Publications by authors named "Gereon R Fink"

510 Publications

Diagnosis of pseudoprogression following lomustine-temozolomide chemoradiation in newly diagnosed glioblastoma patients using FET PET.

Clin Cancer Res 2021 May 4. Epub 2021 May 4.

Dept. of Neurology, University Hospital Cologne.

Background: The CeTeG/NOA-09 phase-III trial demonstrated a significant survival benefit of lomustine-temozolomide chemoradiation in newly diagnosed glioblastoma patients with methylated O6-methylguanine-DNA methyltransferase promoter. Following lomustine-temozolomide chemoradiation, late and prolonged pseudoprogression may occur. We here evaluated the value of amino acid PET using O-(2-[18F]fluoroethyl)-L-tyrosine (FET) for differentiating pseudoprogression from tumor progression.

Methods: We retrospectively identified patients (i) who were treated off-study according to the CeTeG/NOA-09 protocol, (ii) had equivocal MRI findings after radiotherapy, and (iii) underwent additional FET-PET imaging for diagnostic evaluation (number of scans, 1-3). Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) and dynamic FET uptake parameters (e.g., time-to-peak) were calculated. In patients with more than one FET-PET scan, relative changes of TBR values were evaluated, i.e., an increase or decrease of >10% compared to the reference scan was considered as tumor progression or pseudoprogression. Diagnostic performances were evaluated using receiver operating characteristic curve analyses and Fisher's exact test. Diagnoses were confirmed histologically or clinicoradiologically.

Results: We identified 23 patients with 32 FET-PET scans. Within 5-25 weeks after radiotherapy (median time, 9 weeks), pseudoprogression occurred in 11 patients (48%). The parameter TBRmean calculated from the FET-PET performed 10{plus minus}7 days after the equivocal MRI showed the highest accuracy (87%) to identify pseudoprogression (threshold, <1.95; P=0.029). The integration of relative changes of TBRmean further improved the accuracy (91%; P<0.001). Moreover, the combination of static and dynamic parameters increased the specificity to 100% (P=0.005).

Conclusions: The data suggest that FET-PET parameters are of significant clinical value to diagnose pseudoprogression related to lomustine-temozolomide chemoradiation.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0471DOI Listing
May 2021

Hand preference for the visual and auditory modalities in humans.

Sci Rep 2021 Apr 12;11(1):7868. Epub 2021 Apr 12.

Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Centre Jülich, Wilhelm-Johnen-Str., 52428, Jülich, Germany.

The sensory dominance effect refers to the phenomenon that one sensory modality more frequently receives preferential processing (and eventually dominates consciousness and behavior) over and above other modalities. On the other hand, hand dominance is an innate aspect of the human motor system. To investigate how the sensory dominance effect interacts with hand dominance, we applied the adapted Colavita paradigm and recruited a large cohort of healthy right-handed participants (n = 119). While the visual dominance effect in bimodal trials was observed for the whole group (n = 119), about half of the right-handers (48%) showed a visual preference, i.e., their dominant hand effect manifested in responding to the visual stimuli. By contrast, 39% of the right-handers exhibited an auditory preference, i.e., the dominant hand effect occurred for the auditory responses. The remaining participants (13%) did not show any dominant hand preference for either visual or auditory responses. For the first time, the current behavioral data revealed that human beings possess a characteristic and persistent preferential link between different sensory modalities and the dominant vs. non-dominant hand. Whenever this preferential link between the sensory and the motor system was adopted, one dominance effect peaks upon the other dominance effect's best performance.
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http://dx.doi.org/10.1038/s41598-021-87396-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041834PMC
April 2021

Uncovering an Optic Nerve Sheath Meningioma Using 68Ga-DOTATATE PET/CT.

Clin Nucl Med 2021 Apr 5. Epub 2021 Apr 5.

From the Departments of Neurology Diagnostic and Interventional Radiology Nuclear Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne Institute of Neuroscience and Medicine, Research Center Juelich, Juelich Center for Integrated Oncology, Universities of Aachen, Bonn, Cologne, and Düsseldorf, Cologne, Germany.

Abstract: A 56-year-old woman was initially diagnosed with optic neuritis. However, several "red flags" were present: older age at presentation, no multiple sclerosis suspicious findings on MRI, and negative oligoclonal bands. 68Ga-DOTATATE PET/CT confirmed the differential diagnosis of an optic sheath meningioma. Our case stresses the value of the somatostatin receptor ligand PET/CT in patients with suspected optic neuritis if the diagnostic workup does not support immune-mediated pathogenesis.
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http://dx.doi.org/10.1097/RLU.0000000000003619DOI Listing
April 2021

[Neuromuscular complications of SARS-CoV-2 infection-Part 2: muscle disorders].

Nervenarzt 2021 Mar 29. Epub 2021 Mar 29.

Klinik und Poliklinik für Neurologie, Universitätsklinikum Köln, Kerpener Straße 62, 50937, Köln, Deutschland.

Apart from disorders and diseases of the peripheral nerves, symptoms and disorders of the musculature and the neuromuscular transmission have also been described in association with coronavirus disease 2019 (COVID-19). In the second part of our review we provide an overview about frequently reported symptoms, such as myalgia as well as defined disorders, such as rhabdomyolysis, myositis, myasthenia and intensive care unit (ICU)-acquired weakness, which have been described during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections or COVID-19.Furthermore, the criteria for a causality, such as association strength, plausibility, time course, and experimental evidence for a causal association that should be applied for the COVID-19-asssociated neuromuscular conditions described in the two parts of the review are discussed. At present, in addition to anosmia, which is also known in the lay press, myalgia in particular as a nonspecific symptom are frequent sequelae of a symptomatic SARS-CoV‑2 infection. Other neuromuscular complications seem to be principally plausible (considering the pathogenesis) but apparently rare consequences of a SARS-CoV‑2 infection. Prospective or cohort studies are necessary to confirm a causality and assess the risk.
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http://dx.doi.org/10.1007/s00115-021-01093-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005661PMC
March 2021

[Neuromuscular complications of SARS-CoV-2 infections-Part 1: peripheral nerves].

