Publications by authors named "Sergiu Groppa"

106 Publications

Sex-specific signatures of intrinsic hippocampal networks and regional integrity underlying cognitive status in multiple sclerosis.

Brain Commun 2021 23;3(3):fcab198. Epub 2021 Aug 23.

Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz 55131, Germany.

The hippocampus is an anatomically compartmentalized structure embedded in highly wired networks that are essential for cognitive functions. The hippocampal vulnerability has been postulated in acute and chronic neuroinflammation in multiple sclerosis, while the patterns of occurring inflammation, neurodegeneration or compensation have not yet been described. Besides focal damage to hippocampal tissue, network disruption is an important contributor to cognitive decline in multiple sclerosis patients. We postulate sex-specific trajectories in hippocampal network reorganization and regional integrity and address their relationship to markers of neuroinflammation, cognitive/memory performance and clinical severity. In a large cohort of multiple sclerosis patients ( = 476; 337 females, age 35 ± 10 years, disease duration 16 ± 14 months) and healthy subjects ( = 110, 54 females; age 34 ± 15 years), we utilized MRI at baseline and at 2-year follow-up to quantify regional hippocampal volumetry and reconstruct single-subject hippocampal networks. Through graph analytical tools we assessed the clustered topology of the hippocampal networks. Mixed-effects analyses served to model sex-based differences in hippocampal network and subfield integrity between multiple sclerosis patients and healthy subjects at both time points and longitudinally. Afterwards, hippocampal network and subfield integrity were related to clinical and radiological variables in dependency of sex attribution. We found a more clustered network architecture in both female and male patients compared to their healthy counterparts. At both time points, female patients displayed a more clustered network topology in comparison to male patients. Over time, multiple sclerosis patients developed an even more clustered network architecture, though with a greater magnitude in females. We detected reduced regional volumes in most of the addressed hippocampal subfields in both female and male patients compared to healthy subjects. Compared to male patients, females displayed lower volumes of para- and presubiculum but higher volumes of the molecular layer. Longitudinally, volumetric alterations were more pronounced in female patients, which showed a more extensive regional tissue loss. Despite a comparable cognitive/memory performance between female and male patients over the follow-up period, we identified a strong interrelation between hippocampal network properties and cognitive/memory performance only in female patients. Our findings evidence a more clustered hippocampal network topology in female patients with a more extensive subfield volume loss over time. A stronger relation between cognitive/memory performance and the network topology in female patients suggests greater entrainment of the brain's reserve. These results may serve to adapt sex-targeted neuropsychological interventions.
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http://dx.doi.org/10.1093/braincomms/fcab198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417841PMC
August 2021

Translational value of choroid plexus imaging for tracking neuroinflammation in mice and humans.

Proc Natl Acad Sci U S A 2021 Sep;118(36)

Department of Neurology, Focus Program Translational Neuroscience, Rhine Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany;

Neuroinflammation is a pathophysiological hallmark of multiple sclerosis and has a close mechanistic link to neurodegeneration. Although this link is potentially targetable, robust translatable models to reliably quantify and track neuroinflammation in both mice and humans are lacking. The choroid plexus (ChP) plays a pivotal role in regulating the trafficking of immune cells from the brain parenchyma into the cerebrospinal fluid (CSF) and has recently attracted attention as a key structure in the initiation of inflammatory brain responses. In a translational framework, we here address the integrity and multidimensional characteristics of the ChP under inflammatory conditions and question whether ChP volumes could act as an interspecies marker of neuroinflammation that closely interrelates with functional impairment. Therefore, we explore ChP characteristics in neuroinflammation in patients with multiple sclerosis and in two experimental mouse models, cuprizone diet-related demyelination and experimental autoimmune encephalomyelitis. We demonstrate that ChP enlargement-reconstructed from MRI-is highly associated with acute disease activity, both in the studied mouse models and in humans. A close dependency of ChP integrity and molecular signatures of neuroinflammation is shown in the performed transcriptomic analyses. Moreover, pharmacological modulation of the blood-CSF barrier with natalizumab prevents an increase of the ChP volume. ChP enlargement is strongly linked to emerging functional impairment as depicted in the mouse models and in multiple sclerosis patients. Our findings identify ChP characteristics as robust and translatable hallmarks of acute and ongoing neuroinflammatory activity in mice and humans that could serve as a promising interspecies marker for translational and reverse-translational approaches.
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http://dx.doi.org/10.1073/pnas.2025000118DOI Listing
September 2021

Toward future adaptive deep brain stimulation for Parkinson's disease: the novel biomarker - narrowband gamma oscillation.

Neural Regen Res 2022 Mar;17(3):557-558

Movement Disorders and Neurostimulation, Biomedical Statistics and Multimodal Signal Processing, Department of Neurology, Johannes Gutenberg University, Mainz, Germany.

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http://dx.doi.org/10.4103/1673-5374.320984DOI Listing
March 2022

Nonlinear irregularities in Parkinson's disease tremor and essential tremor.

Clin Neurophysiol 2021 Sep 18;132(9):2255-2256. Epub 2021 Jun 18.

Section of Movement Disorders and Neurostimulation, Biomedical Statistics and Multimodal Signal Processing Unit, Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine-Main-Neuronetwork (rmn2), University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr 1, 55131 Mainz, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.clinph.2021.06.002DOI Listing
September 2021

Serum neurofilament levels reflect outer retinal layer changes in multiple sclerosis.

Ther Adv Neurol Disord 2021 25;14:17562864211003478. Epub 2021 May 25.

Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn), University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, Mainz 55131, Germany.

Background: Serum neurofilament light chain (sNfL) and distinct intra-retinal layers are both promising biomarkers of neuro-axonal injury in multiple sclerosis (MS). We aimed to unravel the association of both markers in early MS, having identified that neurofilament has a distinct immunohistochemical expression pattern among intra-retinal layers.

Methods: Three-dimensional (3D) spectral domain macular optical coherence tomography scans and sNfL levels were investigated in 156 early MS patients (female/male: 109/47, mean age: 33.3 ± 9.5 years, mean disease duration: 2.0 ± 3.3 years). Out of the whole cohort, 110 patients had no history of optic neuritis (NHON) and 46 patients had a previous history of optic neuritis (HON). In addition, a subgroup of patients ( = 38) was studied longitudinally over 2 years. Support vector machine analysis was applied to test a regression model for significant changes.

Results: In our cohort, HON patients had a thinner outer plexiform layer (OPL) volume compared to NHON patients ( = -0.016, SE = 0.006,  = 0.013). Higher sNfL levels were significantly associated with thinner OPL volumes in HON patients ( = -6.734, SE = 2.514,  = 0.011). This finding was corroborated in the longitudinal subanalysis by the association of higher sNfL levels with OPL atrophy ( = 5.974, SE = 2.420,  = 0.019). sNfL levels were 75.7% accurate at predicting OPL volume in the supervised machine learning.

Conclusions: In summary, sNfL levels were a good predictor of future outer retinal thinning in MS. Changes within the neurofilament-rich OPL could be considered as an additional retinal marker linked to MS neurodegeneration.
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http://dx.doi.org/10.1177/17562864211003478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155762PMC
May 2021

Identification of Potential Distinguishing Markers for the Use of Cannabis-Based Medicines or Street Cannabis in Serum Samples.

