Dopaminergic modulation of the praxis network in Parkinson's disease.

Apraxia is a deficit in central motor planning impairing praxis functions such as gesture production or tool use that affects a substantial number of patients with advanced Parkinson's disease. We investigated the functional connectivity of the praxis network in patients in early stages of Parkinson's disease having an increased risk for apraxia and evaluated the influence of dopaminergic therapy on praxis abilities and related networks. 13 patients with mild to moderate Parkinson's disease (ON and OFF dopaminergic therapy) and 13 healthy controls completed a praxis sensitive functional MRI task and apraxia assessments. Functional connectivity analyses included a graph theoretical approach analyzing the global efficiency within the praxis network followed by a seed-to-voxel functional connectivity analysis. Patients in the OFF but not in the ON state showed significantly lower praxis scores than controls. Patients in both states displayed higher global efficiency within the praxis network than controls revealing the bilateral supramarginal gyri as hubs. Seed-to-voxel functional connectivity analyses showed aberrations of right-hemispheric praxis areas in the OFF but not in the ON state. Patients in the ON state exhibited a significantly higher functional connectivity between the supramarginal gyrus and the primary motor cortex, basal ganglia, and frontal areas than in the OFF state. Dopaminergic therapy seems to normalize praxis abilities and related praxis networks in early stages of Parkinson's disease potentially by facilitating the propagation of long-term representations of object-related actions to motor execution areas.

Depression, quality of life, activities of daily living, and subjective memory after deep brain stimulation in Parkinson disease-A reliable change index analysis.

OBJECTIVES: In the field of Parkinson disease (PD) research, many studies have shown that deep brain stimulation (DBS) can soften side effects, which arise during long-term medical therapy. This study focuses on the changes in depressive symptoms, quality of life (with the subdivisions physical and mental health), activities of daily living, and subjective memory functioning in PD patients testing the baseline and the outcome 1 year after DBS. METHODS: For the first time, the reliable change index (RCI) methodology was applied to compare PD-DBS patients (n = 22) with best medically treated PD patients (PD-BMT; n = 28), subjects with mild cognitive impairment (MCI, n = 43) and healthy controls (n = 25) in the above-mentioned domains. The used questionnaires included the revised Beck Depression Inventory (BDI-II), the Short Form (36) Health Survey (SF-36), the Bayer Activities of Daily Living Scale (B-ADL), and the Forgetfulness Assessment Inventory (FAI). RESULTS: The reliable change indices show high constant or improved results of the PD-DBS patients in the domains subjective memory (85.7%-100.0%), activities of daily living (60.0%-90.0%), physical health summary (77.8%), depressive symptoms (61.9%), and mental health summary (50.0%) in comparison with the PD-BMT, MCI, and control group. CONCLUSIONS: DBS is an established alternative to best medical treatment of PD. The comparisons between the PD-DBS and PD-BMT groups do suggest that the domains mental health, depressive symptoms, and physical health benefit most, while the domains activities of daily living and subjective memory functioning are rather constant. Nevertheless, further research is needed to identify mechanisms and predictors that lead to improvement in individual cases.

Improving sensitivity, specificity, and reproducibility of individual brainstem activation.

Functional imaging of the brainstem may open new avenues for clinical diagnostics. However, for reliable assessments of brainstem activation, further efforts improving signal quality are needed. Six healthy subjects performed four repeated functional magnetic resonance imaging (fMRI) sessions on different days with jaw clenching as a motor task to elicit activation in the trigeminal motor nucleus. Functional images were acquired with a 7 T MR scanner using an optimized multiband EPI sequence. Activation measures in the trigeminal nucleus and a control region were assessed using different physiological noise correction methods (aCompCor and RETROICOR-based approaches with variable numbers of regressors) combined with cerebrospinal fluid or brainstem masking. Receiver-operating characteristic analyses accounting for sensitivity and specificity, activation overlap analyses to estimate the reproducibility between sessions, and intraclass correlation analyses (ICC) for testing reliability between subjects and sessions were used to systematically compare the physiological noise correction approaches. Masking the brainstem led to increased activation in the target ROI and resulted in higher values for the area under the curve (AUC) as a combined measure for sensitivity and specificity. With the highest values for AUC, activation overlap, and ICC, the most favorable physiological noise correction method was to control for the cerebrospinal fluid time series (aCompCor with one regressor). Brainstem motor nuclei activation can be reliably identified using high-field fMRI with optimized acquisition and processing strategies-even on single-subject level. Applying specific physiological noise correction methods improves reproducibility and reliability of brainstem activation encouraging future clinical applications.