Nervenarzt 2021 Mar 26. Epub 2021 Mar 26.

Klinik und Poliklinik für Neurologie, Universitätsklinikum Köln, Kerpener Straße 62, 50937, Köln, Deutschland.

In recent months various disorders and diseases of the peripheral nerves (including cranial nerves) and the musculature have been described in association with the pulmonary disease coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the first part of our review the current knowledge about a potential association of a SARS-CoV‑2 infection with dysfunction and diseases of cranial and peripheral nerves is discussed. Anosmia, ageusia, motor cranial nerve involvement and Guillain-Barré syndrome (GBS) were described in a temporal association with a SARS-CoV‑2 infection. Several studies could show that anosmia and ageusia were frequent symptoms of a SARS-CoV‑2 infection. In contrast the failure of other cranial nerves has so far only been sporadically described. A number of case reports and case series indicate a causal association between a SARS-CoV‑2 infection and GBS but epidemiological evidence is still lacking.
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http://dx.doi.org/10.1007/s00115-021-01094-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994351PMC
March 2021

Post-COVID-19 encephalomyelitis.

Neurol Res Pract 2021 Mar 15;3(1):18. Epub 2021 Mar 15.

Department of Neurology, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany.

Since the outbreak of coronavirus disease 2019 (COVID-19), a growing number of cases of acute transverse myelitis associated with COVID-19 have been reported. Here, we present the case of a patient who developed sensory ataxia after COVID-19 with MR lesions suggestive for longitudinal myelitis and in the splenium of the corpus callosum. The patient was successfully treated with immunoadsorption.
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http://dx.doi.org/10.1186/s42466-021-00113-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957276PMC
March 2021

Evaluation of FET PET Radiomics Feature Repeatability in Glioma Patients.

Cancers (Basel) 2021 Feb 5;13(4). Epub 2021 Feb 5.

Research Center Juelich, Institute of Neuroscience and Medicine (INM-3, -4, -11), 52425 Juelich, Germany.

Amino acid PET using the tracer O-(2-[F]fluoroethyl)-L-tyrosine (FET) has attracted considerable interest in neurooncology. Furthermore, initial studies suggested the additional diagnostic value of FET PET radiomics in brain tumor patient management. However, the conclusiveness of radiomics models strongly depends on feature generalizability. We here evaluated the repeatability of feature-based FET PET radiomics. A test-retest analysis based on equivalent but statistically independent subsamples of FET PET images was performed in 50 newly diagnosed and histomolecularly characterized glioma patients. A total of 1,302 radiomics features were calculated from semi-automatically segmented tumor volumes-of-interest (VOIs). Furthermore, to investigate the influence of the spatial resolution of PET on repeatability, spherical VOIs of different sizes were positioned in the tumor and healthy brain tissue. Feature repeatability was assessed by calculating the intraclass correlation coefficient (ICC). To further investigate the influence of the isocitrate dehydrogenase (IDH) genotype on feature repeatability, a hierarchical cluster analysis was performed. For tumor VOIs, 73% of first-order features and 71% of features extracted from the gray level co-occurrence matrix showed high repeatability (ICC 95% confidence interval, 0.91-1.00). In the largest spherical tumor VOIs, 67% of features showed high repeatability, significantly decreasing towards smaller VOIs. The IDH genotype did not affect feature repeatability. Based on 297 repeatable features, two clusters were identified separating patients with IDH-wildtype glioma from those with an IDH mutation. Our results suggest that robust features can be obtained from routinely acquired FET PET scans, which are valuable for further standardization of radiomics analyses in neurooncology.
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http://dx.doi.org/10.3390/cancers13040647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915742PMC
February 2021

Developmental Differences in Probabilistic Reversal Learning: A Computational Modeling Approach.

Front Neurosci 2020 18;14:536596. Epub 2021 Jan 18.

Translational Brain Research in Psychiatry and Neurology, Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, University Hospital Aachen, Aachen, Germany.

Cognitive flexibility helps us to navigate through our ever-changing environment and has often been examined by reversal learning paradigms. Performance in reversal learning can be modeled using computational modeling which allows for the specification of biologically plausible models to infer psychological mechanisms. Although such models are increasingly used in cognitive neuroscience, developmental approaches are still scarce. Additionally, though most reversal learning paradigms have a comparable design regarding timing and feedback contingencies, the type of feedback differs substantially between studies. The present study used hierarchical Gaussian filter modeling to investigate cognitive flexibility in reversal learning in children and adolescents and the effect of various feedback types. The results demonstrate that children make more overall errors and regressive errors (when a previously learned response rule is chosen instead of the new correct response after the initial shift to the new correct target), but less perseverative errors (when a previously learned response set continues to be used despite a reversal) adolescents. Analyses of the extracted model parameters of the winning model revealed that children seem to use new and conflicting information less readily than adolescents to update their stimulus-reward associations. Furthermore, more subclinical rigidity in everyday life (parent-ratings) is related to less explorative choice behavior during the probabilistic reversal learning task. Taken together, this study provides first-time data on the development of the underlying processes of cognitive flexibility using computational modeling.
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http://dx.doi.org/10.3389/fnins.2020.536596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848134PMC
January 2021

Feature-based PET/MRI radiomics in patients with brain tumors.

Neurooncol Adv 2020 Dec 23;2(Suppl 4):iv15-iv21. Epub 2021 Jan 23.

Institute of Neuroscience and Medicine (INM-3, -4, -11), Research Center Juelich, Juelich, Germany.

