Identification of Parkinson's Disease Subtypes from Resting-State Electroencephalography.

BACKGROUND: Parkinson's disease (PD) patients present with a heterogeneous clinical phenotype, including motor, cognitive, sleep, and affective disruptions. However, this heterogeneity is often either ignored or assessed using only clinical assessments. OBJECTIVES: We aimed to identify different PD sub-phenotypes in a longitudinal follow-up analysis and their electrophysiological profile based on resting-state electroencephalography (RS-EEG) and to assess their clinical significance over the course of the disease. METHODS: Using electrophysiological features obtained from RS-EEG recordings and data-driven methods (similarity network fusion and source-space spectral analysis), we have performed a clustering analysis to identify disease sub-phenotypes and we examined whether their different patterns of disruption are predictive of disease outcome. RESULTS: We showed that PD patients (n = 44) can be sub-grouped into three phenotypes with distinct electrophysiological profiles. These clusters are characterized by different levels of disruptions in the somatomotor network (Δ and ß band), the frontotemporal network (α2 band) and the default mode network (α1 band), which consistently correlate with clinical profiles and disease courses. These clusters are classified into either moderate (only-motor) or mild-to-severe (diffuse) disease. We showed that EEG features can predict cognitive evolution of PD patients from baseline, when the cognitive clinical scores were overlapped. CONCLUSIONS: The identification of novel PD subtypes based on electrical brain activity signatures may provide a more accurate prognosis in individual patients in clinical practice and help to stratify subgroups in clinical trials. Innovative profiling in PD can also support new therapeutic strategies that are brain-based and designed to modulate brain activity disruption. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Encephalitis with Autoantibodies against the Glutamate Kainate Receptors GluK2.

OBJECTIVE: The objective of this study was to report the identification of antibodies against the glutamate kainate receptor subunit 2 (GluK2-abs) in patients with autoimmune encephalitis, and describe the clinical-immunological features and antibody effects. METHODS: Two sera from 8 patients with similar rat brain immunostaining were used to precipitate the antigen from neuronal cultures. A cell-based assay (CBA) with GluK2-expressing HEK293 cells was used to assess 596 patients with different neurological disorders, and 23 healthy controls. GluK2-ab effects were determined by confocal microscopy in cultured neurons and electrophysiology in GluK2-expressing HEK293 cells. RESULTS: Patients' antibodies precipitated GluK2. GluK2 antibody-specificity was confirmed by CBA, immunoprecipitation, GluK2-immunoabsorption, and GluK2 knockout brain immunohistochemistry. In 2 of 8 samples, antibodies reacted with additional GluK2 epitopes present in GluK1 or GluK3; in both, the reactivity was abrogated after GluK2 immuno-absorption. Six of 8 patients developed acute encephalitis and clinical or magnetic resonance imaging (MRI) features of predominant cerebellar involvement (4 presenting as cerebellitis, which in 2 patients caused obstructive hydrocephalus), and 2 patients had other syndromes (1 with cerebellar symptoms). One of the samples showed mild reactivity with non-kainate receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors [AMPAR] and N-methyl-D-aspartate receptors [NMDAR]) leading to identify 6 additional cases with GluK2-abs among patients with anti-AMPAR (5/71) or anti-NMDAR encephalitis (1/73). GluK2-abs internalized GluK2 in HEK293 cells and neurons; these antibody-effects were reversible in neurons. A significant reduction of GluK2-mediated currents was observed in cells treated with patients' GluK2 serum following the time frame of antibody-mediated GluK2 internalization. INTERPRETATION: GluK2-abs associate with an encephalitis with prominent clinicoradiological cerebellar involvement. The antibody effects are predominantly mediated by internalization of GluK2. ANN NEUROL 2021;90:107-123.

Functional Brain Dysconnectivity in Parkinson's Disease: A 5-Year Longitudinal Study.