Metabolites 2021 May 13;11(5). Epub 2021 May 13.

Institute of Legal Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.

Increasing prescription numbers of cannabis-based medicines raise the question of whether uptake of these medicines can be distinguished from recreational cannabis use. In this pilot study, serum cannabinoid profiles after use of cannabis-based medicines were investigated, in order to identify potential distinguishing markers. Serum samples after use of Sativex, Dronabinol or medical cannabis were collected and analyzed for 18 different cannabinoids, using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Analytes included delta-9-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-nor-9-carboxy-tetrahydrocannabinol, cannabidiol, cannabinol, cannabigerol, cannabichromene, cannabicyclol, tetrahydrocannabivarin, cannabidivarin, tetrahydocannabinolic acid A, cannabidiolic acid, cannabinolic acid, cannabigerolic acid, cannabichromenic acid, cannabicyclolic acid, tetrahydrocannabivarinic acid and cannabidivarinic acid. Cannabinoid profiles of study samples were compared to profiles of street cannabis user samples via principal component analysis and Kruskal-Wallis test. Potential distinguishing markers for Dronabinol and Sativex intake were identified, including 11-hydroxy-tetrahydrocannabinol/delta-9-tetrahydrocannabinol ratios ≥1 and increased concentrations of 11-nor-9-carboxy-tetrahydrocannabinol, cannabidiol or cannabichromene. Larger quantities of minor cannabinoids suggested use of cannabis. Use of medical and street cannabis could not be distinguished, except for use of a cannabidiol-rich strain with higher cannabidiol/delta-9-tetrahydrocannabinol and cannabichromene/delta-9-tetrahydrocannabinol ratios. Findings of the study were used to classify forensic serum samples with self-reported use of cannabis-based medicines.
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http://dx.doi.org/10.3390/metabo11050316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153355PMC
May 2021

Directional Deep Brain Stimulation for Parkinson's Disease: Results of an International Crossover Study With Randomized, Double-Blind Primary Endpoint.

Neuromodulation 2021 May 27. Epub 2021 May 27.

Department of Neurosurgery, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.

Objective: Published reports on directional deep brain stimulation (DBS) have been limited to small, single-center investigations. Therapeutic window (TW) is used to describe the range of stimulation amplitudes achieving symptom relief without side effects. This crossover study performed a randomized double-blind assessment of TW for directional and omnidirectional DBS in a large cohort of patients implanted with a DBS system in the subthalamic nucleus for Parkinson's disease.

Materials And Methods: Participants received omnidirectional stimulation for the first three months after initial study programming, followed by directional DBS for the following three months. The primary endpoint was a double-blind, randomized evaluation of TW for directional vs. omnidirectional stimulation at three months after initial study programming. Additional data recorded at three- and six-month follow-ups included stimulation preference, therapeutic current strength, Unified Parkinson's Disease Rating Scale (UPDRS) part III motor score, and quality of life.

Results: The study enrolled 234 subjects (62 ± 8 years, 33% female). TW was wider using directional stimulation in 183 of 202 subjects (90.6%). The mean increase in TW with directional stimulation was 41% (2.98 ± 1.38 mA, compared to 2.11 ± 1.33 mA for omnidirectional). UPDRS part III motor score on medication improved 42.4% at three months (after three months of omnidirectional stimulation) and 43.3% at six months (after three months of directional stimulation) with stimulation on, compared to stimulation off. After six months, 52.8% of subjects blinded to stimulation type (102/193) preferred the period with directional stimulation, and 25.9% (50/193) preferred the omnidirectional period. The directional period was preferred by 58.5% of clinicians (113/193) vs. 21.2% (41/193) who preferred the omnidirectional period.

Conclusion: Directional stimulation yielded a wider TW compared to omnidirectional stimulation and was preferred by blinded subjects and clinicians.
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http://dx.doi.org/10.1111/ner.13407DOI Listing
May 2021

Proceedings of the Eighth Annual Deep Brain Stimulation Think Tank: Advances in Optogenetics, Ethical Issues Affecting DBS Research, Neuromodulatory Approaches for Depression, Adaptive Neurostimulation, and Emerging DBS Technologies.

Front Hum Neurosci 2021 19;15:644593. Epub 2021 Apr 19.

Neurologischen Klinik Universitätsklinikum Würzburg, Würzburg, Germany.

We estimate that 208,000 deep brain stimulation (DBS) devices have been implanted to address neurological and neuropsychiatric disorders worldwide. DBS Think Tank presenters pooled data and determined that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. The DBS Think Tank was founded in 2012 providing a space where clinicians, engineers, researchers from industry and academia discuss current and emerging DBS technologies and logistical and ethical issues facing the field. The emphasis is on cutting edge research and collaboration aimed to advance the DBS field. The Eighth Annual DBS Think Tank was held virtually on September 1 and 2, 2020 (Zoom Video Communications) due to restrictions related to the COVID-19 pandemic. The meeting focused on advances in: (1) optogenetics as a tool for comprehending neurobiology of diseases and on optogenetically-inspired DBS, (2) cutting edge of emerging DBS technologies, (3) ethical issues affecting DBS research and access to care, (4) neuromodulatory approaches for depression, (5) advancing novel hardware, software and imaging methodologies, (6) use of neurophysiological signals in adaptive neurostimulation, and (7) use of more advanced technologies to improve DBS clinical outcomes. There were 178 attendees who participated in a DBS Think Tank survey, which revealed the expansion of DBS into several indications such as obesity, post-traumatic stress disorder, addiction and Alzheimer's disease. This proceedings summarizes the advances discussed at the Eighth Annual DBS Think Tank.
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http://dx.doi.org/10.3389/fnhum.2021.644593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092047PMC
April 2021

Network Substrates of Centromedian Nucleus Deep Brain Stimulation in Generalized Pharmacoresistant Epilepsy.

Neurotherapeutics 2021 Apr 26. Epub 2021 Apr 26.

Movement Disorders and Neurostimulation, Department of Neurology, Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University Mainz, Rhine Main Neuroscience Network (rmn2), Mainz, Germany.

Deep brain stimulation (DBS), specifically thalamic DBS, has achieved promising results to reduce seizure severity and frequency in pharmacoresistant epilepsies, thereby establishing it for clinical use. The mechanisms of action are, however, still unknown. We evidenced the brain networks directly modulated by centromedian (CM) nucleus-DBS and responsible for clinical outcomes in a cohort of patients uniquely diagnosed with generalized pharmacoresistant epilepsy. Preoperative imaging and long-term (2-11 years) clinical data from ten generalized pharmacoresistant epilepsy patients (mean age at surgery = 30.8 ± 5.9 years, 4 female) were evaluated. Volume of tissue activated (VTA) was included as seeds to reconstruct the targeted network to thalamic DBS from diffusion and functional imaging data. CM-DBS clinical outcome improvement (> 50%) appeared in 80% of patients and was tightly related to VTAs interconnected with a reticular system network encompassing sensorimotor and supplementary motor cortices, together with cerebellum/brainstem. Despite methodological differences, both structural and functional connectomes revealed the same targeted network. Our results demonstrate that CM-DBS outcome in generalized pharmacoresistant epilepsy is highly dependent on the individual connectivity profile, involving the cerebello-thalamo-cortical circuits. The proposed framework could be implemented in future studies to refine stereotactic implantation or the parameters for individualized neuromodulation.
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http://dx.doi.org/10.1007/s13311-021-01057-yDOI Listing
April 2021

Epigallocatechin Gallate in Relapsing-Remitting Multiple Sclerosis: A Randomized, Placebo-Controlled Trial.