Radiomics allows the extraction of quantitative features from medical images such as CT, MRI, or PET, thereby providing additional, potentially relevant diagnostic information for clinical decision-making. Because the computation of these features is performed highly automated on medical images acquired during routine follow-up, radiomics offers this information at low cost. Further, the radiomics features can be used alone or combined with other clinical or histomolecular parameters to generate predictive or prognostic mathematical models. These models can then be applied for various important diagnostic indications in neuro-oncology, for example, to noninvasively predict relevant biomarkers in glioma patients, to differentiate between treatment-related changes and local brain tumor relapse, or to predict treatment response. In recent years, amino acid PET has become an important diagnostic tool in patients with brain tumors. Therefore, the number of studies in patients with brain tumors investigating the potential of PET radiomics or combined PET/MRI radiomics is steadily increasing. This review summarizes current research regarding feature-based PET as well as combined PET/MRI radiomics in neuro-oncology.
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http://dx.doi.org/10.1093/noajnl/vdaa118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829472PMC
December 2020

Nerve conductions studies in experimental models of autoimmune neuritis: A meta-analysis and guideline.

J Neuroimmunol 2021 Mar 28;352:577470. Epub 2020 Dec 28.

Department of Neurology, Faculty of Medicine, University of Cologne and University Hospital Cologne, Cologne, Germany. Electronic address:

Nerve conduction studies (NCS) are essential to assess peripheral nerve fiber function in research models of immune-mediated neuritis. However, the current lack of standard protocols and reference values impedes data comparability across models and studies. We performed a systematic review and subsequent meta-analysis of the last 30 years of NCS of immune-mediated neuritis in Lewis-rats. Twenty-six papers met the inclusion criteria for meta-analysis. Extracted data showed considerable heterogeneity of recorded nerve conduction velocity (NCV) and compound muscle action potential (CMAP). Studies also significantly differed in terms of technical, methodical, and data reporting issues. The heterogeneity of the underlying studies emphasizes the need for standardization when conducting and reporting NCS in rats. We provide normative values for NCS of the sciatic nerve of Lewis rats and propose seven items that should be addressed when NCS are performed when studying immune paradigms in Lewis rats.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577470DOI Listing
March 2021

Selecting the Most Effective DBS Contact in Essential Tremor Patients Based on Individual Tractography.

Brain Sci 2020 Dec 20;10(12). Epub 2020 Dec 20.

Faculty of Medicine and University Hospital Cologne, Department of Neurology, University of Cologne, 50923 Köln, Germany.

Postoperative choice of the most effective deep brain stimulation (DBS) contact in patients with essential tremor (ET) so far relies on lengthy clinical testing. Previous studies showed that the postoperative effectiveness of DBS contacts depends on the distance to the dentatorubrothalamic tract (DRTT). Here, we investigated whether the most effective DBS contact could be determined from calculating stimulation overlap with the individual DRTT. Seven ET patients with bilateral thalamic deep brain stimulation were included retrospectively. Tremor control was assessed for each contact during test stimulation with 2mA. Individual DRTTs were identified from diffusion tensor imaging and contacts were ranked by their stimulation overlap with the respective DRTT in relation to their clinical effectiveness. A linear mixed-effects model was calculated to determine the influence of the DRTT overlap on tremor control. In 92.9% of investigated DBS leads, the contact with the best clinical effect was the contact with the highest or second-highest DRTT-overlap. At the group level, the DRTT-overlap explained 26.7% of the variance in the clinical outcomes ( < 0.001). Our data suggest that the overlap with the DRTT based on individual tractography may serve as a marker to determine the most effective DBS contact in ET patients and reduce burdensome clinical testing in the future.
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http://dx.doi.org/10.3390/brainsci10121015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766799PMC
December 2020

Combined cognitive and motor training improves the outcome in the early phase after stroke and prevents a decline of executive functions: A pilot study.

NeuroRehabilitation 2021 ;48(1):97-108

Medical Faculty and University Hospital Cologne, Department of Neurology, Kerpener Str. 62, Cologne, Germany.

Background: The negative impact of cognitive dysfunction on motor rehabilitation as a relearning-process is well known in stroke patients. However, evidence for combined cognitive and motor training (CMT) is lacking.

Objective: To evaluate the effects of combined CMT in early stroke rehabilitation.

Methods: In a controlled pilot study, 29 moderately affected stroke patients with low-level motor performance and cognitive impairment received motor therapy plus either cognitive (experimental group, EG) or low-frequency ergometer training (control group, CG) for eight days.

Results: Both groups improved their motor functioning significantly. After training, between-group comparison revealed significant differences for cognitive flexibility and trends for set-shifting, working memory, and reaction control in favor of the EG. Within-group effects showed improvement across all cognitive domains in the EG, which correlated with gains in bed-mobility, while the CG showed no significant improvement in cognition. Rather, a trend towards reaction control decline was observed, which correlated with less functional progression and recovery. Furthermore, a decline in cognitive flexibility, set-shifting, and working memory was descriptively observed.

Conclusions: Combined CMT may enhance cognition and motor relearning early after stroke and is superior to single motor training. Further studies are needed to replicate these results and investigate long-term benefits.
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http://dx.doi.org/10.3233/NRE-201583DOI Listing
April 2021

FET PET Radiomics for Differentiating Pseudoprogression from Early Tumor Progression in Glioma Patients Post-Chemoradiation.

Cancers (Basel) 2020 Dec 18;12(12). Epub 2020 Dec 18.

Institute of Neuroscience and Medicine (INM-3, -4, -11), Research Center Juelich, 52425 Juelich, Germany.

Currently, a reliable diagnostic test for differentiating pseudoprogression from early tumor progression is lacking. We explored the potential of O-(2-[F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) radiomics for this clinically important task. Thirty-four patients (isocitrate dehydrogenase (IDH)-wildtype glioblastoma, 94%) with progressive magnetic resonance imaging (MRI) changes according to the Response Assessment in Neuro-Oncology (RANO) criteria within the first 12 weeks after completing temozolomide chemoradiation underwent a dynamic FET PET scan. Static and dynamic FET PET parameters were calculated. For radiomics analysis, the number of datasets was increased to 102 using data augmentation. After randomly assigning patients to a training and test dataset, 944 features were calculated on unfiltered and filtered images. The number of features for model generation was limited to four to avoid data overfitting. Eighteen patients were diagnosed with early tumor progression, and 16 patients had pseudoprogression. The FET PET radiomics model correctly diagnosed pseudoprogression in all test cohort patients (sensitivity, 100%; negative predictive value, 100%). In contrast, the diagnostic performance of the best FET PET parameter (TBR) was lower (sensitivity, 81%; negative predictive value, 80%). The results suggest that FET PET radiomics helps diagnose patients with pseudoprogression with a high diagnostic performance. Given the clinical significance, further studies are warranted.
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http://dx.doi.org/10.3390/cancers12123835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766151PMC
December 2020

Diagnosis of peripheral neuropathy.