BACKGROUND: Tracking longitudinal functional brain dysconnectivity in Parkinson's disease (PD) is a key element to decoding the underlying physiopathology and understanding PD progression. OBJECTIVES: The objectives of this follow-up study were to explore, for the first time, the longitudinal changes in the functional brain networks of PD patients over 5 years and to associate them with their cognitive performance and the lateralization of motor symptoms. METHODS: We used a 5-year longitudinal cohort of PD patients (n = 35) who completed motor and non-motor assessments and sequent resting state (RS) high-density electroencephalography (HD-EEG) recordings at three timepoints: baseline (BL), 3 years follow-up (3YFU) and 5 years follow-up (5YFU). We assessed disruptions in frequency-dependent functional networks over the course of the disease and explored their relation to clinical symptomatology. RESULTS: In contrast with HC (n = 32), PD patients showed a gradual connectivity impairment in α2 (10-13 Hz) and ß (13-30 Hz) frequency bands. The deterioration in the global cognitive assessment was strongly correlated with the disconnected networks. These disconnected networks were also associated with the lateralization of motor symptoms, revealing a dominance of the right hemisphere in terms of impaired connections in the left-affected PD patients in contrast to dominance of the left hemisphere in the right-affected PD patients. CONCLUSIONS: Taken together, our findings suggest that with disease progression, dysconnectivity in the brain networks in PD can reflect the deterioration of global cognitive deficits and the lateralization of motor symptoms. RS HD-EEG may be an early biomarker of PD motor and non-motor progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Free-breathing magnetic resonance imaging with radial k-space sampling for neonates and infants to reduce anesthesia.

BACKGROUND: Conventional chest and abdominal MRI require breath-holds to reduce motion artifacts. Neonates and infants require general anesthesia with intubation to enable breath-held acquisitions. OBJECTIVE: We aimed to validate a free-breathing approach to reduce general anesthesia using a motion-insensitive radial acquisition with respiratory gating. MATERIALS AND METHODS: We retrospectively enrolled children <3 years old who were referred for MRI of the chest or abdomen. They were divided into two groups according to MRI protocol: (1) breath-held scans under general anesthesia with T2-weighted single-shot fast spin-echo (SSFSE) and contrast-enhanced T1-weighted modified Dixon, and (2) free-breathing scans using radial sequences (T2-W MultiVane XD and contrast-enhanced T1-W three-dimensional [3-D] Vane XD). Two readers graded image quality and motion artifacts. RESULTS: We included 23 studies in the free-breathing cohort and 22 in the breath-hold cohort. The overall imaging scores for the free-breathing radial T2-W sequence were similar to the scores for the breath-held T2-W SSFSE sequence (chest, 3.6 vs. 3.2, P=0.07; abdomen, 3.9 vs. 3.7, P=0.66). The free-breathing 3-D radial T1-W sequence also had image quality scores that were similar to the breath-held T1-W sequence (chest, 4.0 vs. 3.0, P=0.06; abdomen, 3.7 vs. 3.9, P=0.15). Increased motion was seen in the abdomen on the radial T2-W sequence (P<0.001), but increased motion was not different in the chest (P=0.73) or in contrast-enhanced T1-W sequences (chest, P=0.39; abdomen, P=0.15). The mean total sequence time was longer in free-breathing compared to breath-held exams (P<0.01); however, this did not translate to longer overall exam times (P=0.94). CONCLUSION: Motion-insensitive radial sequences used for infants and neonates were of similar image quality to breath-held sequences and had decreased sedation and intubation.

Does Quantitative Electroencephalography Refine Preoperative Cognitive Assessment in Parkinson's Disease Patients Treated with Deep Brain Stimulation? A Follow-Up Study.