Neurol Neuroimmunol Neuroinflamm 2021 05 24;8(3). Epub 2021 Mar 24.

From the NeuroCure Clinical Research Center (J.B.-S., F.P., J.D., A.B., V.S.), Charité-Universitätsmedizin Berlin; Medical Image Analysis Center (J.W.), University Basel; Institut for Medical Immunology (C.I.-D., E.H.), Charité-Universitätsmedizin Berlin; Department of Neurology and Neuroimaging Center (B.K.), Johannes Gutenberg University, Mainz; Charité-Universitätsmedizin Berlin (C.P.); NeuroCure Clinical Research Center (H.R., R.R.), Charité-Universitätsmedizin Berlin, Germany; Department of Neurology (O.A.), Medical Faculty, Heinrich Heine University Düsseldorf; Institut für Neuroimmunologie und Multiple Sklerose (C.H.), Universitätsklinikum Hamburg-Eppendorf, Hamburg; Klinik für Neurologie (J.F.), Asklepios Klinik Lübben/Teupitz; Department of Neurology (F.H.), Krankenhaus Martha-Maria Halle-Dölau, Halle/Saale; Medizinische Klinik für Kardiologie und Angiologie (M.L.), Campus Mitte, Charité-Universitätsmedizin Berlin; Institute of Nutritional and Food Sciences (B.Z.), University of Bonn; Department of Neurology and Neuroimaging Center (NIC) (S.G., F.Z.), Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University, Mainz; and Charité-Universitätsmedizin Berlin and SOSTANA GmbH (K.-D.W.), Berlin.

Objective: To assess the safety and efficacy of epigallocatechin-3-gallate (EGCG) add-on to glatiramer acetate (GA) in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods: We enrolled patients with RRMS (aged 18-60 years, Expanded Disability Status Scale [EDSS] score 0-6.5), receiving stable GA treatment in a multicenter, prospective, double-blind, phase II, randomized controlled trial. Participants received up to 800 mg oral EGCG daily over a period of 18 months. The primary outcome was the proportion of patients without new hyperintense lesions on T2-weighted (T2w) brain MRI within 18 months. Secondary end points included additional MRI and clinical parameters. Immunologic effects of EGCG were investigated in exploratory experiments.

Results: A total of 122 patients on GA were randomly assigned to EGCG treatment (n = 62) or placebo (n = 60). We could not demonstrate a difference between groups after 18 months for the primary outcome or other radiologic (T2w lesion volume, T1w hypointense lesion number or volume, number of cumulative contrast-enhancing lesions, percent brain volume change), or clinical (EDSS, MS functional composite, and annualized relapse rate) parameter. EGCG treatment did not affect immune response to GA. Pharmacologic analysis revealed wide ranging EGCG plasma levels. The treatment was well tolerated with a similar incidence of mostly mild adverse events similar in both groups.

Conclusion: In RRMS, oral EGCG add-on to GA was not superior to placebo in influencing MRI and clinical disease activity over 18 months. The treatment was safe at a daily dosage up to 800 mg EGCG. It did not influence immune parameters, despite indication of EGCG being bioavailable in patients.

Classification Of Evidence: This study provides Class II evidence that for patients with RRMS, EGCG added to GA did not significantly affect the development of new hyperintense lesions on T2-weighted brain MRI.

Trial Registration Information: Clinical trial registration number: NCT00525668.
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http://dx.doi.org/10.1212/NXI.0000000000000981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054966PMC
May 2021

Intensity of Respiratory Cortical Arousals Is a Distinct Pathophysiologic Feature and Is Associated with Disease Severity in Obstructive Sleep Apnea Patients.

Brain Sci 2021 Feb 25;11(3). Epub 2021 Feb 25.

Movement Disorders and Neurostimulation, Biomedical Statistics and Multimodal Signal Processing Unit, Department of Neurology, Medical Center of the University of Mainz, 55131 Mainz, Germany.

Background: We investigated whether the number, duration and intensity of respiratory arousals (RA) on C3-electroencephalographic (EEG) recordings correlate with polysomnography (PSG)-related disease severity in obstructive sleep apnea (OSA) patients. We also investigated if every patient might have an individual RA microstructure pattern, independent from OSA-severity.

Methods: PSG recordings of 20 OSA patients (9 female; age 27-80 years) were analyzed retrospectively. Correlation coefficients were calculated between RA microstructure (duration, EEG-intensity) and RA number and respiratory disturbance index (RDI), oxygen desaturation index (ODI) and arousal index (AI). Intraclass correlations (ICC) for both RA duration and intensity were calculated. Sleep stage-specific and apnea- and hypopnea-specific analyses were also done. The probability distributions of duration and intensity were plotted, interpolated with a kernel which fits the distribution. A Bayesian posterior distribution analysis and pair-wise comparisons of each patient with all other 19 patients were performed.

Results: Of the analyzed 2600 RA, strong positive correlations were found between average RA intensity and both RDI and AI. The number of PSG-recorded RA was strongly positively correlated with RDI. Significant correlations between average RA intensity in REM, NREM2 and NREM3 sleep stages and total ODI were identified. No sleep stage-specific correlations of arousal microstructure with age, sex, RDI or AI were identified. Although between-subjects ICC values were <0.25, within-subject ICC values were all >0.7 (all < 0.05). While apnea-related RA duration did not differ from hypopnea-related RA duration, RA intensity was significantly higher ( = 0.00135) in hypopneas than in apneas. A clear individual pattern of arousal duration for each patient was made distinct. For arousal intensity, a Gaussian distribution was identified in most patients. The Bayesian statistics regarding the arousal microstructure showed significant differences between each pair of patients.

Conclusions: Each individual patient with OSA might have an individual pattern of RA intensity and duration indicating a distinct individual pathophysiological feature. Arousal intensity was significantly higher in hypopneic than in apneic events and may be related causally to the diminished (compared to apneas) respiratory distress associated with hypopneas. RA intensity in REM, NREM2 and NREM3 strongly correlated with ODI.
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http://dx.doi.org/10.3390/brainsci11030282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996607PMC
February 2021

Structural brain network characteristics in patients with episodic and chronic migraine.

J Headache Pain 2021 Mar 3;22(1). Epub 2021 Mar 3.

Section of Movement Disorders and Neurostimulation, Biomedical Statistics and Multimodal Signal Processing unit, Department of Neurology, Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

Background: Migraine is a primary headache disorder that can be classified into an episodic (EM) and a chronic form (CM). Network analysis within the graph-theoretical framework based on connectivity patterns provides an approach to observe large-scale structural integrity. We test the hypothesis that migraineurs are characterized by a segregated network.

Methods: 19 healthy controls (HC), 17 EM patients and 12 CM patients were included. Cortical thickness and subcortical volumes were computed, and topology was analyzed using a graph theory analytical framework and network-based statistics. We further used support vector machines regression (SVR) to identify whether these network measures were able to predict clinical parameters.