Neurol Res Pract 2020 15;2:20. Epub 2020 Jul 15.

Department of Neurology, University of Würzburg, Würzburg, Germany.

Introduction: Peripheral neuropathy represents a spectrum of diseases with different etiologies. The most common causes are diabetes, exposure to toxic substances including alcohol and chemotherapeutics, immune-mediated conditions, and gene mutations. A thorough workup including clinical history and examination, nerve conduction studies, and comprehensive laboratory tests is warranted to identify treatable causes.

First Steps: The variability of symptoms allows distinguishing characteristic clinical phenotypes of peripheral neuropathy that should be recognized in order to stratify the diagnostic workup accordingly. Nerve conduction studies are essential to determine the phenotype (axonal versus demyelinating) and severity. Laboratory tests, including genetic testing, CSF examination, nerve imaging, and nerve biopsy, represent additional clinical tests that can be useful in specific clinical scenarios.

Comments: We propose a flow chart based on five common basic clinical patterns of peripheral neuropathy. Based on these five clinical phenotypes, we suggest differential diagnostic pathways in order to establish the underlying cause.

Conclusions: The recognition of characteristic clinical phenotypes combined with nerve conduction studies allows pursuing subsequent diagnostic pathways that incorporate nerve conduction studies and additional diagnostic tests. This two-tiered approach promises higher yield and better cost-effectiveness in the diagnostic workup in patients with peripheral neuropathy.
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http://dx.doi.org/10.1186/s42466-020-00064-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650053PMC
July 2020

Recovery from stroke: current concepts and future perspectives.

Neurol Res Pract 2020 16;2:17. Epub 2020 Jun 16.

Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Centre Jülich, 52425 Jülich, Germany.

Stroke is a leading cause of acquired, permanent disability worldwide. Although the treatment of acute stroke has been improved considerably, the majority of patients to date are left disabled with a considerable impact on functional independence and quality of life. As the absolute number of stroke survivors is likely to further increase due to the demographic changes in our aging societies, new strategies are needed in order to improve neurorehabilitation. The most critical driver of functional recovery post-stroke is neural reorganization. For developing novel, neurobiologically informed strategies to promote recovery of function, an improved understanding of the mechanisms enabling plasticity and recovery is mandatory. This review provides a comprehensive survey of recent developments in the field of stroke recovery using neuroimaging and non-invasive brain stimulation. We discuss current concepts of how the brain reorganizes its functional architecture to overcome stroke-induced deficits, and also present evidence for maladaptive effects interfering with recovery. We demonstrate that the combination of neuroimaging and neurostimulation techniques allows a better understanding of how brain plasticity can be modulated to promote the reorganization of neural networks. Finally, neurotechnology-based treatment strategies allowing patient-tailored interventions to achieve enhanced treatment responses are discussed. The review also highlights important limitations of current models, and finally closes with possible solutions and future directions.
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http://dx.doi.org/10.1186/s42466-020-00060-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650109PMC
June 2020

Verum versus sham tDCS in the treatment of stroke-induced apraxia: study protocol of the randomized controlled trial RAdiCS -"Rehabilitating (stroke-induced) Apraxia with direct Current Stimulation".

Neurol Res Pract 2020 4;2. Epub 2020 Mar 4.

Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Introduction: Stroke is the leading cause of acquired disability in western societies. (Motor) cognitive deficits like apraxia significantly contribute to disability after stroke, harming activities of daily living and rehabilitation outcome. To date, efficient therapeutic options for apraxia remain sparse. Thus, randomized controlled trials (RCTs) are warranted.

Methods: Based on promising results of a pilot study, the on-going RAdiCS (ehabilitating stroke-induced praxia with rect urrent timulation) study is a randomized controlled trial, which follows a double-blinded (investigator and patient), two-arm parallel interventional model. It is designed to include 110 apraxic patients (as diagnosed by the Cologne Apraxia Screening, KAS) in the subacute phase after a left hemisphere (LH) stroke. The University of Cologne initiated the trial, which is conducted in two German Neurorehabilitation Centers.The study aims to evaluate the effect of anodal (versus sham) transcranial direct current stimulation (tDCS) applied over the left posterior parietal cortex (PPC) with an intensity of 2 mA for 10 min on five consecutive days on apraxic deficits. In addition to anodal or sham tDCS, all LH stroke patients undergo a motor (cognitive) training that is performed before and after the stimulation (off-line stimulation).The primary outcome measure is the (differential) change in the overall KAS score after five daily sessions of anodal versus sham tDCS when compared to the baseline assessment before tDCS. Secondary study outcomes include further apraxia scores, aphasia severity, and measures of motor performance and disability after stroke. All outcome measures are obtained in the post-stimulation assessment as well as during follow-up (3-4 months after tDCS).

Perspective: The RCT RAdiCS shall evaluate in a large number of LH stroke patients whether anodal tDCS (compared to sham tDCS) expedites the rehabilitation of apraxia - over and above additional motor (cognitive) training and standard care. A positive study outcome would provide a new strategy for the treatment of apraxia, which hopefully ameliorates the negative impact of apraxia on daily living and long-term outcome.

Trial Registration: Clinical Trials Gov: NCT03185234, registered 14 June 2017 ; Deutsches Register für Klinische Studien: DRKS00012292, registered 01 June 2017.

Trial Status: Participant enrollment began on 22 June 2017. The trial is expected to be completed on 30 June 2022.
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http://dx.doi.org/10.1186/s42466-020-0052-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650086PMC
March 2020

Anodal tDCS over left parietal cortex expedites recovery from stroke-induced apraxic imitation deficits: a pilot study.