OBJECTIVE: Deep brain stimulation (DBS) in Parkinson's disease (PD) is associated with an increased risk of post-operative cognitive deterioration. Preoperative neuropsychological testing can be affected and limited by the patient's collaboration in advanced disease. The purpose of this study was to determine whether preoperative quantitative electroencephalography (qEEG) may be a useful complementary examination technique during preoperative assessment to predict cognitive changes in PD patients treated with DBS. METHODS: We compared the cognitive performance of 16 PD patients who underwent bilateral subthalamic nucleus DBS to the performance of 15 PD controls (matched for age, sex, and education) at baseline and at 24 months. Cognitive scores were calculated for all patients across 5 domains. A preoperative 256-channel resting EEG was recorded from each patient. We computed the global relative power spectra. Correlation and linear regression models were used to assess associations of preoperative EEG measures with post-operative cognitive scores. RESULTS: Slow waves (relative delta and theta band power) were negatively correlated with post-operative cognitive performance, while faster waves (alpha 1) were strongly positively correlated with the same scores (the overall cognitive score, attention, and executive function). Linear models revealed an association of delta power with the overall cognitive score (p = 0.00409, adjusted R2 = 0.6341). Verbal fluency (VF) showed a significant decline after DBS surgery, which was correlated with qEEG measures. CONCLUSIONS: To analyse the side effects after DBS in PD patients, the most important parameter is verbal fluency capacity. In addition, correlation with EEG frequency bands might be useful to detect particularly vulnerable patients for cognitive impairment and be supportive in the selection process of patients considered for DBS.

Effects of Rhythmic Interventions on Cognitive Abilities in Parkinson's Disease.

OBJECTIVE: The objective of this study is to compare 2 different rhythmic, high-intensive interventions, that is, rhythmic speech-language therapy (rSLT) versus rhythmic balance-mobility training (rBMT), against a no-therapy (NT) condition in patients with Parkinson's disease and against healthy controls (HCs) with regard to the change in or enhancement of cognitive abilities. METHODS: The 4 groups (rSLT: N = 16; rBMT: N = 10; NT: N = 18; and HC: N = 17) were matched for age, sex, and educational level and were tested in 6 cognitive domains: working memory, executive function, visuo-construction, episodic memory, attention, and word retrieval. Assessments took place at baseline, at 4 weeks (T1), and at 6 months (T2). Rhythmic interventions were provided 3 times per week for 4 weeks in total. To analyze true intervention effects between groups and across time, statistical analyses included reliable change index. Intergroup differences were assessed with multivariate assessment of variance, while differences within groups were assessed with 95% confidence intervals of mean difference. RESULTS: The rSLT improved working memory and word retrieval (p < 0.05), possibly a beneficial transfer effect of the training method per se. In contrast, the NT group worsened in phonemic and semantic shifting (p < 0.01). Observed improvements in flexibility and in episodic memory in the HC may be linked to training effects of retesting. CONCLUSIONS: Rhythmic cues are resistant to neurodegeneration and have a strong motivating factor. As thus, these may facilitate high-intensive and demanding training. Although both trainings were superior to NT, the improvement of cognitive abilities depends on the specific training method. Further, therapy may be more effective when delivered by a therapist rather than by an impersonal computer program.

A Comparison of Serial Position Effects in Patients with Mild Cognitive Impairment due to Parkinson's Disease or to Alzheimer's Disease.