Results: Network based statistics revealed significantly lower interregional connectivity strength between anatomical compartments including the fronto-temporal, parietal and visual areas in EM and CM when compared to HC. Higher assortativity was seen in both patients' group, with higher modularity for CM and higher transitivity for EM compared to HC. For subcortical networks, higher assortativity and transitivity were observed for both patients' group with higher modularity for CM. SVR revealed that network measures could robustly predict clinical parameters for migraineurs.

Conclusion: We found global network disruption for EM and CM indicated by highly segregated network in migraine patients compared to HC. Higher modularity but lower clustering coefficient in CM is suggestive of more segregation in this group compared to EM. The presence of a segregated network could be a sign of maladaptive reorganization of headache related brain circuits, leading to migraine attacks or secondary alterations to pain.
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http://dx.doi.org/10.1186/s10194-021-01216-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927231PMC
March 2021

Functional and directed connectivity of the cortico-limbic network in mice in vivo.

Brain Struct Funct 2021 Apr 13;226(3):685-700. Epub 2021 Jan 13.

Institute of Physiology, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, 55128, Mainz, Germany.

Higher cognitive processes and emotional regulation depend on densely interconnected telencephalic and limbic areas. Central structures of this cortico-limbic network are ventral hippocampus (vHC), medial prefrontal cortex (PFC), basolateral amygdala (BLA) and nucleus accumbens (NAC). Human and animal studies have revealed both anatomical and functional alterations in specific connections of this network in several psychiatric disorders. However, it is often not clear whether functional alterations within these densely interconnected brain areas are caused by modifications in the direct pathways, or alternatively through indirect interactions. We performed multi-site extracellular recordings of spontaneous activity in three different brain regions to study the functional connectivity in the BLA-NAC-PFC-vHC network of the lightly anesthetized mouse in vivo. We show that BLA, NAC, PFC and vHC are functionally connected in distinct frequency bands and determined the influence of a third brain region on this connectivity. In addition to describing mutual synchronicity, we determined the strength of functional connectivity for each region in the BLA-NAC-PFC-vHC network. We find a region-specificity in the strength of feedforward and feedback connections for each region in its interaction with other areas in the network. Our results provide insights into functional and directed connectivity in the cortico-limbic network of adult wild-type mice, which may be helpful to further elucidate the pathophysiological changes of this network in psychiatric disorders and to develop target-specific therapeutic interventions.
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http://dx.doi.org/10.1007/s00429-020-02202-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981333PMC
April 2021

7 Tesla MRI will soon be helpful to guide clinical practice in multiple sclerosis centres - No.

Mult Scler 2021 03 6;27(3):362-363. Epub 2021 Jan 6.

Focus Program Translational Neuroscience (FTN) and Rhine-Main Neuroscience Network (rmn2), Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

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http://dx.doi.org/10.1177/1352458520969662DOI Listing
March 2021

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity.

Proc Natl Acad Sci U S A 2021 01;118(1)

Department of Neurology, Neuroimmunological Section, University of Rostock, 18051 Rostock, Germany.

Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies ( = 946, = 990). Additionally, effect-modification by medication and photosensitivity-associated variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-β-treated patients. In carriers of :rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.
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http://dx.doi.org/10.1073/pnas.2018457118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817192PMC
January 2021

[Care of patients with Parkinson's disease in Germany: status quo and perspectives as reflected in the digital transition].

Nervenarzt 2021 Jun 16;92(6):602-610. Epub 2020 Nov 16.

Molekulare Neurologie, Universitätsklinikum Erlangen, Schwabachanlage 6, 91054, Erlangen, Deutschland.

As a chronic neurodegenerative disease, Parkinson's disease requires a close cooperation between different specialist disciplines in order to ensure the best possible quality of life for patients. A problem that has been identified is the inadequate communication between the protagonists (e.g. caregivers, physicians and therapists), especially at the sectoral interfaces. Due to structural hurdles, the current process and supply chains for Parkinson's disease do not reflect successful cross-sectoral care. Against the background of the new Digital Care Act in Germany that refunds patient-centered digital healthcare applications (DiGA), innovative, digital care and communication structures can now be established and thus comprehensively revolutionize the care of chronic diseases, such as Parkinson's disease. In this review examples and case application scenarios are presented and critically discussed.
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http://dx.doi.org/10.1007/s00115-020-01027-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667482PMC
June 2021

Mapping of subthalamic nucleus using microelectrode recordings during deep brain stimulation.

Sci Rep 2020 11 6;10(1):19241. Epub 2020 Nov 6.

Movement Disorders and Neurostimulation, Biomedical Statistics and Multimodal Signal Processing Unit, Department of Neurology, Johannes Gutenberg University, Mainz, Germany.

Alongside stereotactic magnetic resonance imaging, microelectrode recording (MER) is frequently used during the deep brain stimulation (DBS) surgery for optimal target localization. The aim of this study is to optimize subthalamic nucleus (STN) mapping using MER analytical patterns. 16 patients underwent bilateral STN-DBS. MER was performed simultaneously for 5 microelectrodes in a setting of Ben's-gun pattern in awake patients. Using spikes and background activity several different parameters and their spectral estimates in various frequency bands including low frequency (2-7 Hz), Alpha (8-12 Hz), Beta (sub-divided as Low_Beta (13-20 Hz) and High_Beta (21-30 Hz)) and Gamma (31 to 49 Hz) were computed. The optimal STN lead placement with the most optimal clinical effect/side-effect ratio accorded to the maximum spike rate in 85% of the implantation. Mean amplitude of background activity in the low beta frequency range was corresponding to right depth in 85% and right location in 94% of the implantation respectively. MER can be used for STN mapping and intraoperative decisions for the implantation of DBS electrode leads with a high accuracy. Spiking and background activity in the beta range are the most promising independent parameters for the delimitation of the proper anatomical site.
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http://dx.doi.org/10.1038/s41598-020-74196-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648837PMC
November 2020

Cross-frequency coupling between gamma oscillations and deep brain stimulation frequency in Parkinson's disease.

Brain 2020 12;143(11):3393-3407

Section of Movement Disorders and Neurostimulation, Biomedical Statistics and Multimodal Signal Processing Unit, Department of Neurology, Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

The disruption of pathologically enhanced beta oscillations is considered one of the key mechanisms mediating the clinical effects of deep brain stimulation on motor symptoms in Parkinson's disease. However, a specific modulation of other distinct physiological or pathological oscillatory activities could also play an important role in symptom control and motor function recovery during deep brain stimulation. Finely tuned gamma oscillations have been suggested to be prokinetic in nature, facilitating the preferential processing of physiological neural activity. In this study, we postulate that clinically effective high-frequency stimulation of the subthalamic nucleus imposes cross-frequency interactions with gamma oscillations in a cortico-subcortical network of interconnected regions and normalizes the balance between beta and gamma oscillations. To this end we acquired resting state high-density (256 channels) EEG from 31 patients with Parkinson's disease who underwent deep brain stimulation to compare spectral power and power-to-power cross-frequency coupling using a beamformer algorithm for coherent sources. To show that modulations exclusively relate to stimulation frequencies that alleviate motor symptoms, two clinically ineffective frequencies were tested as control conditions. We observed a robust reduction of beta and increase of gamma power, attested in the regions of a cortical (motor cortex, supplementary motor area, premotor cortex) and subcortical network (subthalamic nucleus and cerebellum). Additionally, we found a clear cross-frequency coupling of narrowband gamma frequencies to the stimulation frequency in all of these nodes, which negatively correlated with motor impairment. No such dynamics were revealed within the control posterior parietal cortex region. Furthermore, deep brain stimulation at clinically ineffective frequencies did not alter the source power spectra or cross-frequency coupling in any region. These findings demonstrate that clinically effective deep brain stimulation of the subthalamic nucleus differentially modifies different oscillatory activities in a widespread network of cortical and subcortical regions. Particularly the cross-frequency interactions between finely tuned gamma oscillations and the stimulation frequency may suggest an entrainment mechanism that could promote dynamic neural processing underlying motor symptom alleviation.
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http://dx.doi.org/10.1093/brain/awaa297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116448PMC
December 2020

EEG and MEG primers for tracking DBS network effects.