Individual cognitive change after DBS-surgery in Parkinson's disease patients using Reliable Change Index Methodology.

Long-term therapy of Parkinson's disease (PD) with levodopa (L-DOPA) is associated with a high risk of developing motor fluctuations and dyskinesia. Deep brain stimulation (DBS) in PD patients of the subthalamic nucleus can improve these motor complications. Although the positive effect on motor symptoms has been proven, postoperative cognitive decline has been documented. To tackle the impact of PD-DBS on cognition, 18 DBS patients were compared to 25 best medically treated Parkinson's patients, 24 Mild Cognitive Impairment (MCI) patients and 12 healthy controls using the Neuropsychological Test Battery Vienna-long (NTBV-long) for cognitive outcome 12 months after first examination. Reliable change index methodology was used. Overall, there was cognitive change in individual patients, but the change was very heterogeneous with gains and losses. Further research is needed to identify the mechanisms that lead to improvement or deterioration of cognitive functions in individual cases.

Assessment of individual cognitive changes after deep brain stimulation surgery in Parkinson's disease using the Neuropsychological Test Battery Vienna short version.

Long-term therapy of Parkinson's disease with L­DOPA is associated with a high risk of developing motor fluctuations and dyskinesia. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can improve these motor complications. Although the positive effect on motor symptoms has been proven, postoperative cognitive decline has been documented. To tackle the impact of DBS on cognition, 18 DBS patients were compared to 25 best medically treated Parkinson's patients, 24 patients with mild cognitive impairment (MCI) and 12 healthy controls using the Neuropsychological Test Battery Vienna short version (NTBV-short) for cognitive outcome 12 months after the first examination. Reliable change index methodology was used. Roughly 10% of DBS patients showed cognitive decline mainly affecting the domains attention and executive functioning (phonemic fluency). Further research is needed to identify the mechanisms that lead to improvement or deterioration of cognitive functions in individual cases.

Early dysfunctions of fronto-parietal praxis networks in Parkinson's disease.

In Parkinson's disease (PD) the prevalence of apraxia increases with disease severity implying that patients in early stages may already have subclinical deficits. The aim of this exploratory fMRI study was to investigate if subclinical aberrations of the praxis network are already present in patients with early PD. In previous functional imaging literature only data on basal motor functions in PD exists. Thirteen patients with mild parkinsonian symptoms and without clinically diagnosed apraxia and 14 healthy controls entered this study. During fMRI participants performed a pantomime task in which they imitated the use of visually presented objects. Patients were measured ON and OFF dopaminergic therapy to evaluate a potential medication effect on praxis abilities and related brain functions. Although none of the patients was apraxic according to De Renzi ideomotor scores (range 62-72), patients OFF showed significantly lower praxis scores than controls. Patients exhibited significant hyperactivation in left fronto-parietal core areas of the praxis network. Frontal activations were clearly dominant in patients and were correlated with lower individual praxis scores. We conclude that early PD patients already show characteristic signs of praxis network dysfunctions and rely on specific hyperactivations to avoid clinically evident apraxic symptoms. Subclinical apraxic deficits were shown to correlate with an activation shift from left parietal to left frontal areas implying a prospective individual imaging marker for incipient apraxia.

Between- and within-site variability of fMRI localizations.

This study provides first data about the spatial variability of fMRI sensorimotor localizations when investigating the same subjects at different fMRI sites. Results are comparable to a previous patient study. We found a median between-site variability of about 6 mm independent of task (motor or sensory) and experimental standardization (high or low). An intraclass correlation coefficient analysis using data quality measures indicated a major influence of the fMRI site on variability. In accordance with this, within-site localization variability was considerably lower (about 3 mm). We conclude that the fMRI site is a considerable confound for localization of brain activity. However, when performed by experienced clinical fMRI experts, brain pathology does not seem to have a relevant impact on the reliability of fMRI localizations. Hum Brain Mapp 37:2151-2160, 2016. © 2016 Wiley Periodicals, Inc.

Finger dexterity deficits in Parkinson's disease and somatosensory cortical dysfunction.

