 65–80 mild cognitive impairment (MCI). One-hundred and twenty-four YOPD (50.7 ± 7.9 years; 66.1

Introduction:Drooling in Parkinson's disease (PD) is frequent but often goes underrecognized. Our aim was to examine the prevalence of drooling in a PD cohort and compare it with a control group. Specifically, we identified factors associated with drooling and conducted subanalyses in a subgroup of very early PD patients. Patients and Methods. PD patients who were recruited from January 2016 to November 2017 (baseline visit; V0) and evaluated again at a 2-year ± 30-day follow-up (V2) from 35 centers in Spain from the COPPADIS cohort were included in this longitudinal prospective study. Subjects were classified as with or without drooling according to item 19 of the NMSS (Nonmotor Symptoms Scale) at V0, V1 (1-year ± 15 days), and V2 for patients and at V0 and V2 for controls.Results:The frequency of drooling in PD patients was 40.1% (277/691) at V0 (2.4% (5/201) in controls; p < 0.0001), 43.7% (264/604) at V1, and 48.2% (242/502) at V2 (3.2% (4/124) in controls; p < 0.0001), with a period prevalence of 63.6% (306/481). Being older (OR = 1.032; p = 0.012), being male (OR = 2.333; p < 0.0001), having greater nonmotor symptom (NMS) burden at the baseline (NMSS total score at V0; OR = 1.020; p < 0.0001), and having a greater increase in the NMS burden from V0 to V2 (change in the NMSS total score from V0 to V2; OR = 1.012; p < 0.0001) were identified as independent predictors of drooling after the 2-year follow-up. Similar results were observed in the group of patients with ≤2 years since symptom onset, with a cumulative prevalence of 64.6% and a higher score on the UPDRS-III at V0 (OR = 1.121; p = 0.007) as a predictor of drooling at V2.Conclusion:Drooling is frequent in PD patients even at the initial onset of the disease and is associated with a greater motor severity and NMS burden.

Glioma-related epilepsy (GRE) is a hallmark clinical presentation of gliomas with significant impacts on patient quality of life. The current standard of care for seizure management is comprised of anti-seizure medications (ASMs) and surgical resection. Seizures in glioma patients are often drug-resistant and can often recur after surgery despite total tumor resection. Therefore, current research is focused on the pro-epileptic pathological changes occurring in tumor cells and the peritumoral environment. One important contribution to seizures in GRE patients is metabolic reprogramming in tumor and surrounding cells. This is most evident by the significantly heightened seizure rate in patients with isocitrate dehydrogenase mutated (IDHmut) tumors compared to patients with IDH wildtype (IDHwt) gliomas. To gain further insight into glioma metabolism in epileptogenesis, this review compares the metabolic changes inherent to IDHmut vs. IDHwt tumors and describes the pro-epileptic effects these changes have on both the tumor cells and the peritumoral environment. Understanding alterations in glioma metabolism can help to uncover novel therapeutic interventions for seizure management in GRE patients.

BACKGROUND AND OBJECTIVE:A good response to levodopa is a key factor to indicate device-aided therapies in people with Parkinson's disease (PwPD). The aim of the present study was to analyze the response to levodopa in PwPD with motor fluctuations followed for 4 years. PATIENTS AND METHODS:PwPD with motor fluctuations recruited from January 2016 to November 2017 from the COPPADIS cohort and assessed annually (from baseline to 4-year follow-up) during the OFF and ON states were included in this analysis. At each visit, the Unified Parkinson's Disease Rating Scale - part III (UPDRS-III) was applied during the OFF state (without medication during the last 12 h) and during the ON state. General linear model repeated measures were used to test for changes in the mean UPDRS-III-OFF, UPDRS-III-ON, and ΔUPDRS-III (UPDRS-III-OFF - UPDRS-III-ON) between visits. Levodopa equivalent daily dose (LEDD) was included as covariate. RESULTS:Sixty-three patients (63.94 ± 8.42 years old; 68.3% males) were included. Mean disease duration was 7.81 ± 3.64 years. From baseline to 4-year follow-up visit, a significant increase in both the UPDRS-III-OFF (from 27.98 ± 9.58 to 31.75 ± 12.39; p = 0.003) and the UPDRS-III-ON (from 15.92 ± 7.93 to 18.84 ± 8.17; p = 0.006) was observed despite the significant increase in the LEDD (from 896.35 ± 355.65 to 1085.51 ± 488.29; p = 0.003). However, no significant differences were detected between visits in the ΔUPDRS-III. CONCLUSION:In this cohort of PwPD with motor fluctuations, the response to levodopa did not weaken after a 4-year follow-up.