Neurol Res Pract 2019 26;1:38. Epub 2019 Nov 26.

Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Background: To date, specific therapeutic approaches to expedite recovery from apraxic deficits after left hemisphere (LH) stroke remain sparse. Thus, in this pilot study we evaluated the effect of anodal transcranial direct current stimulation (tDCS) in addition to a standardized motor training on apraxic imitation deficits.

Methods: In a rehabilitation hospital, we assessed apraxic, aphasic, and motor deficits in 30 LH stroke patients before and after a five-day standard programme of motor training combined with either anodal (10 min, 2 mA;  = 14) or sham (10 min, 0 mA,  = 16) tDCS applied in a double-blind fashion over left posterior parietal cortex (PPC). Where appropriate, data were analyzed with either t-test, Fisher's exact test, or univariate/ repeated measures ANOVA.

Results: Compared to sham tDCS, five sessions of anodal tDCS expedited recovery from apraxic imitation deficits ( < 0.05): Already after 5 days, the anodal tDCS group showed levels of imitation performance that were achieved in the sham tDCS group after 3 months. However, the primary outcome of the study (i.e., anodal tDCS induced improvement of the total apraxia score) failed significance, and there was no significant tDCS effect on apraxia after 3 months. Anodal tDCS improved grip force (of the contra-lesional, i.e., right hand), but had no effect on aphasia.

Conclusions: Data from this pilot study show that repetitive, anodal tDCS over left PPC combined with a standardized motor training expedites recovery from imitation deficits in LH stroke patients with apraxia (relative to sham stimulation). Results suggest that in patients suffering from apraxic imitation deficits a randomized controlled trial (RCT) is warranted that investigates the effects of tDCS applied over PPC in addition to a standardized motor training.
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http://dx.doi.org/10.1186/s42466-019-0042-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650120PMC
November 2019

Thalamic Deep Brain Stimulation in Essential Tremor Plus Is as Effective as in Essential Tremor.

Brain Sci 2020 Dec 11;10(12). Epub 2020 Dec 11.

Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.

The new essential tremor (ET) classification defined ET-plus (ET-p) as an ET subgroup with additional neurological signs besides action tremor. While deep brain stimulation (DBS) is effective in ET, there are no studies specifically addressing DBS effects in ET-p. 44 patients with medication-refractory ET and thalamic/subthalamic DBS implanted at our center were postoperatively classified into ET and ET-p according to preoperative documentation. Tremor suppression with DBS (stimulation ON vs. preoperative baseline and vs. stimulation OFF), measured via the Fahn-Tolosa-Marin tremor rating scale (TRS), stimulation parameters, and the location of active contacts were compared between patients classified as ET and ET-p. TRS scores at baseline were higher in ET-p. ET-p patients showed comparable tremor reduction as patients with ET, albeit higher stimulation parameters were needed in ET-p. Active electrode contacts were located more dorsally in ET-p of uncertain reason. Our data show that DBS is similarly effective in ET-p compared to ET. TRS scores were higher in ET-p preoperatively, and higher stimulation parameters were needed for tremor reduction compared to ET. The latter may be related to a more dorsal location of active electrode contacts in the ET-p group of this cohort. Prospective studies are warranted to investigate DBS in ET-p further.
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http://dx.doi.org/10.3390/brainsci10120970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763605PMC
December 2020

Stimulus transformation into motor action: Dynamic graph analysis reveals a posterior-to-anterior shift in brain network communication of older subjects.

Hum Brain Mapp 2021 Apr 11;42(5):1547-1563. Epub 2020 Dec 11.

Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Jülich, Germany.

Cognitive performance slows down with increasing age. This includes cognitive processes that are essential for the performance of a motor act, such as the slowing down in response to an external stimulus. The objective of this study was to identify aging-associated functional changes in the brain networks that are involved in the transformation of external stimuli into motor action. To investigate this topic, we employed dynamic graphs based on phase-locking of Electroencephalography signals recorded from healthy younger and older subjects while performing a simple visually-cued finger-tapping task. The network analysis yielded specific age-related network structures varying in time in the low frequencies (2-7 Hz), which are closely connected to stimulus processing, movement initiation and execution in both age groups. The networks in older subjects, however, contained several additional, particularly interhemispheric, connections and showed an overall increased coupling density. Cluster analyses revealed reduced variability of the subnetworks in older subjects, particularly during movement preparation. In younger subjects, occipital, parietal, sensorimotor and central regions were-temporally arranged in this order-heavily involved in hub nodes. Whereas in older subjects, a hub in frontal regions preceded the noticeably delayed occurrence of sensorimotor hubs, indicating different neural information processing in older subjects. All observed changes in brain network organization, which are based on neural synchronization in the low frequencies, provide a possible neural mechanism underlying previous fMRI data, which report an overactivation, especially in the prefrontal and pre-motor areas, associated with a loss of hemispheric lateralization in older subjects.
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http://dx.doi.org/10.1002/hbm.25313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927305PMC
April 2021

Control of response interference: caudate nucleus contributes to selective inhibition.

Sci Rep 2020 12 1;10(1):20977. Epub 2020 Dec 1.

Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Centre Juelich, Juelich, Germany.

While the role of cortical regions in cognitive control processes is well accepted, the contribution of subcortical structures (e.g., the striatum), especially to the control of response interference, remains controversial. Therefore, the present study aimed to investigate the cortical and particularly subcortical neural mechanisms of response interference control (including selective inhibition). Thirteen healthy young participants underwent event-related functional magnetic resonance imaging while performing a unimanual version of the Simon task. In this task, successful performance required the resolution of stimulus-response conflicts in incongruent trials by selectively inhibiting interfering response tendencies. The behavioral results show an asymmetrical Simon effect that was more pronounced in the contralateral hemifield. Contrasting incongruent trials with congruent trials (i.e., the overall Simon effect) significantly activated clusters in the right anterior cingulate cortex, the right posterior insula, and the caudate nucleus bilaterally. Furthermore, a region of interest analysis based on previous patient studies revealed that activation in the bilateral caudate nucleus significantly co-varied with a parameter of selective inhibition derived from distributional analyses of response times. Our results corroborate the notion that the cognitive control of response interference is supported by a fronto-striatal circuitry, with a functional contribution of the caudate nucleus to the selective inhibition of interfering response tendencies.
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http://dx.doi.org/10.1038/s41598-020-77744-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708449PMC
December 2020

Substrate Elasticity Exerts Functional Effects on Primary Microglia.

