Publications by authors named "Florian Amtage"

35 Publications

The rostro-caudal gradient in the prefrontal cortex and its modulation by subthalamic deep brain stimulation in Parkinson's disease.

Sci Rep 2021 Jan 22;11(1):2138. Epub 2021 Jan 22.

Department of Neurology, Medical Center, University of Freiburg, Breisacher Str. 64, 79106, Freiburg, Germany.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) alleviates motor symptoms in Parkinson's disease (PD) but also affects the prefrontal cortex (PFC), potentially leading to cognitive side effects. The present study tested alterations within the rostro-caudal hierarchy of neural processing in the PFC induced by STN-DBS in PD. Granger-causality analyses of fast functional near-infrared spectroscopy (fNIRS) measurements were used to infer directed functional connectivity from intrinsic PFC activity in 24 PD patients treated with STN-DBS. Functional connectivity was assessed ON stimulation, in steady-state OFF stimulation and immediately after the stimulator was switched ON again. Results revealed that STN-DBS significantly enhanced the rostro-caudal hierarchical organization of the PFC in patients who had undergone implantation early in the course of the disease, whereas it attenuated the rostro-caudal hierarchy in late-implanted patients. Most crucially, this systematic network effect of STN-DBS was reproducible in the second ON stimulation measurement. Supplemental analyses demonstrated the significance of prefrontal networks for cognitive functions in patients and matched healthy controls. These findings show that the modulation of prefrontal functional networks by STN-DBS is dependent on the disease duration before DBS implantation and suggest a neurophysiological mechanism underlying the side effects on prefrontally-guided cognitive functions observed under STN-DBS.
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http://dx.doi.org/10.1038/s41598-021-81535-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822958PMC
January 2021

One Pass Thalamic and Subthalamic Stimulation for Patients with Tremor-Dominant Idiopathic Parkinson Syndrome (OPINION): Protocol for a Randomized, Active-Controlled, Double-Blinded Pilot Trial.

JMIR Res Protoc 2018 Jan 30;7(1):e36. Epub 2018 Jan 30.

Department of Stereotactic and Functional Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.

Background: Besides fluctuations, therapy refractory tremor is one of the main indications of deep brain stimulation (DBS) in patients with idiopathic Parkinson syndrome (IPS). Although thalamic DBS (ventral intermediate nucleus [Vim] of thalamus) has been shown to reduce tremor in 85-95% of patients, bradykinesia and rigidity often are not well controlled. The dentato-rubro-thalamic tract (DRT) that can directly be targeted with special diffusion tensor magnetic resonance imaging sequences has been shown as an efficient target for thalamic DBS. The subthalamic nucleus (STN) is typically chosen in younger patients as the target for dopamine-responsive motor symptoms. This study investigates a one-path thalamic (Vim/DRT) and subthalamic implantation of DBS electrodes and possibly a combined stimulation strategy for both target regions.

Objective: This study investigates a one path thalamic (Vim/DRT) and subthalamic implantation of DBS electrodes and a possibly combined stimulation strategy for both target regions.

Methods: This is a randomized, active-controlled, double-blinded (patient- and observer-blinded), monocentric trial with three treatments, three periods and six treatment sequences allocated according to a Williams design. Eighteen patients will undergo one-path thalamic (Vim/DRT) and STN implantation of DBS electrodes. After one month, a double-blinded and randomly-assigned stimulation of the thalamic target (Vim/DRT), the STN and a combined stimulation of both target regions will be performed for a period of three months each. The primary objective is to assess the quality of life obtained by the Parkinson's Disease Questionnaire (39 items) for each stimulation modality. Secondary objectives include tremor reduction (obtained by the Fahn-Tolosa-Marin tremor rating scale, video recordings, the Unified Parkinson's disease rating scale, and by tremor analysis), psychiatric assessment of patients, and to assess the safety of intervention.

Results: At the moment, the recruitment is stopped and 12 patients have been randomized and treated. A futility analysis is being carried out by means of a conditional power analysis.

Conclusions: The approach of the OPINION trial planned to make, for the first time, a direct comparison of the different stimulation conditions (Vim/DRT, compared to STN, compared to Vim/DRT+STN) in a homogeneous patient population and, furthermore, will allow for intraindividual comparison of each condition with the "quality of life" outcome parameter. We hypothesize that the combined stimulation of the STN and the thalamic (Vim/DRT) target will be superior with respect to the patients' quality of life as compared to the singular stimulation of the individual target regions. If this holds true, this work might change the standardized treatment described in the previous section.

Trial Registration: ClinicalTrials.gov: NCT02288468; https://clinicaltrials.gov/ct2/show/NCT02288468 (Archived by WebCite at http://www.webcitation.org/6wlKnt2pJ); and German Clinical Trials Register: DRKS00007526; https://www.drks.de/drks_ web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00007526 (Archived by WebCite at http://www.webcitation.org/6wlKyXZZL).
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http://dx.doi.org/10.2196/resprot.8341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811645PMC
January 2018

Reliability of the Infraspinatus Test in Carpal Tunnel Syndrome: A Clinical Study.

J Clin Diagn Res 2017 May 1;11(5):YC01-YC04. Epub 2017 May 1.

Department of Neurology, Medical Center, University of Freiburg, Germany.

Introduction: Recently, a standardized provocation tests for the infraspinatus muscle, the Infraspinatus test (IsT), aimed at clinically confirming Carpal Tunnel Syndrome (CTS), was validated in a multiple-blind, controlled study.

Aim: The present study was conducted to investigate inter-rater reliability of the IsT under conditions as they occur in daily clinical practice, since this is essential for acceptance of any new test.

Materials And Methods: Two raters from different medical disciplines used the IsT in the same group of subjects at different localities and with an interval of two to four weeks. Arms with symptoms of CTS were examined and compared with a control group of arms without symptoms. Nerve conduction studies were performed in all the subjects. Statistical analysis was performed with Cohen's Kappa (for inter-rater reliability) and McNemar's test (for determining dependencies between arms and raters).

Results: A total of 34 subjects (age 35-86 years) were investigated with the IsT by two raters in a blinded fashion. There was a high agreement between raters with a Kappa statistic of κ=0.868, when performing this new provocation test. The McNemar test did not reveal dependencies between Rater A and Rater B (p=0.6171), nor between the left and right arms of subjects (Rater A: p=0.4533, Rater B: p=0.5023).

Conclusion: The new provocation test of the infraspinatus muscle is not only capable of confirming CTS, as was shown before, but is also a reliable method for use by different examiners under customary conditions.
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http://dx.doi.org/10.7860/JCDR/2017/25096.9831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5483796PMC
May 2017

Adult-Onset Niemann-Pick Disease Type C: Rapid Treatment Initiation Advised but Early Diagnosis Remains Difficult.

Front Neurol 2017 4;8:108. Epub 2017 Apr 4.

Department of Neurology, University Hospital Freiburg, Freiburg im Breisgau, Germany.

