Arterial spin labeling (ASL) has undergone significant development since its inception, with a fo... more Arterial spin labeling (ASL) has undergone significant development since its inception, with a focus on improving standardization and reproducibility of its acquisition and quantification. In a community-wide effort towards robust and reproducible clinical ASL image processing, we developed the software package ExploreASL, allowing standardized analyses across centers and scanners. The procedures used in ExploreASL capitalize on published image processing advancements and address the challenges of multi-center datasets with scanner-specific processing and artifact reduction to limit patient exclusion. ExploreASL is self-contained, written in MATLAB and based on Statistical Parameter Mapping (SPM) and runs on multiple operating systems. The toolbox adheres to previously defined international standards for data structure, provenance, and best analysis practice. ExploreASL was iteratively refined and tested in the analysis of >10,000 ASL scans using different pulse-sequences in a va...
Journal of magnetic resonance imaging : JMRI, Jan 8, 2017
To compare registration strategies to align arterial spin labeling (ASL) with 3D T1-weighted (T1w... more To compare registration strategies to align arterial spin labeling (ASL) with 3D T1-weighted (T1w) images, with the goal of reducing the between-subject variability of cerebral blood flow (CBF) images. Multi-center 3T ASL data were collected at eight sites with four different sequences in the multi-center GENetic Frontotemporal dementia Initiative (GENFI) study. In a total of 48 healthy controls, we compared the following image registration options: (I) which images to use for registration (perfusion-weighted images [PWI] to the segmented gray matter (GM) probability map (pGM) (CBF-pGM) or M0 to T1w (M0-T1w); (II) which transformation to use (rigid-body or non-rigid); and (III) whether to mask or not (no masking, M0-based FMRIB software library Brain Extraction Tool [BET] masking). In addition to visual comparison, we quantified image similarity using the Pearson correlation coefficient (CC), and used the Mann-Whitney U rank sum test. CBF-pGM outperformed M0-T1w (CC improvement 47.2...
Stressors have been related to medically insufficiently explained or functional somatic symptoms ... more Stressors have been related to medically insufficiently explained or functional somatic symptoms (FSS). However, the underlying mechanism of this association is largely unclear. In the current study, we examined whether FSS are associated with different perceived stress and cardiac autonomic nervous system (ANS) levels during a standardized stressful situation, and whether these associations are symptom-specific. We examined 715 adolescents (16.1 years, 51.3% girls) from the Dutch cohort study Tracking Adolescents' Individual Lives Sample during the Groningen Social Stress Test (GSST). FSS were assessed by the Youth Self-Report, and clustered into a cluster of overtiredness, dizziness and musculoskeletal pain and a cluster of headache and gastrointestinal symptoms. Perceived stress levels (i.e. unpleasantness and arousal) were assessed by the Self-Assessment Manikin, and cardiac ANS activity by assessing heart rate variability (HRV-HF) and pre-ejection period (PEP). Perceived st...
International Journal of Psychophysiology Official Journal of the International Organization of Psychophysiology, Feb 1, 2006
The purpose of the current study was to validate the change in thoracic impedance (dZ) derived re... more The purpose of the current study was to validate the change in thoracic impedance (dZ) derived respiratory signal obtained from four spot electrodes against incidental spirometry. Additionally, a similar validation was performed for a dual respiratory belts signal to compare the relative merit of both methods. Participants were 38 healthy adult subjects (half male, half female). Cross-method comparisons were performed at three (paced) respiration frequencies in sitting, supine and standing postures. Multilevel regression was used to examine the within- and between-subjects structure of the relationship between spirometric volume and the respiratory amplitude signals obtained from either dZ or respiratory belts. Both dZ derived respiratory rate and dual belts derived respiratory rate accurately reflected the pacing frequencies. For both methods, fixed factors indicated acceptable but posture-specific regression on spirometric volume. However, random factors indicated large individual differences, which was supported by variability of gain analyses. It was concluded that both the dZ and dual belts methods can be used for measurement of respiratory rate and within-subjects, posture-specific, changes in respiratory volume. The need for frequent subject-specific and posture-specific calibration combined with relatively large measurement errors may strongly limit the usefulness of both methods to assess absolute tidal volume and minute ventilation in ambulatory designs.
Dedicated pairs of isometric wrist flexion tasks, with and without visual feedback of the exerted... more Dedicated pairs of isometric wrist flexion tasks, with and without visual feedback of the exerted torque, were designed to target activation of the CBL and BG in healthy subjects during functional magnetic resonance imaging (fMRI). Selective activation of the cerebellum (CBL) and basal ganglia (BG), often implicated in movement disorders such as tremor and dystonia, may help identify pathological changes and expedite diagnosis. A prototyped MR-compatible wrist torque measurement device, free of magnetic and conductive materials, allowed safe execution of tasks during fMRI without causing artifacts. A significant increase of activity in CBL and BG was found in healthy volunteers during a constant torque task with visual feedback compared to a constant torque task without visual feedback. This study shows that specific pairs of motor tasks using MR-compatible equipment at the wrist allow for targeted activation of CBL and BG, paving a new way for research into the pathophysiology of movement disorders.