Front Cell Neurosci 2020 5;14:590500. Epub 2020 Nov 5.

Department of Neurology, Faculty of Medicine and University Hospital, The University of Cologne, Cologne, Germany.

Microglia-the brain's primary immune cells-exert a tightly regulated cascade of pro- and anti-inflammatory effects upon brain pathology, either promoting regeneration or neurodegeneration. Therefore, harnessing microglia emerges as a potential therapeutic concept in neurological research. Recent studies suggest that-besides being affected by chemokines and cytokines-various cell entities in the brain relevantly respond to the mechanical properties of their microenvironment. For example, we lately reported considerable effects of elasticity on neural stem cells, regarding quiescence and differentiation potential. However, the effects of elasticity on microglia remain to be explored.Under the hypothesis that the elasticity of the microenvironment affects key characteristics and functions of microglia, we established an model of primary rat microglia grown in a polydimethylsiloxane (PDMS) elastomer-based cell culture system. This way, we simulated the brain's physiological elasticity range and compared it to supraphysiological stiffer PDMS controls. We assessed functional parameters of microglia under "resting" conditions, as well as when polarized towards a pro-inflammatory phenotype (M1) by lipopolysaccharide (LPS), or an anti-inflammatory phenotype (M2) by interleukin-4 (IL-4). Microglia viability was unimpaired on soft substrates, but we found various significant effects with a more than two-fold increase in microglia proliferation on soft substrate elasticities mimicking the brain (relative to PDMS controls). Furthermore, soft substrates promoted the expression of the activation marker vimentin in microglia. Moreover, the M2-marker CD206 was upregulated in parallel to an increase in the secretion of Insulin-Like Growth Factor-1 (IGF-1). The upregulation of CD206 was abolished by blockage of stretch-dependent chloride channels. Our data suggest that the cultivation of microglia on substrates of brain-like elasticity promotes a basic anti-inflammatory activation state stretch-dependent chloride channels. The results highlight the significance of the omnipresent but mostly overlooked mechanobiological effects exerted on microglia and contribute to a better understanding of the complex spatial and temporal interactions between microglia, neural stem cells, and glia, in health and disease.
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http://dx.doi.org/10.3389/fncel.2020.590500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674555PMC
November 2020

Network Fingerprint of Stimulation-Induced Speech Impairment in Essential Tremor.

Ann Neurol 2021 02 26;89(2):315-326. Epub 2020 Nov 26.

Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Objective: This study was undertaken to gain insights into structural networks associated with stimulation-induced dysarthria (SID) and to predict stimulation-induced worsening of intelligibility in essential tremor patients with bilateral thalamic deep brain stimulation (DBS).

Methods: Monopolar reviews were conducted in 14 essential tremor patients. Testing included determination of SID thresholds, intelligibility ratings, and a fast syllable repetition task. Volumes of tissue activated (VTAs) were calculated to identify discriminative fibers for stimulation-induced worsening of intelligibility in a structural connectome. The resulting fiber-based atlas structure was then validated in a leave-one-out design.

Results: Fibers determined as discriminative for stimulation-induced worsening of intelligibility were mainly connected to the ipsilateral precentral gyrus as well as to both cerebellar hemispheres and the ipsilateral brain stem. In the thalamic area, they ran laterally to the thalamus and posteromedially to the subthalamic nucleus, in close proximity, mainly anterolaterally, to fibers beneficial for tremor control as published by Al-Fatly et al in 2019. The overlap of the respective clinical stimulation setting's VTAs with these fibers explained 62.4% (p < 0.001) of the variance of stimulation-induced change in intelligibility in a leave-one-out analysis.

Interpretation: This study demonstrates that SID in essential tremor patients is associated with both motor cortex and cerebellar connectivity. Furthermore, the identified fiber-based atlas structure might contribute to future postoperative programming strategies to achieve optimal tremor control without speech impairment in essential tremor patients with thalamic DBS. ANN NEUROL 2021;89:315-326.
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http://dx.doi.org/10.1002/ana.25958DOI Listing
February 2021

Graph Theory Analysis Reveals Resting-State Compensatory Mechanisms in Healthy Aging and Prodromal Alzheimer's Disease.

Front Aging Neurosci 2020 22;12:576627. Epub 2020 Oct 22.

Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Several theories of cognitive compensation have been suggested to explain sustained cognitive abilities in healthy brain aging and early neurodegenerative processes. The growing number of studies investigating various aspects of task-based compensation in these conditions is contrasted by the shortage of data about resting-state compensatory mechanisms. Using our proposed criterion-based framework for compensation, we investigated 45 participants in three groups: (i) patients with mild cognitive impairment (MCI) and positive biomarkers indicative of Alzheimer's disease (AD); (ii) cognitively normal young adults; (iii) cognitively normal older adults. To increase reliability, three sessions of resting-state functional magnetic resonance imaging for each participant were performed on different days (135 scans in total). To elucidate the dimensions and dynamics of resting-state compensatory mechanisms, we used graph theory analysis along with volumetric analysis. Graph theory analysis was applied based on the Brainnetome atlas, which provides a connectivity-based parcellation framework. Comprehensive neuropsychological examinations including the Rey Auditory Verbal Learning Test (RAVLT) and the Trail Making Test (TMT) were performed, to relate graph measures of compensatory nodes to cognition. To avoid false-positive findings, results were corrected for multiple comparisons. First, we observed an increase of degree centrality in cognition related brain regions of the middle frontal gyrus, precentral gyrus and superior parietal lobe despite local atrophy in MCI and healthy aging, indicating a resting-state connectivity increase with positive biomarkers. When relating the degree centrality measures to cognitive performance, we observed that greater connectivity led to better RAVLT and TMT scores in MCI and, hence, might constitute a compensatory mechanism. The detection and improved understanding of the compensatory dynamics in healthy aging and prodromal AD is mandatory for implementing and tailoring preventive interventions aiming at preserved overall cognitive functioning and delayed clinical onset of dementia.
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http://dx.doi.org/10.3389/fnagi.2020.576627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642892PMC
October 2020

Cortical reorganization after motor stroke: A pilot study on differences between the upper and lower limbs.