Niemann-Pick type C disease (NP-C) presents with heterogeneous neurological and psychiatric symptoms. Adult onset is rare and possibly underdiagnosed due to frequent lack of specific and obvious key symptoms. For both early and adolescent/adult onset, the available data from studies and case reports describe a positive effect of Miglustat (symptom relief or stabilization). However, due to the low frequency of NP-C, experience with this therapy is still limited. We describe two adult-onset cases of NP-C. In both cases, vertical supranuclear gaze palsy was not recognized at symptom onset. Correct diagnosis was delayed from onset of symptoms by more than 10 years. The video demonstrates the broad spectrum of symptoms in later stages of the disease. Compared with published data, the treatment outcome observed in our cases after delayed initiation of Miglustat therapy was disappointing, with continuing disease progression in both cases. Thus, early treatment initiation could be necessary to achieve a good symptomatic effect. Hence, early biochemical testing for NP-C should be considered in patients suffering from atypical neurological/neuropsychological and psychiatric symptoms, even in cases of uncertainty.
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http://dx.doi.org/10.3389/fneur.2017.00108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378773PMC
April 2017

Manual MRI morphometry in Parkinsonian syndromes.

Mov Disord 2017 05 2;32(5):778-782. Epub 2017 Feb 2.

Department of Neurology, Philipps University Marburg, Marburg, Germany.

Background: Several morphometric magnetic resonance imaging parameters may serve for differential diagnosis of parkinsonism. The objective of this study was to identify which performs best in clinical routine.

Methods: We acquired multicentric magnetization-prepared rapid gradient echo sequences in patients with Parkinson's disease (n=204), progressive supranuclear palsy (n=106), multiple system atrophy-cerebellar, (n = 21); multiple system atrophy-parkinsonian (n = 60), and healthy controls (n = 73), performed manual planimetric measurements, and calculated receiver operator characteristics with leave-one-out cross-validation to propose cutoff values.

Results: The midsagittal midbrain area was reduced in PSP versus all other groups (P < 0.001). The midsagittal pons area was reduced in MSA-cerebellar, MSA-parkinsonian, and PSP versus PD patients and healthy controls (P < 0.001). The midbrain/pons area ratio was lower in PSP (P < 0.001) and higher in MSA-cerebellar and MSA-parkinsonian versus PD and PSP (P < 0.001).

Conclusions: The midsagittal midbrain area most reliably identified PSP, the midsagittal pons area MSA-cerebellar. The midbrain/pons area ratio differentiated MSA-cerebellar and PSP better than the magnetic resonance-Parkinson index. © 2017 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.26921DOI Listing
May 2017

Deep Brain Stimulation for Tremor Tractographic Versus Traditional (DISTINCT): Study Protocol of a Randomized Controlled Feasibility Trial.

JMIR Res Protoc 2016 Dec 22;5(4):e244. Epub 2016 Dec 22.

Department of Stereotactic and Functional Neurosurgery, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background: Essential tremor is a movement disorder that can result in profound disability affecting the quality of life. Medically refractory essential tremor can be successfully reduced by deep brain stimulation (DBS) traditionally targeting the thalamic ventral intermediate nucleus (Vim). Although this structure can be identified with magnetic resonance (MR) imaging nowadays, Vim-DBS electrodes are still implanted in the awake patient with intraoperative tremor testing to achieve satisfactory tremor control. This can be attributed to the fact that the more effective target of DBS seems to be the stimulation of fiber tracts rather than subcortical nuclei like the Vim. There is evidence that current coverage of the dentatorubrothalamic tract (DRT) results in good tremor control in Vim-DBS. Diffusion tensor MR imaging (DTI) tractography-assisted stereotactic surgery targeting the DRT would therefore not rely on multiple trajectories and intraoperative tremor testing in the awake patient, bearing the potential of more patient comfort and reduced operation-related risks. This is the first randomized controlled trial comparing DTI tractography-assisted stereotactic surgery targeting the DRT in general anesthesia with stereotactic surgery of thalamic/subthalamic region as conventionally used.

Objective: This clinical pilot trial aims at demonstrating safety of DTI tractography-assisted stereotactic surgery in general anesthesia and proving its equality compared to conventional stereotactic surgery with intraoperative testing in the awake patient.

Methods: The Deep Brain Stimulation for Tremor Tractographic Versus Traditional (DISTINCT) trial is a single-center investigator-initiated, randomized, controlled, observer-blinded trial. A total of 24 patients with medically refractory essential tremor will be randomized to either DTI tractography-assisted stereotactic surgery targeting the DRT in general anesthesia or stereotactic surgery of the thalamic/subthalamic region as conventionally used. The primary objective is to assess the tremor reduction, obtained by the Fahn-Tolosa-Marin Tremor Rating Scale in the 2 treatment groups. Secondary objectives include (among others) assessing the quality of life, optimal electrode contact positions, and safety of the intervention. The study protocol has been approved by the independent ethics committee of the University of Freiburg.

Results: Recruitment to the DISTINCT trial opened in September 2015 and is expected to close in June 2017. At the time of manuscript submission the trial is open to recruitment.

Conclusions: The DISTINCT trial is the first to compare DTI tractography-assisted stereotactic surgery with target point of the DRT in general anesthesia to stereotactic surgery of the thalamic/subthalamic region as conventionally used. It can serve as a cornerstone for the evolving technique of DTI tractography-assisted stereotactic surgery.

Clinicaltrial: ClinicalTrials.gov NCT02491554; https://clinicaltrials.gov/ct2/show/NCT02491554 (Archived by WebCite at http://www.webcitation.org/6mezLnB9D). German Clinical Trials Register DRKS00008913; http://drks-neu.uniklinik-freiburg.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00008913 (Archived by WebCite at http://www.webcitation.org/6mezCtxhS).
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http://dx.doi.org/10.2196/resprot.6885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216255PMC
December 2016

Differentiation of neurodegenerative parkinsonian syndromes by volumetric magnetic resonance imaging analysis and support vector machine classification.

Mov Disord 2016 10;31(10):1506-1517

Department of Neurology, University Hospital Gießen and Marburg, Marburg, Germany.

Background: Clinical differentiation of parkinsonian syndromes is still challenging.

Objectives: A fully automated method for quantitative MRI analysis using atlas-based volumetry combined with support vector machine classification was evaluated for differentiation of parkinsonian syndromes in a multicenter study.

Methods: Atlas-based volumetry was performed on MRI data of healthy controls (n = 73) and patients with PD (204), PSP with Richardson's syndrome phenotype (106), MSA of the cerebellar type (21), and MSA of the Parkinsonian type (60), acquired on different scanners. Volumetric results were used as input for support vector machine classification of single subjects with leave-one-out cross-validation.

Results: The largest atrophy compared to controls was found for PSP with Richardson's syndrome phenotype patients in midbrain (-15%), midsagittal midbrain tegmentum plane (-20%), and superior cerebellar peduncles (-13%), for MSA of the cerebellar type in pons (-33%), cerebellum (-23%), and middle cerebellar peduncles (-36%), and for MSA of the parkinsonian type in the putamen (-23%). The majority of binary support vector machine classifications between the groups resulted in balanced accuracies of >80%. With MSA of the cerebellar and parkinsonian type combined in one group, support vector machine classification of PD, PSP and MSA achieved sensitivities of 79% to 87% and specificities of 87% to 96%. Extraction of weighting factors confirmed that midbrain, basal ganglia, and cerebellar peduncles had the largest relevance for classification.

Conclusions: Brain volumetry combined with support vector machine classification allowed for reliable automated differentiation of parkinsonian syndromes on single-patient level even for MRI acquired on different scanners. © 2016 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.26715DOI Listing
October 2016

T2* Relaxometry in Patients with Parkinson's Disease : Use of an Automated Atlas-based Approach.

Clin Neuroradiol 2018 Mar 22;28(1):63-67. Epub 2016 Jun 22.

Department of Neuroradiology, University Medical Center Freiburg, Breisacher Str. 64, 79106, Freiburg, Germany.