INTRODUCTION: The patho-physiological basis for finger dexterity deficits in Parkinson's disease (PD) is controversial. Previously, bradykinesia was regarded as the major mechanism. However, recent research suggested limb-kinetic apraxia as an important component of impaired fine motor skills in PD. In contrast to bradykinesia, limb-kinetic apraxia only marginally responds to dopaminergic treatment. Here we investigate the novel hypothesis that the dexterity deficits are related to an intrinsic dysfunction of primary somatosensory cortex (S1), which is not reversible by dopaminergic medication. METHODS: Applying a standard and approved dexterity task (coin rotation), brain activation networks were investigated using functional magnetic resonance imaging in PD patients both ON and OFF medication and matched healthy controls. RESULTS: PD patients both ON and OFF medication showed impaired S1 activation relative to controls (p < 0.05; region of interest based analysis). The impaired S1 activation remained unchanged by dopaminergic medication. Despite the considerable clinical deficit, no other brain area showed impaired activation. In contrast, structures of the basal ganglia--motor cortex loop responded to dopaminergic medication. Behaviorally, dexterity performance both ON and OFF was significantly (p < 0.05) reduced relative to controls. CONCLUSIONS: Our results provide first evidence that dexterity deficits in PD are related to an S1 dysfunction which is insensitive to dopaminergic treatment.

Comparing the Microvascular Specificity of the 3- and 7-T BOLD Response Using ICA and Susceptibility-Weighted Imaging.

In functional MRI it is desirable for the blood-oxygenation level dependent (BOLD) signal to be localized to the tissue containing activated neurons rather than the veins draining that tissue. This study addresses the dependence of the specificity of the BOLD signal - the relative contribution of the BOLD signal arising from tissue compared to venous vessels - on magnetic field strength. To date, studies of specificity have been based on models or indirect measures of BOLD sensitivity such as signal to noise ratio and relaxation rates, and assessment has been made in isolated vein and tissue voxels. The consensus has been that ultra-high field systems not only significantly increase BOLD sensitivity but also specificity, that is, there is a proportionately reduced signal contribution from draining veins. Specificity was not quantified in prior studies, however, due to the difficulty of establishing a reliable network of veins in the activated volume. In this study we use a map of venous vessel networks extracted from 7 T high resolution Susceptibility-Weighted Images to quantify the relative contributions of micro- and macro-vasculature to functional MRI results obtained at 3 and 7 T. High resolution measurements made here minimize the contribution of physiological noise and Independent Component Analysis (ICA) is used to separate activation from technical, physiological, and motion artifacts. ICA also avoids the possibility of timing-dependent bias from different micro- and macro-vasculature responses. We find a significant increase in the number of activated voxels at 7 T in both the veins and the microvasculature - a BOLD sensitivity increase - with the increase in the microvasculature being higher. However, the small increase in sensitivity at 7 T was not significant. For the experimental conditions of this study, our findings do not support the hypothesis of an increased specificity of the BOLD response at ultra-high field.

Variability of clinical functional MR imaging results: a multicenter study.

PURPOSE: To investigate intersite variability of clinical functional magnetic resonance (MR) imaging, including influence of task standardization on variability and use of various parameters to inform the clinician whether the reliability of a given functional localization is high or low. MATERIALS AND METHODS: Local ethics committees approved the study; all participants gave written informed consent. Eight women and seven men (mean age, 40 years) were prospectively investigated at three experienced functional MR sites with 1.5- (two sites) or 3-T (one site) MR. Nonstandardized motor and highly standardized somatosensory versions of a frequently requested clinical task (localization of the primary sensorimotor cortex) were used. Perirolandic functional MR variability was assessed (peak activation variability, center of mass [COM] variability, intraclass correlation values, overlap ratio [OR], activation size ratio). Data quality measures for functional MR images included percentage signal change (PSC), contrast-to-noise ratio (CNR), and head motion parameters. Data were analyzed with analysis of variance and a correlation analysis. RESULTS: Localization of perirolandic functional MR activity differed by 8 mm (peak activity) and 6 mm (COM activity) among sites. Peak activation varied up to 16.5 mm (COM range, 0.4-16.5 mm) and 45.5 mm (peak activity range, 1.8-45.5 mm). Signal strength (PSC, CNR) was significantly lower for the somatosensory task (mean PSC, 1.0% ± 0.5 [standard deviation]; mean CNR, 1.2 ± 0.4) than for the motor task (mean PSC, 2.4% ± 0.8; mean CNR, 2.9 ± 0.9) (P < .001, both). Intersite variability was larger with low signal strength (negative correlations between signal strength and peak activation variability) even if the task was highly standardized (mean OR, 22.0% ± 18.9 [somatosensory task] and 50.1% ± 18.8 [motor task]). CONCLUSION: Clinical practice and clinical functional MR biomarker studies should consider that the center of task-specific brain activation may vary up to 16.5 mm, with the investigating site, and should maximize functional MR signal strength and evaluate reliability of local results with PSC and CNR.