BACKGROUND:Detection of suicidal ideation (SI) is key for trying to prevent suicide. The aim of this study was to analyze the frequency of SI and related factors in Spanish people with Parkinson's Disease (PwPD) and to compare them with a control group.METHODS:PD patients and controls recruited from the Spanish cohort COPPADIS from January 2016 to November 2017 were included. Two visits were conducted: V0 (baseline); V2 (2-year ± 1 month follow-up). SI was defined as a score ≥1 on item nine of the Beck Depression Inventory-II (BDI-II). Regression analyses were conducted to identify factors related to SI.RESULTS:At baseline, 693 PwPD (60.2% males; 62.59 ± 8.91 years old) and 207 controls (49.8% males; 60.99 ± 8.32 years old) were included. No differences between PwPD and controls were detected in SI frequency at either V0 (5.1% [35/693] vs. 4.3% [9/207]; p = 0.421) or at V2 (5.1% [26/508] vs. 4.8% [6/125]; p = 0.549). Major depression (MD) and a worse quality of life were associated with SI at both visits in PwPD: V0 (MD, OR = 5.63; p = 0.003; PDQ-39, OR = 1.06; p = 0.021); V2 (MD, OR = 4.75; p = 0.027; EUROHIS-QOL8, OR = 0.22; p = 0.006). A greater increase in the BDI-II total score from V0 to V2 was the only factor predicting SI at V2 (OR = 1.21; p = 0.002) along with an increase in the total number of non-antiparkinsonian drugs (OR = 1.39; p = 0.041).CONCLUSION:The frequency of SI (5%) in PwPD was similar to in controls. Depression, a worse quality of life, and a greater comorbidity were related to SI.

Electrocorticography (ECoG) data are commonly obtained during drug-resistant epilepsy (DRE) workup, in which subdural grids and stereotaxic depth electrodes are placed on the cortex for weeks at a time, with the goal of elucidating seizure origination. ECoG data can also be recorded from neuromodulatory devices, such as responsive neurostimulation (RNS), which involves the placement of electrodes deep in the brain. Of the neuromodulatory devices, RNS is the first to use recorded ECoG data to direct the delivery of electrical stimulation in order to control seizures. In this review, we first introduced the clinical management for epilepsy, and discussed the steps from seizure onset to surgical intervention. We then reviewed studies discussing the emergence and therapeutic mechanism behind RNS, and discussed why RNS may be underperforming despite an improved seizure detection mechanism. We discussed the potential utility of incorporating machine learning techniques to improve seizure detection in RNS, and the necessity to change RNS targets for stimulation, in order to account for the network theory of epilepsy. We concluded by commenting on the current and future status of neuromodulation in managing epilepsy, and the role of predictive algorithms to improve outcomes.

BACKGROUND AND OBJECTIVE:Caregiver burden in Parkinson's disease (PD) has been studied in many cross-sectional studies but poorly in longitudinal ones. The aim of the present study was to analyze the change in burden, strain, mood, and quality of life (QoL) after a 2-year follow-up in a cohort of caregivers of patients with PD and also to identify predictors of these changes. PATIENTS AND METHODS:PD patients and their caregivers who were recruited from January/2016 to November/2017 from 35 centers of Spain from the COPPADIS cohort were included in the study. They were evaluated again at 2-year follow-up. Caregivers completed the Zarit Caregiver Burden Inventory (ZCBI), Caregiver Strain Index (CSI), Beck Depression Inventory-II (BDI-II), and EUROHIS-QOL 8-item index (EUROHIS-QOL8) at baseline (V0) and at 2-year follow-up (V2). General linear model repeated measure and lineal regression models were applied. RESULTS:Significant changes, indicating an impairment, were detected on the total score of the ZCBI (p < 0.0001), CSI (p < 0.0001), BDI-II (p = 0.024), and EUROHIS-QOL8 (p = 0.002) in 192 PD caregivers (58.82 ± 11.71 years old; 69.3% were females). Mood impairment (BDI-II; β = 0.652; p < 0.0001) in patients from V0 to V2 was the strongest factor associated with caregiver's mood impairment after the 2-year follow-up. Caregiver's mood impairment was the strongest factor associated with an increase from V0 to V2 on the total score of the ZCBI (β = 0.416; p < 0.0001), CSI (β = 0.277; p = 0.001), and EUROHIS-QOL (β = 0.397; p = 0.002). CONCLUSION:Burden, strain, mood, and QoL were impaired in caregivers of PD patients after a 2-year follow-up. Mood changes in both the patient and the caregiver are key aspects related to caregiver burden increase.