Hum Brain Mapp 2021 Mar 9;42(4):1013-1033. Epub 2020 Nov 9.

Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Stroke patients suffering from hemiparesis may show substantial recovery in the first months poststroke due to neural reorganization. While reorganization driving improvement of upper hand motor function has been frequently investigated, much less is known about the changes underlying recovery of lower limb function. We, therefore, investigated neural network dynamics giving rise to movements of both the hands and feet in 12 well-recovered left-hemispheric chronic stroke patients and 12 healthy participants using a functional magnetic resonance imaging sparse sampling design and dynamic causal modeling (DCM). We found that the level of neural activity underlying movements of the affected right hand and foot positively correlated with residual motor impairment, in both ipsilesional and contralesional premotor as well as left primary motor (M1) regions. Furthermore, M1 representations of the affected limb showed significantly stronger increase in BOLD activity compared to healthy controls and compared to the respective other limb. DCM revealed reduced endogenous connectivity of M1 of both limbs in patients compared to controls. However, when testing for the specific effect of movement on interregional connectivity, interhemispheric inhibition of the contralesional M1 during movements of the affected hand was not detected in patients whereas no differences in condition-dependent connectivity were found for foot movements compared to controls. In contrast, both groups featured positive interhemispheric M1 coupling, that is, facilitation of neural activity, mediating movements of the affected foot. These exploratory findings help to explain why functional recovery of the upper and lower limbs often develops differently after stroke, supporting limb-specific rehabilitative strategies.
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http://dx.doi.org/10.1002/hbm.25275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856649PMC
March 2021

Entorhinal Tau Predicts Hippocampal Activation and Memory Deficits in Alzheimer's Disease.

J Alzheimers Dis 2020 ;78(4):1601-1614

Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Jülich, Jülich, Germany.

Background: To date, it remains unclear how amyloid plaques and neurofibrillary tangles are related to neural activation and, consequently, cognition in Alzheimer's disease (AD). Recent findings indicate that tau accumulation may drive hippocampal hyperactivity in cognitively normal aging, but it remains to be elucidated how tau accumulation is related to neural activation in AD.

Objective: To determine whether the association between tau accumulation and hippocampal hyperactivation persists in mild cognitive impairment (MCI) and mild dementia or if the two measures dissociate with disease progression, we investigated the relationship between local tau deposits and memory-related neural activation in MCI and mild dementia due to AD.

Methods: Fifteen patients with MCI or mild dementia due to AD underwent a neuropsychological assessment and performed an item memory task during functional magnetic resonance imaging. Cerebral tau accumulation was assessed using positron emission tomography and [18F]-AV-1451.

Results: Entorhinal, but not global tau accumulation, was highly correlated with hippocampal activation due to visual item memory encoding and predicted memory loss over time. Neural activation in the posterior cingulate cortex and the fusiform gyrus was not significantly correlated with tau accumulation.

Conclusion: These findings extend previous observations in cognitively normal aging, demonstrating that entorhinal tau continues to be closely associated with hippocampal hyperactivity and memory performance in MCI and mild dementia due to AD. Furthermore, data suggest that this association is strongest in medial temporal lobe structures. In summary, our data provide novel insights into the relationship of tau accumulation to neural activation and memory in AD.
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http://dx.doi.org/10.3233/JAD-200835DOI Listing
January 2020

Early treatment response assessment using F-FET PET compared to contrast-enhanced MRI in glioma patients following adjuvant temozolomide chemotherapy.

J Nucl Med 2020 Nov 6. Epub 2020 Nov 6.

University Hospital Cologne, Germany.

The goal of this study was to compare the value of contrast-enhanced MRI and O-(2-[F]fluoroethyl)-L-tyrosine (F-FET) PET for response assessment in glioma patients following adjuvant temozolomide chemotherapy (TMZ). After biopsy or resection and completion of radiotherapy with concomitant TMZ, 41 newly diagnosed and histomolecularly characterized glioma patients (glioblastoma, 90%; age range, 20-79 years) were subsequently treated with adjuvant TMZ. MR and F-FET PET imaging were performed at baseline and after the second cycle of adjuvant TMZ. We obtained F-FET metabolic tumor volumes (MTV) as well as mean and maximum tumor-to-brain ratios (TBRmean, TBRmax). Threshold values of F-FET PET parameters to predict outcome were established by ROC analyses using a median progression-free survival (PFS) of ≥9 months and overall survival (OS) of ≥15 months as reference. MRI response assessment was based on RANO criteria. The predictive value of changes of F-FET PET and MRI parameters on survival was evaluated subsequently using univariate and multivariate survival estimates. After two cycles of adjuvant TMZ chemotherapy, a treatment-induced reduction of MTV and TBRmax predicted a significantly longer PFS and OS (both P ≤ 0.03; univariate survival analyses) while RANO criteria were not significant ( > 0.05). Multivariate survival analysis revealed that TBRmax changes predicted a prolonged PFS ( = 0.012) and changes of MTV a prolonged OS ( = 0.005) independent of O6-methylguanine-DNA-methyltransferase promoter methylation and other strong prognostic factors. Changes of F-FET PET parameters appear to be helpful for identifying responders to adjuvant TMZ early after treatment initiation.
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http://dx.doi.org/10.2967/jnumed.120.254243DOI Listing
November 2020

Identifying neurological comorbidities in obstructive sleep apnea patients through polysomnography.

Sleep Breath 2020 Oct 22. Epub 2020 Oct 22.

Intersom Köln, Center of Sleep Medicine and Sleep Research, Cologne, Germany.