Neuroimage 2021 01 12;224:117447. Epub 2020 Oct 12.

Movement disorders and Neurostimulation, Biomedical Statistics and Multimodal Signal Processing Unit, Department of Neurology, University Medical Center of the Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany. Electronic address:

Deep brain stimulation (DBS) is an effective treatment method for a range of neurological and psychiatric disorders. It involves implantation of stimulating electrodes in a precisely guided fashion into subcortical structures and, at a later stage, chronic stimulation of these structures with an implantable pulse generator. While the DBS surgery makes it possible to both record brain activity and stimulate parts of the brain that are difficult to reach with non-invasive techniques, electroencephalography (EEG) and magnetoencephalography (MEG) provide complementary information from other brain areas, which can be used to characterize brain networks targeted through DBS. This requires, however, the careful consideration of different types of artifacts in the data acquisition and the subsequent analyses. Here, we review both the technical issues associated with EEG/MEG recordings in DBS patients and the experimental findings to date. One major line of research is simultaneous recording of local field potentials (LFPs) from DBS targets and EEG/MEG. These studies revealed a set of cortico-subcortical coherent networks functioning at distinguishable physiological frequencies. Specific network responses were linked to clinical state, task or stimulation parameters. Another experimental approach is mapping of DBS-targeted networks in chronically implanted patients by recording EEG/MEG responses during stimulation. One can track responses evoked by single stimulation pulses or bursts as well as brain state shifts caused by DBS. These studies have the potential to provide biomarkers for network responses that can be adapted to guide stereotactic implantation or optimization of stimulation parameters. This is especially important for diseases where the clinical effect of DBS is delayed or develops slowly over time. The same biomarkers could also potentially be utilized for the online control of DBS network effects in the new generation of closed-loop stimulators that are currently entering clinical use. Through future studies, the use of network biomarkers may facilitate the integration of circuit physiology into clinical decision making.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117447DOI Listing
January 2021

Corticoperipheral neuromuscular disconnection in obstructive sleep apnoea.

Brain Commun 2020 11;2(1):fcaa056. Epub 2020 May 11.

Movement Disorders and Neurostimulation, Biomedical Statistics and Multimodal Signal Processing Unit, Department of Neurology, University Medical Center of Johannes Gutenberg University Mainz, 55131 Mainz, Germany.

The roles of central nervous mechanisms and cortical output in obstructive sleep apnoea remain unclear. We addressed corticomuscular coupling between cortical sensorimotor areas and lower facial motor units as a mechanistic pathway and as a possible surrogate marker of corticoperipheral motor control in obstructive sleep apnoea. In this exploratory cross-sectional retrospective study, we analysed EEG (C3 and C4 leads) and chin EMG from polysomnography recordings in 86 participants (22 females; age range: 26-81 years): 27 with mild (respiratory disturbance index = 5-15 events/h), 21 with moderate (15-30 events/h) and 23 with severe obstructive sleep apnoea (>30 events/h) and 15 control subjects (<5 events/h). By computing C3-/C4-EEG-chin EMG coherence of signal dynamics in time and frequency domains, we investigated corticomuscular coupling between cortical sensorimotor areas and lower facial motor units with increasing obstructive sleep apnoea severity during the entire sleeping time, during different sleep stages and during obstructive respiratory events, including 5 s before (stable breathing) and after events (breathing resumption). In addition, we studied a possible influence of body mass index and autonomic nervous system activation. We found that both average and respiratory event-specific corticomuscular coupling between cortical sensorimotor areas and lower facial motor units weakened significantly with increasing obstructive sleep apnoea severity, was strongest during N3 and weakened in N1, N2 and rapid eye movement stages (in decreasing order). Coupling increases significantly during the obstructive respiratory events compared with coupling just before and following them. Results were independent of body mass index or autonomic nervous system activation. We conclude that obstructive respiratory events in obstructive sleep apnoea are very strongly associated both quantitatively and temporally with the degree of disconnection within the cortical sensorimotor areas-lower facial motor units pathway. This quite coordinated activity pattern suggests a cortical sensorimotor area-driven obstructive respiratory event pattern generator and a central motor output disorder in obstructive sleep apnoea.
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http://dx.doi.org/10.1093/braincomms/fcaa056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425403PMC
May 2020

Cardiac phenotype in -related syndromes: A multicenter cohort study.

Neurology 2020 11 10;95(21):e2866-e2879. Epub 2020 Sep 10.