Background: Magnetic resonance (MR) relaxometry is of increasing scientific relevance in neurodegenerative disorders but is still not established in clinical routine. Several studies have investigated relaxation time alterations in disease-specific areas in Parkinson's disease (PD), all using manually drawn regions of interest (ROI). Implementing MR relaxometry into the clinical setting involves the reduction of time needed for postprocessing using an investigator-independent and reliable approach. The aim of this study was to evaluate an automated, atlas-based ROI method for evaluating T2* relaxation times in patients with PD.

Method: Automated atlas-based ROI analysis of quantitative T2* maps were generated from 20 PD patients and 20 controls. To test for the accuracy of the atlas-based ROI segmentation, we evaluated the spatial overlap in comparison with manually segmented ROIs using the Dice similarity coefficient (DSC). Additionally, we tested for group differences using our automated atlas-based ROIs of the putamen, globus pallidus, and substantia nigra.

Results: A good spatial overlap accuracy was shown for the automated segmented putamen (mean DSC, 0.64 ± 0.04) and was inferior but still acceptable for the substantia nigra (mean DSC, 0.50 ± 0.17). Based on our automated defined ROI selection, a significant decrease of T2* relaxation time was found in the putamen as well as in the internal and external globus pallidus in PD patients compared with healthy controls.

Conclusion: Automated digital brain atlas-based approaches are reliable, more objective and time-efficient, and therefore have the potential to replace the time-consuming manual drawing of ROIs.
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http://dx.doi.org/10.1007/s00062-016-0523-2DOI Listing
March 2018

One-pass deep brain stimulation of dentato-rubro-thalamic tract and subthalamic nucleus for tremor-dominant or equivalent type Parkinson's disease.

Acta Neurochir (Wien) 2016 Apr 15;158(4):773-781. Epub 2016 Feb 15.

Department of Stereotactic and Functional Neurosurgery, Freiburg University Medical Center, Freiburg, Germany.

Background: Refractory tremor in tremor-dominant (TD) or equivalent-type (EQT) idiopathic Parkinson's syndrome (IPS) poses the challenge of choosing the best target region to for deep brain stimulation (DBS). While the subthalamic nucleus is typically chosen in younger patients as the target for dopamine-responsive motor symptoms, it is more complicated if tremor does not (fully) respond under trial conditions. In this report, we present the first results from simultaneous bilateral DBS of the DRT (dentato-rubro-thalamic tract) and the subthalamic nucleus (STN) in two elderly patients with EQT and TD IPS and dopamine-refractory tremor.

Methods: Two patients received bilateral octopolar DBS electrodes in the STN additionally traversing the DRT region. Achieved electrode positions were determined with helical CT, overlaid onto DTI tractography data, and compared with clinical data of stimulation response.

Results: Both patients showed immediate and sustained improvement of their tremor, bilaterally.

Conclusions: The proposed approach appears to be safe and feasible and a combined stimulation of the two target regions was performed tailored to the patients' symptoms. Clinically, no neuropsychiatric effects were seen. Our pilot data suggest a viable therapeutic option to treat the subgroup of TD and EQT IPS and with tremor as the predominant symptom. A clinical study to further investigate this approach (

Opinion: www.clinicaltrials.gov ; NCT02288468) is the focus of our ongoing research.
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http://dx.doi.org/10.1007/s00701-016-2725-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791468PMC
April 2016

Deep Brain Stimulation in Neurological and Psychiatric Disorders.

Dtsch Arztebl Int 2015 Aug;112(31-32):519-26

Abteilung Stereotaktische und Funktionelle Neurochirurgie, Universitätsklinikum der Albert-Ludwigs-Universität Freiburg, Klinik für Neurologie und Neurophysiologie, Albert-Ludwigs-Universität Freiburg, Neurologische Klinik und Poliklinik, Universit7auml;sklinikum Würzburg, Klinik für Psychiatrie und Psychotherapie, Universitätsklinikum.

Background: Deep brain stimulation (DBS) is the chronic electrical stimulation of selected target sites in the brain through stereotactically implanted electrodes. More than 150 000 patients around the world have been treated to date with DBS for medically intractable conditions. The indications for DBS include movement disorders, epilepsy, and some types of mental illness.

Methods: This review is based on relevant publications retrieved by a selective search in PubMed and the Cochrane Library, and on the current guidelines of the German Neurological Society (Deutsche Gesellschaft für Neurologie, DGN).

Results: DBS is usually performed to treat neurological diseases, most often movement disorders and, in particular, Parkinson's disease. Multiple randomized controlled trials (RCTs) have shown that DBS improves tremor, dyskinesia, and quality of life in patients with Parkinson's disease by 25% to 50%, depending on the rating scales used. DBS for tremor usually involves stimulation in the cerebello-thalamo-cortical regulatory loop. In an RCT of DBS for the treatment of primary generalized dystonia, the patients who underwent DBS experienced a 39.3% improvement of dystonia, compared to only 4.9% in the control group. Two multicenter trials of DBS for depression were terminated early because of a lack of efficacy.

Conclusion: DBS is an established treatment for various neurological and psychiatric diseases. It has been incorporated in the DGN guidelines and is now considered a standard treatment for advanced Parkinson's disease. The safety and efficacy of DBS can be expected to improve with the application of new technical developments in electrode geometry and new imaging techniques. Controlled trials would be helpful so that DBS could be extended to further indications, particularly psychiatric ones.
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http://dx.doi.org/10.3238/arztebl.2015.0519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980304PMC
August 2015

18F-FDG PET Is an Early Predictor of Overall Survival in Suspected Atypical Parkinsonism.

J Nucl Med 2015 Oct 30;56(10):1541-6. Epub 2015 Jul 30.

Department of Nuclear Medicine, University Hospital of Freiburg, Freiburg, Germany.

Unlabelled: Early prognostic stratification is desirable in patients with suspected atypical parkinsonian syndromes (APSs) for optimal treatment and counseling. We investigated the prognostic value of imaging disease-specific metabolism patterns with 18F-FDG PET compared with that of clinical diagnosis.

Methods: Seventy-eight patients with suspected APS at study inclusion underwent a follow-up of up to 5.9 y after prospective 18F-FDG PET imaging. Survival data were analyzed by Kaplan-Meier and Cox regression analyses according to diagnostic classifications provided by 18F-FDG PET at baseline and clinical diagnoses after a median follow-up of 1 y after PET.

Results: Forty-four of 78 patients were alive 4.7±0.6 y after PET. Patients diagnosed with an APS by PET or 1-y clinical follow-up showed a significantly shorter median survival time (4.1 y, age-adjusted hazard ratios [HRs]=3.8 for both classifiers) than those diagnosed with Lewy-body diseases (LBDs; majority Parkinson disease [PD]; median survival time not reached). Subgroup classifications of progressive supranuclear palsy/corticobasal degeneration (PSP/CBD) or multiple-system atrophy (MSA) by PET and clinical follow-up were associated with significantly shorter survival than PD. Age-adjusted mortality was significantly increased for PSP/CBD (HR=5.2) and MSA (HR=5.6) classified by PET, but for PSP/CBD only when diagnosed by clinical follow-up (HR=4.5). Patients with a PET pattern suggestive of PD with dementia/dementia with Lewy bodies (PDD/DLB) exhibited a trend toward shorter survival than those with PD (P=0.07), whereas patients classified as PDD/DLB by clinical follow-up did not (P=0.65).