OBJECTIVE: The first (primacy region) and last (recency region) items of a word list are generally better memorized than items from the middle region. The recency effect depends on short-term memory (STM) and the primacy effect on long-term memory (LTM), where verbal information is transferred from STM into LTM by maintenance rehearsal. We compared the serial position effects (SPE) between patients with mild cognitive impairment (MCI) due to Parkinson's disease (PD), i.e., PD-MCI, and patients with MCI due to Alzheimer's disease (AD-MCI), and evaluated the influence of SPE and frontostriatal deficits on verbal memory recall. METHODS: Four similar groups of subjects participated in the study: 26 PD-MCI patients, 26 cognitively normal patients with PD (PD-CN), 26 AD-MCI patients, and 26 normal controls (NC). Verbal episodic memory, verbal span, attentional capacity, executive functions, and verbal working memory performance were assessed. Measures for primacy and recency regions were defined at the first trial of a 16-items word list. Hierarchical regression models were used to investigate the contribution of frontostriatal deficits beyond SPE on verbal memory recall performance ("long-delay free recall") in PD and AD patients. RESULTS: Primacy effects were significantly diminished in both PD-MCI and AD-MCI patients relative to NC and PD-CN (all p < 0.01). Compared to PD-MCI patients, AD-MCI patients exhibited significantly worse "delayed-recall 'savings'." Reduced primacy effect was predictive for decreased recall performance in PD and AD. The conducted hierarchical regression model revealed that in PD, but not in AD patients, performance of attention and executive function significantly increased the prediction of free recalled words. CONCLUSIONS: Reduced recall performance is likely due to impaired transition of newly learned material from STM into LTM in AD and in PD. Whereas AD-MCI patients suffer from a storage deficit, the similarly reduced recall performance found in patients with PD-MCI may additionally be related to deficient attentional and executive capacity.

Parkinson disease and the risk of epileptic seizures.

OBJECTIVE: To assess the association between incident Parkinson disease (PD) and subsequent incident epileptic seizures. METHODS: We conducted a retrospective cohort study with a nested case-control analysis using data from the U.K. Clinical Practice Research Datalink. We identified patients aged ≥40 years with an incident diagnosis of PD between 1995 and 2016 and a matched comparison group of PD-free individuals. We calculated crude incidence rates (IRs) with 95% confidence intervals (CIs) of epileptic seizures in PD patients and the PD-free comparison group, and corresponding crude incidence rate ratios (IRRs). In the nested case-control analysis, we calculated adjusted odds ratios (adj. ORs) of incident PD among cases with incident epileptic seizures and seizure-free controls overall and stratified by various seizure-provoking comorbidities. RESULTS: Among 23,086 incident PD patients and 92,343 PD-free individuals, we identified 898 patients with incident epileptic seizures. The crude IR of epileptic seizures in PD patients was 266.7/100,000 person-years (95% CI = 235.6-297.7), and in PD-free individuals it was 112.4/100,000 person-years (95% CI = 103.5-121.3; IRR = 2.37, 95% CI = 2.06-2.73). The adj. OR of epileptic seizures was 1.68 (95% CI = 1.43-1.98) in PD patients compared with PD-free individuals. PD patients with comorbid brain disorders (adj. OR = 12.36, 95% CI = 8.74-17.48) or with > 1 seizure-provoking comorbidity (adj. OR = 13.24, 95% CI = 10.15-17.25) were at the highest risk of epileptic seizures compared with PD-free individuals with no seizure-provoking comorbidities. INTERPRETATION: This study suggests that incident PD is associated with an increased risk of incident epileptic seizures. Ann Neurol 2018;83:363-374.

A retrospective cohort study of children with spinal muscular atrophy type 2 receiving anesthesia for intrathecal administration of nusinersen.