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http://dx.doi.org/10.1007/s11325-020-02231-wDOI Listing
October 2020

Subthalamic Stimulation Improves Quality of Sleep in Parkinson Disease: A 36-Month Controlled Study.

J Parkinsons Dis 2021 ;11(1):323-335

Department of Neurology, University Hospital of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

Background: Sleep disturbances and neuropsychiatric symptoms are some of the most common nonmotor symptoms in Parkinson's disease (PD). The effect of subthalamic stimulation (STN-DBS) on these symptoms beyond a short-term follow-up is unclear.

Objective: To examine 36-month effects of bilateral STN-DBS on quality of sleep, depression, anxiety, and quality of life (QoL) compared to standard-of-care medical therapy (MED) in PD.

Methods: In this prospective, controlled, observational, propensity score matched, international multicenter study, we assessed sleep disturbances using the PDSleep Scale-1 (PDSS), QoL employing the PDQuestionnaire-8 (PDQ-8), motor disorder with the Scales for Outcomes in PD (SCOPA), anxiety and depression with the Hospital Anxiety and Depression Scale (HADS), and dopaminergic medication requirements (LEDD). Within-group longitudinal outcome changes were tested using Wilcoxon signed-rank and between-group longitudinal differences of change scores with Mann-Whitney U tests. Spearman correlations analyzed the relationships of outcome parameter changes at follow-up.

Results: Propensity score matching applied on 159 patients (STN-DBS n = 75, MED n = 84) resulted in 40 patients in each treatment group. At 36-month follow-up, STN-DBS led to significantly better PDSS and PDQ-8 change scores, which were significantly correlated. We observed no significant effects for HADS and no significant correlations between change scores in PDSS, HADS, and LEDD.

Conclusions: We report Class IIb evidence of beneficial effects of STN-DBS on quality of sleep at 36-month follow-up, which were associated with QoL improvement independent of depression and dopaminergic medication. Our study highlights the importance of sleep for assessments of DBS outcomes.
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http://dx.doi.org/10.3233/JPD-202278DOI Listing
January 2021

Beneficial nonmotor effects of subthalamic and pallidal neurostimulation in Parkinson's disease.

Brain Stimul 2020 Nov - Dec;13(6):1697-1705. Epub 2020 Oct 7.

University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology, Cologne, Germany; Department of Neurology, University Hospital Giessen and Marburg, Campus Marburg, Germany.

Background: Subthalamic (STN) and pallidal (GPi) deep brain stimulation (DBS) improve quality of life, motor, and nonmotor symptoms (NMS) in advanced Parkinson's disease (PD). However, few studies have compared their nonmotor effects.

Objective: To compare nonmotor effects of STN-DBS and GPi-DBS.

Methods: In this prospective, observational, multicenter study including 60 PD patients undergoing bilateral STN-DBS (n = 40) or GPi-DBS (n = 20), we examined PDQuestionnaire (PDQ), NMSScale (NMSS), Unified PD Rating Scale-activities of daily living, -motor impairment, -complications (UPDRS-II, -III, -IV), Hoehn&Yahr, Schwab&England Scale, and levodopa-equivalent daily dose (LEDD) preoperatively and at 6-month follow-up. Intra-group changes at follow-up were analyzed with Wilcoxon signed-rank or paired t-test, if parametric tests were applicable, and corrected for multiple comparisons. Inter-group differences were explored with Mann-Whitney-U/unpaired t-tests. Analyses were performed before and after propensity score matching which balanced out demographic and preoperative clinical characteristics. Strength of clinical changes was assessed with effect size.

Results: In both groups, PDQ, UPDRS-II, -IV, Schwab&England Scale, and NMSS improved significantly at follow-up. STN-DBS was significantly better for LEDD reduction, GPi-DBS for UPDRS-IV. While NMSS total score outcomes were similar, explorative NMSS domain analyses revealed distinct profiles: Both targets improved sleep/fatigue and mood/cognition, but only STN-DBS the miscellaneous (pain/olfaction) and attention/memory and only GPi-DBS cardiovascular and sexual function domains.

Conclusions: To our knowledge, this is the first study to report distinct patterns of beneficial nonmotor effects of STN-DBS and GPi-DBS in PD. This study highlights the importance of NMS assessments to tailor DBS target choices to patients' individual motor and nonmotor profiles.
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http://dx.doi.org/10.1016/j.brs.2020.09.019DOI Listing
April 2021

Introduction to spasticity and related mouse models.

Exp Neurol 2021 01 29;335:113491. Epub 2020 Sep 29.

University of Cologne, Faculty of Medicine, University Hospital Cologne, Department of Neurology, Cologne, Germany; Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Germany. Electronic address:

Although spasticity is one of the most common causes of motor disability worldwide, its precise definition and pathophysiology remain elusive, which to date renders its experimental targeting tricky. At least in part, this difficulty is caused by heterogeneous phenotypes of spasticity-causing neurological disorders, all causing spasticity by involving upper motor neurons. The most common clinical symptoms are a series of rapid muscle contractions (clonus), an increased muscle tone (hypertonia), and augmented tendon reflex activity (hyperreflexia). This muscle overactivity is due to disturbed inhibition of spinal reflexes following upper motor neuron dysfunction. Despite a range of physical and pharmacological therapies ameliorating the symptoms, their targeted application remains difficult. Therefore, to date, spasticity impacts rehabilitative therapy, and no therapy exists that reverses the pathology completely. In contrast to the incidence and importance of spasticity, only very little pre-clinical work in animal models exists, and this research is focused on the cat or the rat spastic tail model to decipher altered reflexes and excitability of the motor neurons in the spinal cord. Meanwhile, the characterization of spasticity in clinically more relevant mouse models of neurological disorders, such as stroke, remains understudied. Here, we provide a brief introduction into the clinical knowledge and therapy of spasticity and an in-depth review of pre-clinical studies of spasticity in mice including the current experimental challenges for clinical translation.
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http://dx.doi.org/10.1016/j.expneurol.2020.113491DOI Listing
January 2021