Conclusion: 18F-FDG PET is an early predictor of survival in patients with clinically suspected APS. Detection of cortical or subcortical hypometabolism by 18F-FDG PET is an unfavorable predictor. Risk stratification by 18F-FDG PET appears to be at least as predictive as the 1-y follow-up clinical diagnosis. This finding strongly supports the early inclusion of PET imaging in patient care.
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http://dx.doi.org/10.2967/jnumed.115.159822DOI Listing
October 2015

Assessment of planning performance in clinical samples: Reliability and validity of the Tower of London task (TOL-F).

Neuropsychologia 2015 Aug 18;75:646-55. Epub 2015 Jul 18.

Department of Neurology, University Medical Center, University of Freiburg, Germany; Freiburg Brain Imaging, University of Freiburg, Germany; BrainLinks-BrainTools Cluster of Excellence, University of Freiburg, Germany.

Objective: Executive deficits are frequent sequelae of neurological and psychiatric disorders, but their adequate neuropsychological assessment is still a matter of contention, given that executive tasks draw on a multitude of cognitive processes that are often not sufficiently specified. In line with this, results on psychometric properties of the Tower of London, a task measuring planning ability as a prototypical executive function, are equivocal and furthermore lacking completely for adult clinical populations.

Methods: We used a structurally balanced item set implemented in the Tower of London (Freiburg version, TOL-F) that accounts for major determinants of problem difficulty beyond the commonly used minimum number of moves to solution. Split-half reliability, internal consistency, and criterion-related concurrent validity of TOL-F accuracy were assessed in patients with stroke (N = 60), Parkinson syndrome (N = 51), and mild cognitive impairment (N = 29), and healthy adults (N = 155).

Results: Across samples, mean split-half and lower-bound indices of reliability of accuracy scores were adequate (r ≥ .7) or higher. Compared to a subset of healthy controls matched for age, sex, and education levels, deficits in planning accuracy emerged for all three clinical samples.

Conclusions: Based on consistently adequate reliability and a good criterion-related validity of accuracy scores, the TOL-F demonstrates its utility for testing planning ability in clinical samples and healthy adults. Using item sets systematically accounting for several determinants of task difficulty can thus significantly enhance the contended reliability of executive tasks and provide an opportunity to resolve the underspecification of cognitive processes contributing to executive functioning in health and disease.
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http://dx.doi.org/10.1016/j.neuropsychologia.2015.07.017DOI Listing
August 2015

Suppression of enhanced physiological tremor via stochastic noise: initial observations.

PLoS One 2014 14;9(11):e112782. Epub 2014 Nov 14.

Department of Neurology and Neurophysiology, University Freiburg, Freiburg, Germany.

Enhanced physiological tremor is a disabling condition that arises because of unstable interactions between central tremor generators and the biomechanics of the spinal stretch reflex. Previous work has shown that peripheral input may push the tremor-related spinal and cortical systems closer to anti-phase firing, potentially leading to a reduction in tremor through phase cancellation. The aim of the present study was to investigate whether peripherally applied mechanical stochastic noise can attenuate enhanced physiological tremor and improve motor performance. Eight subjects with enhanced physiological tremor performed a visuomotor task requiring the right index finger to compensate a static force generated by a manipulandum to which Gaussian noise (3-35 Hz) was applied. The finger position was displayed on-line on a monitor as a small white dot which the subjects had to maintain in the center of a larger green circle. Electromyogram (EMG) from the active hand muscles and finger position were recorded. Performance was measured by the mean absolute deviation of the white dot from the zero position. Tremor was identified by the acceleration in the frequency range 7-12 Hz. Two different conditions were compared: with and without superimposed noise at optimal amplitude (determined at the beginning of the experiment). The application of optimum noise reduced tremor (accelerometric amplitude and EMG activity) and improved the motor performance (reduced mean absolute deviation from zero). These data provide the first evidence of a significant reduction of enhanced physiological tremor in the human sensorimotor system due to application of external stochastic noise.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0112782PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232445PMC
December 2015

A disease-specific metabolic brain network associated with corticobasal degeneration.

Brain 2014 Nov 9;137(Pt 11):3036-46. Epub 2014 Sep 9.

1 Centre for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA

Corticobasal degeneration is an uncommon parkinsonian variant condition that is diagnosed mainly on clinical examination. To facilitate the differential diagnosis of this disorder, we used metabolic brain imaging to characterize a specific network that can be used to discriminate corticobasal degeneration from other atypical parkinsonian syndromes. Ten non-demented patients (eight females/two males; age 73.9 ± 5.7 years) underwent metabolic brain imaging with (18)F-fluorodeoxyglucose positron emission tomography for atypical parkinsonism. These individuals were diagnosed clinically with probable corticobasal degeneration. This diagnosis was confirmed in the three subjects who additionally underwent post-mortem examination. Ten age-matched healthy subjects (five females/five males; age 71.7 ± 6.7 years) served as controls for the imaging studies. Spatial covariance analysis was applied to scan data from the combined group to identify a significant corticobasal degeneration-related metabolic pattern that discriminated (P < 0.001) the patients from the healthy control group. This pattern was characterized by bilateral, asymmetric metabolic reductions involving frontal and parietal cortex, thalamus, and caudate nucleus. These pattern-related changes were greater in magnitude in the cerebral hemisphere opposite the more clinically affected body side. The presence of this corticobasal degeneration-related metabolic topography was confirmed in two independent testing sets of patient and control scans, with elevated pattern expression (P < 0.001) in both disease groups relative to corresponding normal values. We next determined whether prospectively computed expression values for this pattern accurately discriminated corticobasal degeneration from multiple system atrophy and progressive supranuclear palsy (the two most common atypical parkinsonian syndromes) on a single case basis. Based upon this measure, corticobasal degeneration was successfully distinguished from multiple system atrophy (P < 0.001) but not progressive supranuclear palsy, presumably because of the overlap (∼ 24%) that existed between the corticobasal degeneration- and the progressive supranuclear palsy-related metabolic topographies. Nonetheless, excellent discrimination between these disease entities was achieved by computing hemispheric asymmetry scores for the corticobasal degeneration-related pattern on a prospective single scan basis. Indeed, a logistic algorithm based on the asymmetry scores combined with separately computed expression values for a previously validated progressive supranuclear palsy-related pattern provided excellent specificity (corticobasal degeneration: 92.7%; progressive supranuclear palsy: 94.1%) in classifying 58 testing subjects. In conclusion, corticobasal degeneration is associated with a reproducible disease-related metabolic covariance pattern that may help to distinguish this disorder from other atypical parkinsonian syndromes.
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http://dx.doi.org/10.1093/brain/awu256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208467PMC
November 2014

Role of semiquantitative assessment of regional binding potential in 123I-FP-CIT SPECT for the differentiation of frontotemporal dementia, dementia with Lewy bodies, and Alzheimer's dementia.

Clin Nucl Med 2015 Jan;40(1):e27-33

From the *Department of Nuclear Medicine, †Centre of Geriatrics and Gerontology, Departments of ‡Radiation Oncology, §Psychiatry and Psychotherapy, and ¶Neurology, University Hospital Freiburg, Freiburg, Germany.

Introduction: I-FP-CIT SPECT is increasingly used to differentiate between Alzheimer's dementia (AD) and dementia with Lewy bodies (DLB). The role of I-FP-CIT SPECT in frontotemporal dementia (FTD) is rather unclear, albeit nigrostriatal involvement may occur. The aim of this study was to evaluate its role in the differentiation of FTD, DLB, and AD.