INTRODUCTION: Spinal muscular atrophy is characterized by loss of motor neurons in the anterior horn of the spinal cord with resultant proximal muscle weakness. Intrathecal nusinersen has revolutionized the treatment of spinal muscular atrophy. We reviewed the perioperative care of 61 anesthetics performed on eight patients with spinal muscular atrophy type 2 who received nusinersen over 30 months in conjunction with nusinersen's phase 3 clinical trials. METHODS: Anesthesia was induced in all patients with sevoflurane, nitrous oxide, and oxygen (30%) via facemask. A peripheral intravenous line was placed after the loss of consciousness in all but three procedures. General anesthesia was maintained in 58 anesthetics with a propofol infusion at 250-300 µg/kg/min, while the remainder was maintained with inhalational anesthetics. The airway was managed via facemask or nasal cannula in all but two procedures, in whom a laryngeal mask airway was placed. We analyzed patient demographics, duration of anesthesia and of postanesthesia care unit stay, discharge destination, preprocedure oxygen saturation (SaO2 ), postanesthesia care unit discharge oxygen saturation, and occurrence of unanticipated admission or postdischarge hospitalization. RESULTS: Eight American Society of Anesthesiologists physical status three patients (3 male: 5 female) with a median age of 4.1 (2.1-7.8) years and median weight of 13.2 (10-24.7) kg, underwent 61 anesthetics for nusinersen administration or sham procedure. There were no intraoperative anesthetic complications of unanticipated cardiovascular instability, major neurologic events, respiratory failure, or death. Anesthesiologists performed 83% of the procedures. CONCLUSION: Nusinersen has revolutionized the care of patients with spinal muscular atrophy type 2 and anesthesiologists will be involved in its administration. We found that routine anesthetic care was safe and effective.

Clinical evoked potentials in neurology: a review of techniques and indications.

Evoked potentials (EPs) are a powerful and cost-effective tool for evaluating the integrity and function of the central nervous system. Although imaging techniques, such as MRI, have recently become increasingly important in the diagnosis of neurological diseases, over the past 30 years, many neurologists have continued to employ EPs in specific clinical applications. This review presents an overview of the recent evolution of 'classical' clinical applications of EPs in terms of early diagnosis and disease monitoring and is an extension of a previous review published in this journal in 2005 by Walsh and collaborators. We also provide an update on emerging EPs based on gustatory, olfactory and pain stimulation that may be used as clinically relevant markers of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and cortical or peripheral impaired pain perception. EPs based on multichannel electroencephalography recordings, known as high-density EPs, help to better differentiate between healthy subjects and patients and, moreover, they provide valuable spatial information regarding the site of the lesion. EPs are reliable disease-progression biomarkers of several neurological diseases, such as multiple sclerosis and other demyelinating disorders. Overall, EPs are excellent neurophysiological tools that will expand standard clinical practice in modern neurology.

A new role for evoked potentials in MS? Repurposing evoked potentials as biomarkers for clinical trials in MS.

Evoked potentials (EP) characterize signal conduction in selected tracts of the central nervous system in a quantifiable way. Since alteration of signal conduction is the main mechanism of symptoms and signs in multiple sclerosis (MS), multimodal EP may serve as a representative measure of the functional impairment in MS. Moreover, EP have been shown to be predictive for disease course, and thus might help to select patient groups at high risk of progression for clinical trials. EP can detect deterioration, as well as improvement of impulse propagation, independently from the mechanism causing the change. Therefore, they are candidates for biomarkers with application in clinical phase-II trials. Applicability of EP in multicenter trials has been limited by different standards of registration and assessment.

Fine Motor Function Skills in Patients with Parkinson Disease with and without Mild Cognitive Impairment.

AIMS: The objective of this study was to investigate the relation between impaired fine motor skills in Parkinson disease (PD) patients and their cognitive status, and to determine whether fine motor skills are more impaired in PD patients with mild cognitive impairment (MCI) than in non-MCI patients. METHODS: Twenty PD MCI and 31 PD non-MCI patients (mean age 66.7 years, range 50-84, 36 males/15 females), all right-handed, took part in a motor performance test battery. Steadiness, precision, dexterity, velocity of arm-hand movements, and velocity of wrist-finger movements were measured and compared across groups and analyzed for confounders (age, sex, education, severity of motor symptoms, and disease duration). Statistical analysis included t tests corrected for multiple testing, and a linear regression with stepwise elimination procedure was used to select significant predictors for fine motor function. RESULTS: PD MCI patients performed significantly worse in precision (p < 0.05), dexterity (p < 0.05), and velocity (arm-hand movements; p < 0.05) compared to PD non-MCI patients. The fine motor function skills were confounded by age. CONCLUSIONS: Fine motor skills in PD MCI patients are impaired compared to PD non-MCI patients. Investigating the relation between the fine motor performance and MCI in PD might be a relevant subject for future research.