From the Department of Clinical and Experimental Epilepsy (S.B., S.M.S.), UCL Queen Square Institute of Neurology, London; Chalfont Centre for Epilepsy (S.B., S.M.S.), Bucks, UK; Division of Pediatric Neurology (M.A.M., A.S.H., B.K., M.M., L.P.), Department of Neurobiology, and Division of Cardiology (M.C.), Department of Pediatrics, Duke University, School of Medicine, Durham, NC; Centre for Inherited Cardiovascular Diseases (R.A.G.-R., J.P.K.), Great Ormond Street Hospital for Children NHS Foundation Trust; Institute of Cardiovascular Science(R.A.G.-R., J.P.K.), University College London, London, UK; Child Neuropsychiatry Unit (E.D.G., A.G., L.P., M.S., E.V.), IRCCs Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, DINOG-MI, University of Genoa; Department of Pediatric Neuroscience (A.G., T.G., N.N., F.R.), Fondazione IRCCS Istituto Neurologico Carlo Besta; Unit of Child Neuropsychiatry (L.P.), ASST Fatebenefratelli Sacco, Milan, Italy; Paediatric Neurology Department (J.C., C.F., L.P.-P., A.A.), Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona University, Member of the International Alternating Hemiplegia in Childhood Research Consortium IAHCRC and of the European Reference Network ERN EpiCARE, Barcelona, Spain; Department of Neurology (A.B., C.M.), Wake Forest School of Medicine, Winston-Salem, NC; Neurology Department (R.S.), Centro Hospitalar e Universitario do Porto-Hospital de Santo António, Porto, Portugal; Clinic for Child Neurology and Psychiatry (V.B., A.P.), Department of Child Neurology, Medical Faculty University of Belgrade, Serbia; Department of Human Genetics (Q.S.P.), Graduate School of Public Health, University of Pittsburgh, PA; Department of Pediatric Neurology (J.P.), Medical University of Silesia, Katowice, Poland; Clinical Neurosciences (K.V., J.H.C.), Developmental Neuroscience Programme, UCL Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital for Children NHS Foundation Trust, Member of the International Alternating Hemiplegia in Childhood Research Consortium IAHCRC and of the European Reference Network ERN EpiCARE, London, UK; Sydney Children's Hospital (A.M.E.B.), Randwick; Department of Cardiology (A.M.D.), The Royal Children's Hospital, Melbourne, University of Melbourne; Department of Neurology (M.M.R.), Royal Children's Hospital, Melbourne; Agnes Ginges Centre for Molecular Cardiology (C.S.), Centenary Institute, University of Sydney; Epilepsy Research Centre (G.H., I.E.S.), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC; Department of Paediatrics (I.E.S.), University of Melbourne, Royal Children's Hospital, Florey and Murdoch Children's Research Institutes, Melbourne, Australia; Department of Clinical Epileptology, Sleep Disorders and Functional Neurology in Children (A.A., E.P.), University Hospitals of Lyon (HCL), Member of the International Alternating Hemiplegia in Childhood Research Consortium IAHCRC and of the European Reference Network ERN EpiCARE, Lyon, France; Paediatric Neurology Unit (I.C.), CMIN, Centro Hospitalar e Universitario Porto, Porto, Portugal; Clinical Neurophysiology Unit (C.Z.), IRCCS "E. Medea," Bosisio Parini (LC), Italy; Department of Neurology (J.N.), CHUV and Université de Lausanne, Switzerland; Second Department of Neurology (K.D.), Institute Psychiatry and Neurology, Warsaw, Poland; Association AHC18+ e. V. (Germany) and Polish Association for People Affected by AHC, ahc-pl (M.P.); Department of Developmental Neurology (M.M.B.), Medical University of Gdańsk, Poland; Neurology Department (S.W.), University Hospital Antwerp; Neurogenetics Group (S.W.), University Antwerp, Belgium; First Department of Pediatrics (R.P.), "Agia Sofia" Children Hospital, National & Kapodistrian University of Athens, Greece; Department of Neurology (S.G.), University Medical Center of the Johannes Gutenberg University Mainz, Germany; Ion Channel Research Unit (D.S.S.), Department of Medicine/Cardiology and Pharmacology, Duke University Medical Center, Durham, NC; Cardiovascular Research Institute (G.S.P.), Weill Cornell Medical College, New York, NY; The Heart Centre (A.T.), Queen Mary University of London; Department of Pathology (M.A.), Great Ormond Street Hospital for Children NHS Foundation Trust; Department of Neuropathology (Z.M., M.T.), Institute of Neurology, University College London, UK; and ICT and Data Analysis Section (R.V.), Euro-Mediterranean Institute of Science and Technology (I.E.ME.S.T.), Palermo, Italy.

Objective: To define the risks and consequences of cardiac abnormalities in -related syndromes.

Methods: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an knock-in mouse (Mashl) to determine the sequence of events in seizure-related cardiac death.

Results: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death.

Conclusions: We found increased prevalence of ECG dynamic abnormalities in all -related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine -related disease. -related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.
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http://dx.doi.org/10.1212/WNL.0000000000010794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734736PMC
November 2020

Normative vs. patient-specific brain connectivity in deep brain stimulation.

Neuroimage 2021 01 28;224:117307. Epub 2020 Aug 28.

Movement Disorders & Neuromodulation Unit, Department for Neurology, Charité - University Medicine Berlin, Germany.

Brain connectivity profiles seeding from deep brain stimulation (DBS) electrodes have emerged as informative tools to estimate outcome variability across DBS patients. Given the limitations of acquiring and processing patient-specific diffusion-weighted imaging data, a number of studies have employed normative atlases of the human connectome. To date, it remains unclear whether patient-specific connectivity information would strengthen the accuracy of such analyses. Here, we compared similarities and differences between patient-specific, disease-matched and normative structural connectivity data and their ability to predict clinical improvement. Data from 33 patients suffering from Parkinson's Disease who underwent surgery at three different centers were retrospectively collected. Stimulation-dependent connectivity profiles seeding from active contacts were estimated using three modalities, namely patient-specific diffusion-MRI data, age- and disease-matched or normative group connectome data (acquired in healthy young subjects). Based on these profiles, models of optimal connectivity were calculated and used to estimate clinical improvement in out of sample data. All three modalities resulted in highly similar optimal connectivity profiles that could largely reproduce findings from prior research based on this present novel multi-center cohort. In a data-driven approach that estimated optimal whole-brain connectivity profiles, out-of-sample predictions of clinical improvements were calculated. Using either patient-specific connectivity (R = 0.43 at p = 0.001), an age- and disease-matched group connectome (R = 0.25, p = 0.048) and a normative connectome based on healthy/young subjects (R = 0.31 at p = 0.028), significant predictions could be made. Our results of patient-specific connectivity and normative connectomes lead to similar main conclusions about which brain areas are associated with clinical improvement. Still, although results were not significantly different, they hint at the fact that patient-specific connectivity may bear the potential of explaining slightly more variance than group connectomes. Furthermore, use of normative connectomes involves datasets with high signal-to-noise acquired on specialized MRI hardware, while clinical datasets as the ones used here may not exactly match their quality. Our findings support the role of DBS electrode connectivity profiles as a promising method to investigate DBS effects and to potentially guide DBS programming.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117307DOI Listing
January 2021

Lack of Accredited Clinical Training in Movement Disorders in Europe, Egypt, and Tunisia.

J Parkinsons Dis 2020 ;10(4):1833-1843

Department of Neurology, Pauls Stradiņš Clinical University Hospital, Riga, Latvia.

Background: Little information is available on the official postgraduate and subspecialty training programs in movement disorders (MD) in Europe and North Africa.

Objective: To survey the accessible MD clinical training in these regions.

Methods: We designed a survey on clinical training in MD in different medical fields, at postgraduate and specialized levels. We assessed the characteristics of the participants and the facilities for MD care in their respective countries. We examined whether there are structured, or even accredited postgraduate, or subspecialty MD training programs in neurology, neurosurgery, internal medicine, geriatrics, neuroradiology, neuropediatrics, and general practice. Participants also shared their suggestions and needs.

Results: The survey was completed in 31/49 countries. Structured postgraduate MD programs in neurology exist in 20 countries; structured neurology subspecialty training exists in 14 countries and is being developed in two additional countries. Certified neurology subspecialty training was reported to exist in 7 countries. Recommended reading lists, printed books, and other materials are the most popular educational tools, while courses, lectures, webinars, and case presentations are the most popular learning formats. Mandatory activities and skills to be certified were not defined in 15/31 countries. Most participants expressed their need for a mandatory postgraduate MD program and for certified MD sub-specialization programs in neurology.

Conclusion: Certified postgraduate and subspecialty training exists only in a minority of European countries and was not found in the surveyed Egypt and Tunisia. MD training should be improved in many countries.
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http://dx.doi.org/10.3233/JPD-202000DOI Listing
January 2020

Neuroimaging and electrophysiology meet invasive neurostimulation for causal interrogations and modulations of brain states.

Neuroimage 2020 10 4;220:117144. Epub 2020 Jul 4.