Methods: We analyzed 34 patients with clinical diagnosis of FTD (n = 13), DLB (n = 12), and AD (n = 9) undergoing combined F-FDG PET and I-FP-CIT SPECT. We performed a semiquantitative region of interest-based analysis to determine the binding potential values in caudate nucleus, putamen, and whole striatum including the caudate/putamen binding potential ratio and asymmetry indices. The receiver operating characteristic analyses and multinomial logistic regression were conducted to assess discrimination accuracy.

Results: The putaminal binding potential separated DLB from AD with high accuracy (area under the receiver operating characteristic curve [AUC], 0.94). It also discriminated FTD from DLB with high accuracy (AUC, 0.92), whereas differentiation between FTD and AD was less accurate (AUC, 0.74). The binding potential ratio also provided high accuracy for differentiation of FTD and DLB (AUC, 0.91). Combination of these 2 parameters yielded slightly higher results for differentiation of FTD and DLB (AUC, 0.97). In a group including all patients, accuracy remained very high for DLB (AUC, 0.95), whereas values for FTD (AUC, 0.81) and AD (AUC, 0.80) were lower.

Conclusions: Semiquantitative assessment of striatal dopamine transporter availability can differentiate between FTD and DLB as well as DLB and AD with high accuracy, whereas discrimination between AD and FTD is limited.
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http://dx.doi.org/10.1097/RLU.0000000000000554DOI Listing
January 2015

Estrogen intake and copper depositions: implications for Alzheimer's disease?

Case Rep Neurol 2014 May 19;6(2):181-7. Epub 2014 Jun 19.

Department of Neurology, University Medical Center Freiburg, Germany.

We present a patient with chronic postmenopausal estrogen intake with presence of Kayser-Fleischer ring in the cornea and Alzheimer's disease and discuss the pathophysiological mechanisms of estrogen intake and copper accumulation in various tissues, including the central nervous system. Sonography was compatible with copper accumulation in the basal ganglia, but the patient showed no clinical signs of Wilson's disease. Magnetic resonance imaging and positron emission tomography revealed a typical pattern for Alzheimer's disease. We propose increased copper levels as a direct effect of estrogen intake due to an augmented ATP7A-mRNA in the intestine. Moreover, we discuss the impact of elevated free serum copper on accompanying Alzheimer's disease, knowing that copper plays a crucial role in the formation of amyloid plaques and tau aggregation. This might offer a partial explanation for the observation that postmenopausal estrogen therapy is associated with a higher risk of mild cognitive impairment and Alzheimer's disease.
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http://dx.doi.org/10.1159/000363688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105953PMC
May 2014

Functional correlates of vertical gaze palsy and other ocular motor deficits in PSP: an FDG-PET study.

Parkinsonism Relat Disord 2014 Aug 4;20(8):898-906. Epub 2014 Jun 4.

Department of Nuclear Medicine, University Medical Center Freiburg, Freiburg, Germany.

Objective: To determine the functional correlates of vertical gaze palsy and other ocular motor deficits in patients with progressive supranuclear palsy (PSP) using [(18)F]fluorodeoxyglucose (FDG-)PET.

Methods: Twenty-six patients with PSP underwent clinical examination of vertical gaze combined with FDG-PET scans to assess regional cerebral glucose metabolism as a marker of neuronal activity. Of these, eighteen PSP patients were also investigated by electrical nystagmography to determine horizontal ocular motor deficits. Statistical parametric mapping analyses were performed to correlate regional neuronal activity with ocular motor functions.

Results: In categorical comparisons, patients with downward gaze palsy showed a significantly reduced glucose metabolism in bilateral anterior cingulate gyrus and right lingual gyrus compared to those without downward gaze palsy. Maximum velocity of horizontal saccades was positively correlated with glucose metabolism of the rostral vermis and lingual gyrus; regional metabolism of oculomotor vermis was associated with peak velocity of the optokinetic reflex. Analysis of smooth pursuit eye movement amplitude and peak velocity of corrective saccades showed positive correlation with metabolism in bilateral inferior parietal lobe and inferior part of the frontal eye field. All paradigms of smooth pursuit showed positive association with glucose metabolism in V5.

Conclusions: Ocular motor functions in PSP are correlated with neuronal activity in distinct anatomical regions. These include the anterior cingulate gyrus (downward gaze palsy), rostral cerebellum (saccades), oculomotor vermis (optokinetic reflex) and inferior parietal as well as temporal regions and frontal eye field (smooth pursuit). These findings provide a deeper insight into the pathophysiology of PSP-associated ocular motor abnormalities.
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http://dx.doi.org/10.1016/j.parkreldis.2014.05.013DOI Listing
August 2014

Syndrome-specific patterns of regional cerebral glucose metabolism in posterior cortical atrophy in comparison to dementia with Lewy bodies and Alzheimer's disease--a [F-18]-FDG pet study.

J Neuroimaging 2015 Mar-Apr;25(2):281-288. Epub 2014 Mar 5.

Centre of Geriatrics and Gerontology Freiburg, Germany.

Background: Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome with visuospatial deficits. PET studies have identified hypometabolism of the occipital cortex in PCA. There is, however, a huge overlap in clinical presentation and involvement of the occipital cortex between PCA, dementia with Lewy bodies (DLB), and Alzheimer's disease (AD). Syndrome-specific patterns of metabolism have not yet been demonstrated that allow for a reliable differentiation with [F-18]-FDG-PET.

Methods: A total of 33 dementia patients (PCA n = 6, DLB n = 12, AD n = 15) who underwent [F-18]-FDG-PET imaging and a neuropsychological examination were retrospectively analyzed. Group comparisons of regional cerebral glucose metabolism were calculated with statistical parametric mapping. Extracted clusters were used to evaluate discrimination accuracy by logistic regression.

Results: PCA patients showed a syndrome-specific area of hypometabolism in the right lateral temporooccipital cortex. DLB patients showed specific hypometabolism predominantly in the left occipital cortex. Logistic regression based on these two regions correctly separated patients with a sensitivity/specificity of 83/93% for PCA, 75/86% for DLB and 67/78% for AD. Overall accuracy was 73%.

Conclusion: [F-18]-FDG-PET could reveal syndrome-specific patterns of glucose metabolism in PCA and DLB. Accurate group discrimination in the differential diagnosis of dementia with visuospatial impairment is feasible.
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http://dx.doi.org/10.1111/jon.12104DOI Listing
April 2016

Neuronal correlates of clinical asymmetry in progressive supranuclear palsy.

Clin Nucl Med 2014 Apr;39(4):319-25

From the *Department of Neurology, †Freiburg Brain Imaging (FBI), ‡Department of Psychiatry and Psychotherapy, §Department of Nuclear Medicine, University Medical Center Freiburg, Freiburg; and ¶Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany.

Purpose: Progressive supranuclear palsy (PSP) is characterized by a symmetric hypokinetic syndrome with early falls and vertical supranuclear gaze palsy. However, clinically asymmetric manifestations occur, resembling idiopathic Parkinson disease or corticobasal degeneration. The aim of this study was to determine the neuronal correlates of patients suffering from PSP with a lateralized disease manifestation (hemi-PSP) in comparison to patients with symmetric clinical presentation (symPSP) and corticobasal degeneration.