Correlation of EEG slowing with cognitive domains in nondemented patients with Parkinson's disease.

BACKGROUND: Cognitive deficits in Parkinson's disease (PD) are heterogeneous and can be classified into cognitive domains. Quantitative EEG is related to and predictive of cognitive status in PD. In this cross-sectional study, the relationship of cognitive domains and EEG slowing in PD patients without dementia is investigated. METHODS: A total of 48 patients with idiopathic PD were neuropsychologically tested. Cognitive domain scores were calculated combining Z-scores of test variables. Slowing of EEG was measured with median EEG frequency. Linear regression was used for correlational analyses and to control for confounding factors. RESULTS: EEG median frequency was significantly correlated to cognitive performance in most domains (episodic long-term memory, rho = 0.54; overall cognitive score, rho = 0.47; fluency, rho = 0.39; attention, rho = 0.37; executive function, rho = 0.34), but not to visuospatial functions and working memory. CONCLUSION: Global EEG slowing is a marker for overall cognitive impairment in PD and correlates with impairment in the domains attention, executive function, verbal fluency, and episodic long-term memory, but not with working memory and visuospatial functions. These disparate effects warrant further investigations.

Directional deep brain stimulation: an intraoperative double-blind pilot study.

Deep brain stimulation of different targets has been shown to drastically improve symptoms of a variety of neurological conditions. However, the occurrence of disabling side effects may limit the ability to deliver adequate amounts of current necessary to reach the maximal benefit. Computed models have suggested that reduction in electrode size and the ability to provide directional stimulation could increase the efficacy of such therapies. This has never been demonstrated in humans. In the present study, we assess the effect of directional stimulation compared to omnidirectional stimulation. Three different directions of stimulation as well as omnidirectional stimulation were tested intraoperatively in the subthalamic nucleus of 11 patients with Parkinson's disease and in the nucleus ventralis intermedius of two other subjects with essential tremor. At the trajectory chosen for implantation of the definitive electrode, we assessed the current threshold window between positive and side effects, defined as the therapeutic window. A computed finite element model was used to compare the volume of tissue activated when one directional electrode was stimulated, or in case of omnidirectional stimulation. All but one patient showed a benefit of directional stimulation compared to omnidirectional. A best direction of stimulation was observed in all the patients. The therapeutic window in the best direction was wider than the second best direction (P = 0.003) and wider than the third best direction (P = 0.002). Compared to omnidirectional direction, the therapeutic window in the best direction was 41.3% wider (P = 0.037). The current threshold producing meaningful therapeutic effect in the best direction was 0.67 mA (0.3-1.0 mA) and was 43% lower than in omnidirectional stimulation (P = 0.002). No complication as a result of insertion of the directional electrode or during testing was encountered. The computed model revealed a volume of tissue activated of 10.5 mm(3) in omnidirectional mode, compared with 4.2 mm(3) when only one electrode was used. Directional deep brain stimulation with a reduced electrode size applied intraoperatively in the subthalamic nucleus as well as in the nucleus ventralis intermedius of the thalamus significantly widened the therapeutic window and lowered the current needed for beneficial effects, compared to omnidirectional stimulation. The observed side effects related to direction of stimulation were consistent with the anatomical location of surrounding structures. This new approach opens the door to an improved deep brain stimulation therapy. Chronic implantation is further needed to confirm these findings.

Combined visual and motor evoked potentials predict multiple sclerosis disability after 20 years.