Movement Disorders and Neurostimulation, Biomedical Statistics and Multimodal Signal Processing Unit, Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Germany. Electronic address:

Deep brain stimulation (DBS) has developed over the last twenty years into a highly effective evidenced-based treatment option for neuropsychiatric disorders. Moreover, it has become a fascinating tool to provide illustrative insights into the functioning of brain networks. New anatomical and pathophysiological models of DBS action have accelerated our understanding of neurological and psychiatric disorders and brain functioning. The description of the brain networks arose through the unique ability to illustrate long-range interactions between interconnected brain regions as derived from state-of-the-art neuroimaging (structural, diffusion, and functional MRI) and the opportunity to record local and large-scale brain activity at millisecond temporal resolution (microelectrode recordings, local field potential, electroencephalography, and magnetoencephalography). In the first part of this review, we describe how neuroimaging techniques have led to current understanding of DBS effects, by identifying and refining the DBS targets and illustrate the actual view on the relationships between electrode locations and clinical effects. One step further, we discuss how neuroimaging has shifted the view of localized DBS effects to a modulation of specific brain circuits, which has been possible from the combination of electrode location reconstructions with recently introduced network imaging methods. We highlight how these findings relate to clinical effects, thus postulating neuroimaging as a key factor to understand the mechanisms of DBS action on behavior and clinical effects. In the second part, we show how invasive electrophysiology techniques have been efficiently integrated into the DBS set-up to precisely localize the neuroanatomical targets of DBS based on distinct region-specific patterns of neural activity. Next, we show how multi-site electrophysiological recordings have granted a real-time window into the aberrant brain circuits within and beyond DBS targets to quantify and map the dynamic properties of rhythmic oscillations. We also discuss how DBS alters the transient synchrony states of oscillatory networks in temporal and spatial domains during resting, task-based and motion conditions, and how this modulation of brain states ultimately shapes the functional response. Finally, we show how a successful decoding and management of electrophysiological proxies (beta bursts, phase-amplitude coupling) of aberrant brain circuits was translated into adaptive DBS stimulation paradigms for a targeted and state-dependent invasive electrical neuromodulation.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117144DOI Listing
October 2020

Pre-dopa Deep Brain Stimulation: Is Early Deep Brain Stimulation Able to Modify the Natural Course of Parkinson's Disease?

Front Neurosci 2020 5;14:492. Epub 2020 Jun 5.

Movement Disorders and Neurostimulation, Department of Neurology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Deep brain stimulation (DBS) is an established therapy for the management of Parkinson's disease (PD). However, DBS is indicated as the disease progresses and motor complications derived from pharmacological therapy arise. Here, we evaluate the potential of DBS prior to levodopa (L-Dopa) in improving quality of life (QoL), challenging the state of the art for DBS therapy. We present data on clinical manifestation, decision finding during early indication to DBS, and trajectories after DBS. We further discuss current paradigms for DBS and hypothesize on possible mechanisms. Six patients, between 50 and 67 years old, presenting at least 5 years of PD symptoms, and without L-Dopa therapy initiation, received subthalamic nucleus (STN) DBS implantation. In the six PD cases, indication for DBS was not driven by motor complications, as supported by current guidelines, but by relevant QoL impairment and patient's reluctance to initiate L-Dopa treatment. All patients treated with STN-DBS prior to L-Dopa presented improvement in motor and non-motor symptoms and significant QoL improvement. All patients reduced the intake of dopamine agonists, and five are currently free from L-Dopa medication, with no reported adverse events. We introduce a multicenter observational study to investigate whether early DBS treatment may affect the natural course of PD. Early application of DBS instead of L-Dopa administration could have a pathophysiological basis and be prompted by a significant incline on QoL through disease progression; however, the clinical value of this proposed paradigm shift should be addressed in clinical trials aimed at modulating the natural course of PD.
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http://dx.doi.org/10.3389/fnins.2020.00492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292013PMC
June 2020

Myelination- and immune-mediated MR-based brain network correlates.

J Neuroinflammation 2020 Jun 12;17(1):186. Epub 2020 Jun 12.

Department of Neurology with Institute of Translational Neurology, Münster University Hospital, Münster, Germany.

Background: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by inflammatory and neurodegenerative processes. Despite demyelination being a hallmark of the disease, how it relates to neurodegeneration has still not been completely unraveled, and research is still ongoing into how these processes can be tracked non-invasively. Magnetic resonance imaging (MRI) derived brain network characteristics, which closely mirror disease processes and relate to functional impairment, recently became important variables for characterizing immune-mediated neurodegeneration; however, their histopathological basis remains unclear.

Methods: In order to determine the MRI-derived correlates of myelin dynamics and to test if brain network characteristics derived from diffusion tensor imaging reflect microstructural tissue reorganization, we took advantage of the cuprizone model of general demyelination in mice and performed longitudinal histological and imaging analyses with behavioral tests. By introducing cuprizone into the diet, we induced targeted and consistent demyelination of oligodendrocytes, over a period of 5 weeks. Subsequent myelin synthesis was enabled by reintroduction of normal food.

Results: Using specific immune-histological markers, we demonstrated that 2 weeks of cuprizone diet induced a 52% reduction of myelin content in the corpus callosum (CC) and a 35% reduction in the neocortex. An extended cuprizone diet increased myelin loss in the CC, while remyelination commenced in the neocortex. These histologically determined dynamics were reflected by MRI measurements from diffusion tensor imaging. Demyelination was associated with decreased fractional anisotropy (FA) values and increased modularity and clustering at the network level. MRI-derived modularization of the brain network and FA reduction in key anatomical regions, including the hippocampus, thalamus, and analyzed cortical areas, were closely related to impaired memory function and anxiety-like behavior.

Conclusion: Network-specific remyelination, shown by histology and MRI metrics, determined amelioration of functional performance and neuropsychiatric symptoms. Taken together, we illustrate the histological basis for the MRI-driven network responses to demyelination, where increased modularity leads to evolving damage and abnormal behavior in MS. Quantitative information about in vivo myelination processes is mirrored by diffusion-based imaging of microstructural integrity and network characteristics.
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http://dx.doi.org/10.1186/s12974-020-01827-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293122PMC
June 2020

Clinical implications of serum neurofilament in newly diagnosed MS patients: A longitudinal multicentre cohort study.

EBioMedicine 2020 Jun 24;56:102807. Epub 2020 May 24.

Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.

Background: We aim to evaluate serum neurofilament light chain (sNfL), indicating neuroaxonal damage, as a biomarker at diagnosis in a large cohort of early multiple sclerosis (MS) patients.

Methods: In a multicentre prospective longitudinal observational cohort, patients with newly diagnosed relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) were recruited between August 2010 and November 2015 in 22 centers. Clinical parameters, MRI, and sNfL levels (measured by single molecule array) were assessed at baseline and up to four-year follow-up.

Findings: Of 814 patients, 54.7% (445) were diagnosed with RRMS and 45.3% (369) with CIS when applying 2010 McDonald criteria (RRMS[2010] and CIS[2010]). After reclassification of CIS[2010] patients with existing CSF analysis, according to 2017 criteria, sNfL levels were lower in CIS[2017] than RRMS[2017] patients (9.1 pg/ml, IQR 6.2-13.7 pg/ml, n = 45; 10.8 pg/ml, IQR 7.4-20.1 pg/ml, n = 213; p = 0.036). sNfL levels correlated with number of T2 and Gd+ lesions at baseline and future clinical relapses. Patients receiving disease-modifying therapy (DMT) during the first four years had higher baseline sNfL levels than DMT-naïve patients (11.8 pg/ml, IQR 7.5-20.7 pg/ml, n = 726; 9.7 pg/ml, IQR 6.4-15.3 pg/ml, n = 88). Therapy escalation decisions within this period were reflected by longitudinal changes in sNfL levels.