A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease.

To identify rare causal variants in late-onset Parkinson disease (PD), we investigated an Austrian family with 16 affected individuals by exome sequencing. We found a missense mutation, c.1858G>A (p.Asp620Asn), in the VPS35 gene in all seven affected family members who are alive. By screening additional PD cases, we saw the same variant cosegregating with the disease in an autosomal-dominant mode with high but incomplete penetrance in two further families with five and ten affected members, respectively. The mean age of onset in the affected individuals was 53 years. Genotyping showed that the shared haplotype extends across 65 kilobases around VPS35. Screening the entire VPS35 coding sequence in an additional 860 cases and 1014 controls revealed six further nonsynonymous missense variants. Three were only present in cases, two were only present in controls, and one was present in cases and controls. The familial mutation p.Asp620Asn and a further variant, c.1570C>T (p.Arg524Trp), detected in a sporadic PD case were predicted to be damaging by sequence-based and molecular-dynamics analyses. VPS35 is a component of the retromer complex and mediates retrograde transport between endosomes and the trans-Golgi network, and it has recently been found to be involved in Alzheimer disease.

How much are clinical fMRI reports influenced by standard postprocessing methods? An investigation of normalization and region of interest effects in the medial temporal lobe.

Recent evidence has indicated that standard postprocessing methods such as template-based region of interest (ROI) definition and normalization of individual brains to a standard template may influence final outcome of functional magnetic resonance imaging investigations. Here, we provide the first comprehensive investigation into whether ROI definition and normalization may also change the clinical interpretation of patient data. A series of medial temporal lobe epilepsy patients were investigated with a clinical memory paradigm and individually delineated as well as template-based ROIs. Different metrics for activation quantification were applied. Results show that the application of template-based ROIs can significantly change the clinical interpretation of individual patient data. This relates to sensitivity for brain activation and hemispheric dominance. We conclude that individual ROIs should be defined on nontransformed functional data and that use of more than one metric for activation quantification is beneficial.

PARK11 gene (GIGYF2) variants Asn56Ser and Asn457Thr are not pathogenic for Parkinson's disease.

The GIGYF2 (Grb10-Interacting GYF Protein-2) gene has recently been proposed to be the responsible gene for the PARK11 locus. Ten different putative pathogenic variants were identified in cohorts of Parkinson's disease (PD) patients from Italy and France. Among these variants Asn56Ser and Asn457Thr were found repeatedly. In the present study we screened 669 PD patients (predominantly of central European origin) and 1051 control individuals for the presence of these two variants. Asn56Ser was found in one patient with a positive family history of the disease and in one control individual. The affected sister of the patient did not carry this variant. Asn457Thr was found in one patient, who was exceptional for his Egyptian origin and in three control individuals. This variant was not found in 50 control individuals from Egypt. We conclude that neither of these two variants plays a major role in the pathogenesis of PD in our study population.

Does clinical memory fMRI provide a comprehensive map of medial temporal lobe structures?

Successful clinical application of fMRI tasks requires reliable knowledge about the brain structures mapped by the task. With memory fMRI, diverging evidence exists concerning the location of major signal sources as well as hippocampal contributions. To clarify these issues, we investigated a frequently applied memory test (home town walking) in 33 patients with unilateral medial temporal lobe pathology, comparing healthy and diseased hemispheres. We focused on a detailed investigation of individual fMRI maps on non-transformed high-resolution functional images. Results show a clear dominance of activations around the collateral sulcus, corresponding to parahippocampal and entorhinal cortex activities. Hippocampus activity was absent in the vast majority of patients. The diseased hemispheres showed lower activation than the healthy hemispheres. We conclude that (1) the investigated memory test may be successfully applied for evaluation of the parahippocampal cortex, (2) the hippocampus is not reliably mapped by the task, and (3) the methods described for investigation of individual high-resolution functional images allow generation of application profiles for clinical fMRI tasks.