BACKGROUND: The development of predictors of multiple sclerosis (MS) disability is difficult due to the complex interplay of pathophysiological and adaptive processes. OBJECTIVE: The purpose of this study was to investigate whether combined evoked potential (EP)-measures allow prediction of MS disability after 20 years. METHODS: We examined 28 patients with clinically definite MS according to Poser's criteria with Expanded Disability Status Scale (EDSS) scores, combined visual and motor EPs at entry (T0), 6 (T1), 12 (T2) and 24 (T3) months, and a cranial magnetic resonance imaging (MRI) scan at T0 and T2. EDSS testing was repeated at year 14 (T4) and year 20 (T5). Spearman rank correlation was used. We performed a multivariable regression analysis to examine predictive relationships of the sum of z-transformed EP latencies (s-EPT0) and other baseline variables with EDSST5. RESULTS: We found that s-EPT0 correlated with EDSST5 (rho=0.72, p<0.0001) and ΔEDSST5-T0 (rho=0.50, p=0.006). Backward selection resulted in the prediction model: E (EDSST5)=3.91-2.22×therapy+0.079×age+0.057×s-EPT0 (Model 1, R (2)=0.58) with therapy as binary variable (1=any disease-modifying therapy between T3 and T5, 0=no therapy). Neither EDSST0 nor T2-lesion or gadolinium (Gd)-enhancing lesion quantities at T0 improved prediction of EDSST5. The area under the receiver operating characteristic (ROC) curve was 0.89 for model 1. CONCLUSIONS: These results further support a role for combined EP-measures as predictors of long-term disability in MS.

Electrophysiological markers and predictors of the disease course in primary progressive multiple sclerosis.

BACKGROUND: Currently no valid surrogate marker exists for primary progressive multiple sclerosis (PPMS). OBJECTIVE: Our aim was to prospectively investigate multimodal evoked potentials (EPs) as markers and predictors of the disease course in PPMS. METHODS: Twenty-two PPMS patients were prospectively examined with visual, somatosensory and motor EPs and Expanded Disability Status Scale (EDSS) assessments at baseline (T0) and at six-month intervals over three years. Spearman rank correlation was used to determine the relationship between EP measures and EDSS. The relationship between disease evolution and a numerical score derived from z-transformed EP-latencies (s-EP-Q) and baseline characteristics was further assessed using multivariable linear regression analysis. RESULTS: s-EP-Q correlated with EDSS score at all points in time in cross-sectional comparison (0.53≤rs ≤0.68; 0.0007≤p≤0.0232) and also longitudinally by trend (rs=0.46, p=0.0740). The s-EP-QT0 correlated with the EDSS score at year 3 (T6) (r s=0.77, p<0.0001). The s-EP-Q changes became statistically significant six months before corresponding changes were seen in the EDSS score. EDSST6 as predicted by EDSST6 = -1.027+0.037* age+0.217* s-EP-QT0 + 0.695* EDSST0 correlated with the observed values (rs=0.92, p<0.0001). CONCLUSIONS: Multimodal EPs correlate well with disability in PPMS, and allow some prediction of the disease course over three years. These findings support a role of EPs as surrogate markers in clinical trials in PPMS.

Improved characterization of visual evoked potentials in multiple sclerosis by topographic analysis.

In multiple sclerosis (MS), the combination of visual, somatosensory and motor evoked potentials (EP) has been shown to be highly correlated with the Expanded Disability Severity Scale (EDSS) and to predict the disease course. In the present study, we explored whether the significance of the visual EP (VEP) can be improved with multichannel recordings (204 electrodes) and topographic analysis (tVEP). VEPs were analyzed in 83 MS patients (median EDSS 2.0; 52 % with history of optic neuritis; hON) and 47 healthy controls (HC). TVEP components were automatically defined on the basis of spatial similarity between the scalp potential fields (topographic maps) of single subjects' VEPs and reference maps generated from HC. Non-ambiguous measures of latency, amplitude and configuration were derived from the maps reflecting the P100 component. TVEP was compared to conventional analysis (cVEP) with respect to reliability in HC, validity using descriptors of logistic regression models, and sensitivity derived from receiver operating characteristics curves. In tVEP, reliability tended to be higher for measurement of amplitude (p = 0.06). Regression models on diagnosis (MS vs. HC) and hON were more favorable using tVEP- versus cVEP-predictors. Sensitivity was increased in tVEP versus cVEP: 72 % versus 60 % for diagnosis, and 88 % versus 77 % for hON. The advantage of tVEP was most pronounced in pathological VEPs, in which cVEPs were often ambiguous. TVEP is a reliable, valid, and sensitive method of objectively quantifying pathological VEP in particular. In combination with other EP modalities, tVEP may improve the monitoring of disease course in MS.