Interpretation: Assessment of sNfL increases diagnostic accuracy, is associated with disease course prognosis and may, particularly when measured longitudinally, facilitate therapeutic decisions.

Funding: Supported the German Federal Ministry for Education and Research, the German Research Council, and Hertie-Stiftung.
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http://dx.doi.org/10.1016/j.ebiom.2020.102807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251380PMC
June 2020

Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis.

J Neurol Neurosurg Psychiatry 2020 07 5;91(7):681-686. Epub 2020 May 5.

Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany

Objective: To determine the prevalence of antibodies to Epstein-Barr virus (EBV) in a large cohort of patients with early multiple sclerosis (MS).

Methods: Serum samples were collected from 901 patients with a clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS) participating in the German National MS cohort, a prospective cohort of patients with early MS with stringent inclusion criteria. Epstein-Barr nuclear antigen (EBNA)-1 and viral capsid antigen (VCA) antibodies were measured in diluted sera by chemiluminescence immunoassays (CLIAs). Sera of EBNA-1 and VCA antibody-negative patients were retested undiluted by an EBV IgG immunoblot. For comparison, we retrospectively analysed the EBV seroprevalence across different age cohorts, ranging from 0 to >80 years, in a large hospital population (N=16 163) from Berlin/Northern Germany.

Results: EBNA-1 antibodies were detected by CLIA in 839 of 901 patients with CIS/RRMS. Of the 62 patients without EBNA-1 antibodies, 45 had antibodies to VCA as detected by CLIA. In all of the remaining 17 patients, antibodies to EBV were detected by immunoblot. Altogether, 901 of 901 (100%) patients with CIS/RRMS were EBV-seropositive. EBV seropositivity increased with age in the hospital population but did not reach 100% in any of the investigated age cohorts.

Conclusion: The complete EBV seropositivity in this large cohort of patients with early MS strengthens the evidence for a role of EBV in MS. It also suggests that a negative EBV serology in patients with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS.
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http://dx.doi.org/10.1136/jnnp-2020-322941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361012PMC
July 2020

Is ε4 associated with cognitive performance in early MS?

Neurol Neuroimmunol Neuroinflamm 2020 07 1;7(4). Epub 2020 May 1.

From the Department of Neurology and Focus Program Translational Neuroscience (FTN) (S.E., C.G., M.M., S.B., S.G., F.Z., C.M.L., F.L.), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Germany; Department of Neurology (A.S.), Inselspital, Bern University Hospital, University of Bern, Switzerland; Department of Neurology (A.S., B.A., R.G.), St. Josef-Hospital, Ruhr-University Bochum; Institute of Medical Biostatistics (G.T.), Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz; Department of Neurology (A. Bayas), Klinikum Augsburg; Department of Neurology (A. Berthele, B.H.), Klinikum rechts der Isar, Technical University of Munich; Institut für Neuroimmunologie und Multiple Sklerose (C.H.), Universitätsklinikum Hamburg-Eppendorf; Clinic of Neurology (L.K., S.G.M., H.W.), University Hospital Münster, Westphalian-Wilhelms-University Münster; Institute of Clinical Neuroimmunology (T.K.), Ludwig Maximilian University of Munich; Department of Neurology (R.A.L.), University Hospital Erlangen; NeuroCure Clinical Research Center and Experimental and Clinical Research Center (F.P.), Charité - Universitätsmedizin Berlin and Max Delbrueck Center for Molecular Medicine; Department of Neurology (M.S.), Hannover Medical School; Department of Neurology (B.T.), Philipps-University Marburg; Department of Neurology (F.T.B.), University of Leipzig; Department of Neurology (H.T.), University of Ulm; Clinic of Neurology Dietenbronn (H.T.), Schwendi; Neurology (F.W.), Max-Planck-Institute of Psychiatry, Munich; Neurological Clinic (F.W.), Sana Kliniken des Landkreises Cham; Department of Neurology (B.W.), University of Heidelberg; Department. of Neurology (U.K.Z.), University of Rostock; Central Information Office (CIO) (G.A.), Philipps-University Marburg; and Genetic and Molecular Epidemiology Group (C.M.L.), Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Germany.

Objective: To assess the impact of polymorphisms on cognitive performance in patients newly diagnosed with clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS).

Methods: This multicenter cohort study included 552 untreated patients recently diagnosed with CIS or RRMS according to the 2005 revised McDonald criteria. The single nucleotide polymorphisms rs429358 (ε4) and rs7412 (ε2) of the haplotype were assessed by allelic discrimination assays Cognitive performance was evaluated using the 3-second paced auditory serial addition test and the Multiple Sclerosis Inventory Cognition (MUSIC). Sum scores were calculated to approximate the overall cognitive performance and memory-centered cognitive functions. The impact of the carrier status on cognitive performance was assessed using multiple linear regression models, also including demographic, clinical, MRI, and lifestyle factors.

Results: ε4 homozygosity was associated with lower overall cognitive performance, whereas no relevant association was observed for ε4 heterozygosity or ε2 carrier status. Furthermore, higher disability levels, MRI lesion load, and depressive symptoms were associated with lower cognitive performance. Patients consuming alcohol had higher test scores than patients not consuming alcohol. Female sex, lower disability, and alcohol consumption were associated with better performance in the memory-centered subtests of MUSIC, whereas no relevant association was observed for carrier status.

Conclusion: Along with parameters of a higher disease burden, ε4 homozygosity was identified as a potential predictor of cognitive performance in this large cohort of patients with CIS and early RRMS.
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http://dx.doi.org/10.1212/NXI.0000000000000728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217661PMC
July 2020

Gray matter network reorganization in multiple sclerosis from 7-Tesla and 3-Tesla MRI data.

Ann Clin Transl Neurol 2020 04 7;7(4):543-553. Epub 2020 Apr 7.

Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Objective: The objective of this study was to determine the ability of 7T-MRI for characterizing brain tissue integrity in early relapsing-remitting MS patients compared to conventional 3T-MRI and to investigate whether 7T-MRI improves the performance for detecting cortical gray matter neurodegeneration and its associated network reorganization dynamics.

Methods: Seven early relapsing-remitting MS patients and seven healthy individuals received MRI at 7T and 3T, whereas 30 and 40 healthy controls underwent separate 3T- and 7T-MRI sessions, respectively. Surface-based cortical thickness (CT) and gray-to-white contrast (GWc) measures were used to model morphometric networks, analyzed with graph theory by means of modularity, clustering coefficient, path length, and small-worldness.

Results: 7T-MRI had lower CT and higher GWc compared to 3T-MRI in MS. CT and GWc measures robustly differentiated MS from controls at 3T-MRI. 7T- and 3T-MRI showed high regional correspondence for CT (r = 0.72, P = 2e-78) and GWc (r = 0.83, P = 5.5e-121) in MS patients. MS CT and GWc morphometric networks at 7T-MRI showed higher modularity, clustering coefficient, and small-worldness than 3T, also compared to controls.

Interpretation: 7T-MRI allows to more precisely quantify morphometric alterations across the cortical mantle and captures more sensitively MS-related network reorganization. Our findings open new avenues to design more accurate studies quantifying brain tissue loss and test treatment effects on tissue repair.
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http://dx.doi.org/10.1002/acn3.51029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187719PMC
April 2020
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