Methods: Twenty-three patients with PSP and 8 patients with corticobasal degeneration according to standard diagnostic criteria underwent F-fluorodeoxyglucose (FDG) PET scans to assess disease-specific patterns of regional cerebral glucose metabolism reflecting neuronal activity. Group differences were analyzed by statistical parametric mapping and region-of-interest analyses.

Results: Clinically, 14 patients presented with symPSP while 9 patients were considered as hemi-PSP. Patients with symPSP or hemi-PSP showed similar bilateral medial frontal hypometabolism compared to corticobasal degeneration patients. In contrast, corticobasal degeneration patients exhibited a prominent parietal hypometabolism compared to both symPSP and hemi-PSP patients. SymPSP patients showed no significant hypometabolism compared to hemi-PSP, whereas hemi-PSP patients presented with significant hypometabolism of the motor thalamus, middle cingulate gyrus, and sensorimotor cortex contralateral to the most affected body side compared to symPSP patients.

Conclusions: The present study demonstrates that a more pronounced and asymmetric involvement of cortical and subcortical motor areas is associated with a lateralized disease manifestation of PSP. Furthermore, these findings strongly suggest that FDG PET imaging may assist the challenging clinical differentiation between hemi-PSP and corticobasal degeneration by depicting disease-specific patterns of regional cerebral glucose metabolism.
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http://dx.doi.org/10.1097/RLU.0000000000000373DOI Listing
April 2014

Hypokinesia upon Pallidal Deep Brain Stimulation of Dystonia: Support of a GABAergic Mechanism.

Front Neurol 2013 Dec 5;4:198. Epub 2013 Dec 5.

Department of Stereotactic and Functional Neurosurgery, University Medical Center Freiburg , Freiburg , Germany.

In the past, many studies have documented the beneficial effects of deep brain stimulation (DBS) in the globus pallidus internus for treatment of primary segmental or generalized dystonia. Recently however, several reports focused on DBS-induced hypokinesia or freezing of gait (FOG) as a side effect in these patients. Here we report on two patients suffering from FOG after successful treatment of their dystonic movement disorder with pallidal high frequency stimulation (HFS). Several attempts to reduce the FOG resulted in worsening of the control of dystonia. In one patient levodopa treatment was initialized which was somewhat successful to relieve FOG. We discuss the possible mechanisms of hypokinetic side effects of pallidal DBS which can be explained by the hypothesis of selective GABA release as the mode of action of HFS. Pallidal HFS is also effective in treating idiopathic Parkinson's disease as a hypokinetic disorder which at first sight seems to be a paradox. In our view, however, the GABAergic hypothesis can explain this and other clinical observations.
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http://dx.doi.org/10.3389/fneur.2013.00198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3851850PMC
December 2013

Neural correlates of cognitive dysfunction in Lewy body diseases and tauopathies: combined assessment with FDG-PET and the CERAD test battery.

Brain Lang 2013 Nov 31;127(2):307-14. Epub 2013 Oct 31.

Department of Neurology, University Hospital Freiburg, Freiburg, Germany; Department of Psychiatry, University Hospital Freiburg, Freiburg, Germany. Electronic address:

We investigated disease-specific cognitive profiles and their neural correlates in Lewy-body diseases (LBD) and tauopathies by CERAD assessment and FDG-PET. Analyses revealed a significant interaction between reduced semantic fluency in tauopathies and impaired verbal learning in LBD. Semantic fluency discriminated between groups with high accuracy (83%). Compared to LBD, tauopathy patients showed bilateral hypometabolism of midbrain, thalamus, middle cingulate gyrus and supplementary motor/premotor cortex. In the reverse contrast, LBD patients exhibited bilateral hypometabolism in posterior parietal cortex, precuneus and inferior temporal gyrus extending into occipital and frontal cortices. In diagnosis-independent voxel-based analyses, verbal learning/memory correlated with left temporal and right parietal metabolism, while fluency was coupled to bilateral striatal and frontal metabolism. Naming correlated with left frontal metabolism and drawing with metabolism in bilateral temporal and left frontal regions. In line with disease-specific patterns of regional glucose metabolism, tauopathies and LBD show distinct cognitive profiles, which may assist clinical differentiation.
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http://dx.doi.org/10.1016/j.bandl.2013.10.004DOI Listing
November 2013

123I-iodobenzamide SPECT is not an independent predictor of dopaminergic responsiveness in patients with suspected atypical parkinsonian syndromes.

J Nucl Med 2013 Dec 10;54(12):2081-6. Epub 2013 Oct 10.

Department of Neurology, University Hospital Freiburg, Freiburg, Germany.

Unlabelled: The prediction of dopaminergic responsiveness in patients with parkinsonism is desirable for effective treatment strategies. We investigated whether striatal dopamine D2/D3 receptor (D2R) binding assessed by (123)I-iodobenzamide SPECT is an independent predictor of dopaminergic responsiveness in patients with parkinsonism.

Methods: Seventy-eight patients with clinically suspected atypical parkinsonian syndrome (APS) were prospectively recruited for imaging. To quantify striatal D2R binding, (123)I-iodobenzamide SPECT datasets were subjected to an observer-independent, regions-of-interest analysis. A final clinical diagnosis of Lewy-body disease (LBD) or APS was made after a mean follow-up of 12 mo. On the basis of follow-up data, dopaminergic responsiveness was classified as 0 (none), 1 (transient), 2 (sustained mild), or 3 (sustained strong). Uni- and multivariate analyses of the relationship between treatment response, D2R binding, and confounding variables were conducted.

Results: Sixty patients with clinically verified LBD (n = 28; 22/28 with Parkinson disease) or APS (n = 32), in whom dopaminergic responsiveness could be assessed (n = 19/13/15/13 in categories 0/1/2/3; 18 were excluded because of insufficient dosing), were included in the statistical analysis. Univariate analyses revealed that a sustained treatment response was significantly associated with higher D2R binding, clinical diagnosis of LBD, lower Hoehn and Yahr scores, and younger age. After multivariate correction of D2R binding for diagnosis, age, symptom duration, Hoehn and Yahr score, and dopaminergic pretreatment, no association was found between D2R binding and treatment response, either in the pooled group or in LBD or APS subgroups.

Conclusion: Striatal D2R binding assessed by (123)I-iodobenzamide SPECT does not provide additional predictive information about treatment response beyond other clinical variables, most notably the clinical diagnosis.
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http://dx.doi.org/10.2967/jnumed.113.122010DOI Listing
December 2013

Psychiatric side-effects of bilateral deep brain stimulation for movement disorders.

Acta Neurochir Suppl 2013 ;117:47-51

Division of Stereotactic and Functional Neurosurgery, Department of General Neurosurgery, Neurosurgical Clinic, University Medical Center Freiburg, Breisacher Straße 64, Freiburg, D-79106, Germany,

Introduction: The effects of deep brain stimulation (DBS) on cognitive functions, and its psychiatric side-effects, are still controversial. The present study investigated psychiatric comorbidity and postoperative effects of DBS of different targets on mood and psychological functions in 81 patients with a mean follow-up of 37 months.

Methods: A total of 109 patients underwent implantation of DBS electrodes between 2001 and 2006; it was possible to evaluate 81 patients by a psychiatric test battery using the "Neuropsychiatric Inventory". To evaluate the possible influence of the target, we analyzed the data without 16 patients with DBS surgery for other diseases (e.g., epilepsia, cluster headache) or unilateral implantation only. The resulting population (n = 65, mean age 61 years, range 23-78 years, male:female 42:23) consisted of 43 Parkinson's disease patients stimulated in the subthalamic nucleus, ten dystonia patients stimulated in the globus pallidus internus, and 12 tremor patients in the ventral intermediate nucleus.