High-frequency multimodal training with a focus on Tai Chi in people with Parkinson's disease: a pilot study.

Background and objectives: Cognitive decline is an important and common complication in patients with Parkinson's disease (PD) since it significantly reduces the quality of life. A breakthrough in treating and preventing cognitive decline in PD remains to be achieved. This study aimed to evaluate the effectiveness of high-frequency and intensive multimodal training in improving motor and cognitive function. Methods: Twenty-eight patients diagnosed with idiopathic PD completed a comprehensive neuropsychological test battery and were neurologically examined. The patients of the intervention group (n = 15) underwent 2 weekly sessions of Tai Chi therapy over 4 weeks and participated in an individually tailored training program consisting of two modules (smartphone-based speech training and cognitive training). A matched control group consisted of n = 13 patients with PD who received computer-assisted cognitive training. The data were analyzed with repeated-measures ANOVA. Results: Four weeks of high-frequency training showed significant effects on verbal and figural episodic memory and visuospatial function in the intervention group.Compared to the control group, the cognitive performance of the intervention group improved significantly in visuospatial function and figural episodic memory. A significant improvement was also shown in the intervention group in the Tinetti Mobility Test and the Epworth Sleepiness Scale. The significant effects in the Tinetti mobility test remained after the 6 months follow-up. After the intervention, the patients reported high motivation and satisfaction with the multimodal training. Conclusion: In patients with PD, a multimodal training program not only improves gait and stability but may also contribute to improving cognition. Clinical trial registration: ClinicalTrials.gov Identifier: NCT04103255; https://register.clinicaltrials.gov/prs/app/action/LoginUser?ts=1&cx=-jg9qo4.

Electrophysiological signatures of anxiety in Parkinson's disease.

Anxiety is a common non-motor symptom in Parkinson's disease (PD) occurring in up to 31% of the patients and affecting their quality of life. Despite the high prevalence, anxiety symptoms in PD are often underdiagnosed and, therefore, undertreated. To date, functional and structural neuroimaging studies have contributed to our understanding of the motor and cognitive symptomatology of PD. Yet, the underlying pathophysiology of anxiety symptoms in PD remains largely unknown and studies on their neural correlates are missing. Here, we used resting-state electroencephalography (RS-EEG) of 68 non-demented PD patients with or without clinically-defined anxiety and 25 healthy controls (HC) to assess spectral and functional connectivity fingerprints characterizing the PD-related anxiety. When comparing the brain activity of the PD anxious group (PD-A, N = 18) to both PD non-anxious (PD-NA, N = 50) and HC groups (N = 25) at baseline, our results showed increased fronto-parietal delta power and decreased frontal beta power depicting the PD-A group. Results also revealed hyper-connectivity networks predominating in delta, theta and gamma bands against prominent hypo-connectivity networks in alpha and beta bands as network signatures of anxiety in PD where the frontal, temporal, limbic and insular lobes exhibited the majority of significant connections. Moreover, the revealed EEG-based electrophysiological signatures were strongly associated with the clinical scores of anxiety and followed their progression trend over the course of the disease. We believe that the identification of the electrophysiological correlates of anxiety in PD using EEG is conducive toward more accurate prognosis and can ultimately support personalized psychiatric follow-up and the development of new therapeutic strategies.