Probing overtly spoken language at sentential level: a comprehensive high-field BOLD-fMRI protocol reflecting everyday language demands.

Regarding the application of functional magnetic resonance imaging (fMRI) to preoperative mapping of language, the majority of previous studies applied silent vocalization at word level. Since mapping of language targets the protection of overt communication, the selection of the stimulation paradigm is a crucial issue. Typically, everyday language demands overt speech with construction of syntactically and semantically complete sentences. Here, 23 healthy right-handed subjects performed overt vocalization of complete german sentences. Subjects produced these sentences based on visually presented semantic choices. Special efforts were undertaken to minimize motion artifacts and maximize signal gain on a 3-T MR unit. Compared to previous studies, results showed a larger amount of highly reliable fMRI activations over the whole brain. Particularly, high sensitivity was found for Broca's and Wernicke's regions, as well as anterior and inferior temporal areas. Regarding the left hemisphere, simultaneous "Broca" and "Wernicke" activities were found in 95% of all subjects. When including atypical lateralizations, "Broca" and "Wernicke" activations were found in every subject. Overt vocalization at sentential level represents a new comprehensive language task with the potential to generate reliable activation maps that reflect brain activity associated with everyday language demands.

Cortical lateralization of bilateral symmetric chin movements and clinical relevance in tumor patients--a high field BOLD-FMRI study.

Although unilateral lesion studies concerning the opercular part of primary motor cortex report clinically severe motor deficits (e.g. anarthria, masticatory paralysis), functional lateralization of this area has not yet been addressed in neuroimaging studies. Using BOLD-FMRI, this study provides the first quantitative evaluation of a possible cortical lateralization of symmetric chin movements (rhythmic contraction of masticatory muscles) in right-handed healthy subjects and presurgical patients suffering tumorous lesions in the opercular primary motor cortex. Data were analyzed according to "activation volume" and "activation intensity". At group level, results showed a strong left-hemispheric dominance for chin movements in the group of healthy subjects. In contrast, patients indicated dominance of the healthy hemisphere. Here, a clinically relevant dissociation was found between "activation volume" and "activation intensity": Although "activation volume" may be clearly lateralized to the healthy hemisphere, "activation intensity" may indicate residual functionally important tissue close to the pathological tissue. In these cases, consideration of BOLD-FMRI maps with the exclusive focus on "activation volume" may lead to erroneous presurgical conclusions. We conclude that comprehensive analyses of presurgical fMRI data may help to avoid sustained postoperative motor deficits and dysarthria in patients with lesions in the opercular part of primary motor cortex.

Contrast-to-noise ratio (CNR) as a quality parameter in fMRI.

PURPOSE: To evaluate the impact of data quality on the localization of brain activation in functional magnetic resonance imaging (fMRI) and to explore whether the temporal contrast-to-noise-ratio (CNR) provides a quantitative parameter to estimate fMRI quality. MATERIALS AND METHODS: We investigated two methods for defining the CNR by comparing them on a single-run, single session, as well as on a group-wise basis. The CNRs of healthy subjects and a group of patients with brain lesions were calculated using two different strategies: one based on a general linear model (GLM) analysis (CNR_SPM), and one that acts as an adaptive low-pass filter and assumes that the high-frequency components contain the temporal noise (CNR_SG). Runs with low CNR were identified as outliers using a common exclusion criterion (2 x standard deviation (SD)). RESULTS: The results of the two CNR methods are highly correlated. Both between and within subjects and patients the CNR showed quite large variations, but the average CNR did not differ between a group of healthy subjects and a patient group. In total, seven of 213 runs (3.3% of all runs) had to be excluded when CNR_SG was used, and 14 of 213 (6.6%) runs had to be excluded when CNR_SPM was used. CONCLUSION: Calculating the CNR using an adaptive low-pass filter gives similar results to a GLM-based approach and could be advantageous for cases in which the hemodynamic response function (HRF) differs significantly from common assumptions. The CNR can be used to identify and exclude runs with suboptimal CNR, and to identify sessions with insufficient data quality. The CNR may serve as a quantitative and intuitive parameter to assess the performance and quality of clinical fMRI investigations, including information on both functional performance (contrast) and data quality (noise caused by the system and physiology).