Results: There was a high rate of preoperative psychiatric comorbidity, which is reflected by a high rate of patients with preoperative medication of neuroleptic drugs (18.4 %, especially clozapin 14.7 %) and antidepressive drugs (16.5 %). Depression was the most common psychiatric side-effect after DBS, occurring in 47.7 % of all patients (31/65 patients), without significant preference to a specific target (STN: 42 %, Gpi: 60 %, VIM: 58 %). Delusion (n = 5 out of 43 PD patients, 11.6 %), euphoria (n = 1, 2.3 %) and disinhibition (n = 3, 7.0 %) were seen in the PD patients only.

Conclusion: A wide range of behavioural changes may be seen following DBS. Depression was the most common side-effect after DBS, and occurred independently of the target. PD patients, in contrast to dystonia and tremor patients, developed complications in all tested subgroups, with varying frequencies. Preoperative evaluation for psychiatric and cognitive dysfunction is crucial to identify patients who are at specific risk for psychiatric complications.
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http://dx.doi.org/10.1007/978-3-7091-1482-7_8DOI Listing
January 2014

Behind the screen: pseudobulbar symptoms after deep brain stimulation.

Acta Neurochir Suppl 2013 ;117:43-6

Department of Neurology, University Medical Center Freiburg, Breisacherstr. 64, Freiburg, 79106, Germany,

Background: Thalamotomy was formerly used to treat different tremor syndromes. Nowadays, deep brain stimulation has become an established technique to treat -different movement disorders. The combination of these two stereotactic interventions is rare.

Clinical Presentation: We present a patient in which a right-sided tremor -syndrome with an underlying pathology of combined essential tremor and Parkinsonian tremor was successfully treated initially with a left-sided thalamotomy and subsequently with -bilateral deep brain stimulation in the subthalamic nucleus.

Results: Deep brain stimulation in the subthalamic nucleus resulted in hemidystonia, pathological laughing and crying, dysarthria and dysphagia, all due to dislocation of the stimulation electrodes contacting the internal capsule. After discontinuation of the high-frequency stimulation these side-effects disappeared, but were then reactivated by an LCD television in stand-by mode.

Conclusion: In this report we discuss the pathophysiology of pseudobulbar symptoms and pathological laughing and crying in context of thalamotomy and dislocated DBS electrodes. Furthermore, we report on the occurrence that magnetic fields in the household have an impact on deep brain stimulation, even if they are in stand-by mode.
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http://dx.doi.org/10.1007/978-3-7091-1482-7_7DOI Listing
January 2014

[¹⁸F]FDG-PET is superior to [¹²³I]IBZM-SPECT for the differential diagnosis of parkinsonism.

Neurology 2012 Sep 22;79(13):1314-22. Epub 2012 Aug 22.

Department of Neurology, University of Freiburg, Germany.

Objective: Imaging of regional cerebral glucose metabolism with PET and striatal dopamine D2/D3 receptors (D2R) with SPECT improves the differential diagnosis of parkinsonism. We prospectively investigated 1) the diagnostic merits of these approaches in differentiating between Lewy body diseases (LBD; majority Parkinson disease [PD]) and atypical parkinsonian syndromes (APS); 2) the diagnostic value of [¹⁸F]fluorodeoxyglucose (FDG)-PET to differentiate among APS subgroups.

Methods: Ninety-five of 107 consecutive patients with clinically suspected APS referred for imaging were recruited. [¹⁸F]FDG-PET scans were analyzed by visual assessment (including individual voxel-based statistical maps). Based on a priori defined disease-specific patterns, patients with putative APS were differentiated from LBD (first level) and allocated to the subgroups multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal degeneration (CBD) (second level). [¹²³I] iodobenzamide (IBZM)-SPECT datasets were subjected to an observer-independent regions-of-interest analysis to assess striatal D2R availability. Movement disorder specialists made final clinical diagnoses after a median follow-up time of 12 months.

Results: Seventy-eight patients with clinically verified APS (n = 44) or LBD (n = 34) were included in the statistical analysis. The area under the receiver operating characteristic curve for discrimination between APS and LBD was significantly larger for [¹⁸F]FDG-PET (0.94) than for [¹²³I]IBZM-SPECT (0.74; p = 0.0006). Sensitivity/specificity of [¹⁸F]FDG-PET for diagnosing APS was 86%/91%, respectively. Sensitivity/specificity of [¹⁸F]FDG-PET in identifying APS subgroups was 77%/97% for MSA, 74%/95% for PSP, and 75%/92% for CBD.

Conclusions: The diagnostic accuracy of [¹⁸F]FDG-PET for discriminating LBD from APS is considerably higher than for [¹²³I]IBZM-SPECT. [¹⁸F]FDG-PET reliably differentiates APS subgroups.
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http://dx.doi.org/10.1212/WNL.0b013e31826c1b0aDOI Listing
September 2012

Assessment of striatal dopamine D2/D3 receptor availability with PET and 18F-desmethoxyfallypride: comparison of imaging protocols suited for clinical routine.

J Nucl Med 2012 Oct 16;53(10):1558-64. Epub 2012 Aug 16.

Department of Neurology, University Hospital Freiburg, Freiburg, Germany.

Unlabelled: Assessment of striatal dopamine receptor availability with (18)F-desmethoxyfallypride PET is of high diagnostic utility in parkinsonism. The present study was undertaken to define the optimal clinical scan protocol with regard to quantification accuracy and scan time.

Methods: Fourteen patients with parkinsonian syndromes underwent (18)F-desmethoxyfallypride PET over 90 min. Volume-of-interest analyses were performed after spatial normalization, with the right and left caudate nuclei and putamina as target regions and the cerebellum as reference region. The estimate of target region binding potential (relative to nondisplaceable radioligand in tissue) (BP(ND)) provided by the 2-step simplified reference tissue model (SRTM2) served as the reference standard. Additional analyses included the multilinear reference tissue model 2 (MRTM2), noninvasive graphical analyses, and single-scan analyses (peak-equilibrium analysis at 35-65 min [PEA]; pseudoequilibrium analysis at 60-90 min [PsEA]).

Results: SRTM2 and MRTM2 yielded virtually identical results (mean BP(ND) difference = 0.1% ± 0.5%, r(2) = 1.0). Noninvasive graphical analyses with and without inclusion of the k(2)' term were affected by a small BP(ND) bias (2.5% ± 3.6% and -5.0% ± 6.7%, respectively), although correlations with SRTM2 were still excellent (r(2) = 1.0 and 0.98, respectively). In turn, single-scan analyses suffered from limited precision (PEA, mean BP(ND) bias = 0.7% ± 13.0%, r(2) = 0.90) or a considerable positive bias (PsEA, 19.2% ± 7.1%, r(2) = 0.98). Shortening scan time to 70 and 60 min resulted in an acceptable average BP(ND) change (<5% decline) for SRTM2/MRTM2 and graphical analysis with inclusion of the k(2)' term, respectively.

Conclusion: Kinetic reference tissue model analyses of (18)F-desmethoxyfallypride PET data offer the least biased results at a well-tolerable scan duration and should thus be pursued whenever possible. Single-scan analyses may be pragmatic alternatives that, however, suffer from a relevant positive bias (PsEA) or limited precision (PEA).
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http://dx.doi.org/10.2967/jnumed.112.103812DOI Listing
October 2012

Proximal stimulus confirms carpal tunnel syndrome--a new test? --a clinical and electrophysiologic, multiple-blind, controlled study.

J Clin Neurophysiol 2012 Feb;29(1):89-95

Department of Nursing Sciences/Gerontology, University of Health Sciences, Medical Informatics and Technology, Hall, Austria.

Purpose: In patients with carpal tunnel syndrome (CTS), a proximal stimulus can sometimes evoke typical symptoms. Explanations for this phenomenon include local disturbance of arterial circulation, stimulation of trigger points, and the double crush syndrome (DCS). The aim of this study was to investigate the value of these hypotheses with a new provocation test performed on the infraspinatus muscle (infraspinatus test [IsT]) in a multiple-blind, controlled study.

Methods: Thirty-four subjects were recruited, tested with IsT, and measured with nerve conduction velocity (NCV). Additionally, the Tinel sign (TS) was examined. The McNemar test was used to compare the IsT and NCV with the subjects' symptoms. The Fisher exact test was used to correlate IsT and symptoms.

Results: In the McNemar test, IsT showed no significant difference to the NCV (P = 0.18, sensitivity: 69.7%, specificity: 87.1%) regarding the subjects' symptoms (P = 0.2888, sensitivity 80.6%, specificity 93.9%). The Fisher exact test proved the significance of the IsT with regard to symptoms (P < 0.0001).

Conclusions: Pressure exerted on a certain point of the infraspinatus muscle has significant diagnostic power and may be a valuable clinical test in everyday practice. We discuss the arguments for and against a new, latent trigger point and whether other mechanisms may play a role.
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http://dx.doi.org/10.1097/WNP.0b013e318246b87dDOI Listing
February 2012

Impact of a weekly dance class on the functional mobility and on the quality of life of individuals with Parkinson's disease.

Front Aging Neurosci 2011 10;3:14. Epub 2011 Oct 10.

Cortical Motor Control Laboratory, Department of Neurology and Neurophysiology, University Hospital of Freiburg Freiburg im Breisgau, Germany.

Individuals with Parkinson's disease (PD) mainly suffer from motor impairments which increase the risk of falls and lead to a decline of quality of life. Several studies investigated the long-term effect of dance for people with PD. The aims of the present study were to investigate (i) the short-term effects of dance (i.e., the effect immediately after the dance class) on motor control in individuals with PD and (ii) the long-term effects of 8 months of participation in the weekly dance class on the quality of life of the PD patients and their caregivers. The dance lessons took place in a ballet studio and were led by a professional dancer. Eleven people with moderate to severe PD (58-85 years old) were subjected to a motor and quality of life assessments. With respect to the motor assessments the unified Parkinson disease rating scale III (UPDRS III), the timed up and go test (TUG), and the Semitandem test (SeTa) before and after the dance class were used. With respect to the quality of life and well-being we applied quality of life scale (QOLS) as well as the Westheimer questionnaire. Additionally, we asked the caregivers to fill out the Questionnaire for caregivers. We found a significant beneficial short-term effect for the total score of the UPDRS motor score. The strongest improvements were in rigidity scores followed by significant improvements in hand movements, finger taps, and facial expression. No significant changes were found for TUG and for SeTa. The results of the questionnaires showed positive effects of the dance class on social life, health, body-feeling and mobility, and on everyday life competences of the PD patients. Beneficial effect was also found for the caregivers. The findings demonstrate that dance has beneficial effect on the functional mobility of individuals with PD. Further, dance improves the quality of life of the patients and their caregivers. Dance may lead to better therapeutic strategies as it is engaging and enjoyable.
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http://dx.doi.org/10.3389/fnagi.2011.00014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189543PMC
November 2011

Dual-biomarker imaging of regional cerebral amyloid load and neuronal activity in dementia with PET and 11C-labeled Pittsburgh compound B.

J Nucl Med 2011 Mar 14;52(3):393-400. Epub 2011 Feb 14.

Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany.

Unlabelled: PET studies with biomarkers of regional neuronal activity (cerebral glucose metabolism or blood flow [CBF]) and amyloid-β (Aβ) depositions provide complementary information for the early diagnosis of dementia and follow-up of patients with dementia. We investigated the validity of relative regional CBF estimates (R(1)) gained from pharmacokinetic analyses of (11)C-labeled Pittsburgh compound B ((11)C-PIB) PET studies as a marker of neuronal activity and neurodegeneration.

Methods: Twenty-two patients with cognitive impairment (16 patients with early Alzheimer disease) underwent (18)F-FDG and (11)C-PIB PET studies for the assessment of regional glucose metabolism and Aβ load. Parametric images of R(1) (relative CBF) and binding potential (BP(ND); Aβ load) were generated by 2-step simplified reference tissue model (SRTM2) analyses of dynamic (11)C-PIB data. Volume-of-interest and voxel-based statistical analyses were performed to investigate the association between normalized (18)F-FDG uptake and (11)C-PIB R(1) and the correlation of these measures with symptom severity (Mini-Mental State Examination [MMSE] scores) in patients with Alzheimer disease.

Results: SRTM2 analyses provided high-quality (11)C-PIB R(1) images that were comparable to (18)F-FDG PET images. Regional (11)C-PIB R(1) values strongly correlated with normalized regional (18)F-FDG uptake when correlations were calculated separately for each patient (R(2) [mean ± SD], 0.73 ± 0.11) or across all regions of all patients (R(2), 0.62). A regression model including (18)F-FDG uptake, subject identification, and region grouping (into cortical, subcortical, and limbic regions to allow for possible differences in flow/metabolism coupling) accounted for 86% of total (11)C-PIB R(1) variability. Voxel-based correlation analyses of (18)F-FDG uptake and (11)C-PIB R(1) with MMSE scores revealed similar core findings of positive correlations in the posterior cingulate gyrus/precuneus and negative correlations (preserved activity) in the bilateral sensorimotor cortex. There was no correlation between Aβ load (BP(ND)) and MMSE scores.

Conclusion: These results strongly suggest that (11)C-PIB R(1) can serve as a complementary biomarker of neuronal activity and, thus, neurodegeneration in addition to Aβ load given by (11)C-PIB BP(ND). Further studies are needed to validate the diagnostic value of dual-biomarker (11)C-PIB PET studies in comparison with combined (18)F-FDG and (11)C-PIB PET studies. Compared with the latter, dual-biomarker (11)C-PIB PET greatly reduces costs and burden for patients.
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http://dx.doi.org/10.2967/jnumed.110.083683DOI Listing
March 2011

On the estimation of the direction of information flow in networks of dynamical systems.

J Neurosci Methods 2011 Mar 28;196(1):182-9. Epub 2010 Dec 28.

Department of Physics, University of Freiburg, Hermann-Herder-Str. 3, 79104 Freiburg, Germany.

The inference of the interaction structure in networks of dynamical systems promises novel insights into the functioning or malfunctioning of systems in the neurosciences. This may improve the understanding of mechanisms underlying several diseases like tremor disorders and might eventually help to cure patients. Of particular interest is the estimation of the direction of information flow for which different methods have been suggested and have been applied to data from human tremor. Based on a simulated system motivated by the human tremor application we analyze the performance of three methods. The abilities and limitations of the individual techniques are compared and discussed. An application to essential tremor complements this investigation.
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http://dx.doi.org/10.1016/j.jneumeth.2010.12.019DOI Listing
March 2011