Essential tremor (ET) is one of the most common hyperkinetic movement disorders. Previous researc... more Essential tremor (ET) is one of the most common hyperkinetic movement disorders. Previous research into the pathophysiology of ET suggested underlying cerebellar abnormalities. In this study, we added electromyography as an index of tremor intensity to functional Magnetic Resonance Imaging (EMG-fMRI) to study a group of ET patients selected according to strict criteria to achieve maximal homogeneity. With this approach we expected to improve upon the localization of the bilateral cerebellar abnormalities found in earlier fMRI studies. We included 21 propranolol sensitive patients, who were not using other tremor medication, with a definite diagnosis of ET defined by the Tremor Investigation Group. Simultaneous EMG-fMRI recordings were performed while patients were off tremor medication. Patients performed unilateral right hand and arm extension, inducing tremor, alternated with relaxation (rest). Twenty-one healthy, age- and sex-matched participants mimicked tremor during right arm extension. EMG power variability at the individual tremor frequency as a measure of tremor intensity variability was used as a regressor, mathematically independent of the block regressor, in the general linear model used for fMRI analysis, to find specific tremor-related activations. Block-related activations were found in the classical upper-limb motor network, both for ET patients and healthy participants in motor, premotor and supplementary motor areas. In ET patients, we found tremor-related activations bilaterally in the cerebellum: in left lobules V, VI, VIIb and IX and in right lobules V, VI, VIIIa and b, and in the brainstem. In healthy controls we found simulated tremor-related activations in right cerebellar lobule V. Our results expand on previous findings of bilateral cerebellar involvement in ET. We have identified specific areas in the bilateral somatomotor regions of the cerebellum: lobules V, VI and VIII.
Glucagon-like peptide-1 (GLP-1) affects appetite, supposedly mediated via the central nervous sys... more Glucagon-like peptide-1 (GLP-1) affects appetite, supposedly mediated via the central nervous system (CNS). We investigate if modulation of CNS responses to palatable food consumption may be a mechanism by which GLP-1 contributes to the central regulation of feeding. Using functional-MRI, we determined effects of endogenous GLP-1 and treatment with the GLP-1 analogue liraglutide on CNS activation to chocolate milk receipt. Study 1 included 20 healthy lean individuals and 20 obese patients with type 2 diabetes (T2DM). Scans were performed on two occasions: during infusion of the GLP-1 receptor antagonist exendin9-39 (blocking actions of endogenous GLP-1), and during placebo infusion. Study 2 was a randomised, cross-over intervention study in 20 T2DM patients, comparing treatment with liraglutide to insulin, after 10-days and 12-weeks. Compared to lean individuals, T2DM patients showed reduced activation to chocolate milk in right insula (P=0.04). In lean individuals, blockade of endo...
Science gateways provide user interfaces and highlevel services to access and manage applications... more Science gateways provide user interfaces and highlevel services to access and manage applications and data collections on distributed resources. They facilitate users to perform data analysis on distributed computing infrastructures (DCIs) without getting involved into the technical details. The e-BioInfra Gateway is a science gateway for biomedical data analysis on a national grid infrastructure, which has been successfully adopted for neuroscience research. Necessary improvements in this gateway motivated the design of a new next generation of e-BioInfra Gateway. In this paper we describe the motivation, requirements and design of this new gateway, which is based on the WS-PGRADE/gUSE SG framework, allowing for support for other types of DCIs. The new gateway has additional generic data and meta-data management facilities to access and manage (biomedical) data servers, and to provide an integrated and datacentric user interaction. Its first prototype is implemented and deployed for the computational neuroscience research community of the Academic
Background: Functional MRI combined with electromyography (EMG-fMRI) is a new technique to invest... more Background: Functional MRI combined with electromyography (EMG-fMRI) is a new technique to investigate the functional association of movement to brain activations. Thalamic stereotactic surgery is effective in reducing tremor. However, while some patients have satisfying benefit, others have only partial or temporary relief. This could be due to suboptimal targeting in some cases. By identifying tremor-related areas, EMG-fMRI could provide more insight into the pathophysiology of tremor and be potentially useful in refining surgical targeting.
The extent to which variation in posture and respiration can confound pre-ejection period and res... more The extent to which variation in posture and respiration can confound pre-ejection period and respiratory sinus arrhythmia (RSA) as indices of cardiac sympatho-vagal activity was examined. Within-subjects changes in these measures were assessed in 36 subjects during different postures and (paced) respiratory frequencies. Changes from supine to sitting to standing led to reduced RSA values and longer pre-ejection periods, reflecting the known decrease in vagal but not the increase of sympathetic activity. Multilevel path analysis showed that within-subjects changes in sympatho-vagal balance were faithfully reflected by changes in interbeat interval, but imperfectly by changes in RSA and pre-ejection period. It was concluded that pre-ejection period should be stratified for posture and RSA for respiratory frequency to reliably index changes in sympatho-vagal balance when these factors are prone to change (e.g., during 24-h ambulatory recording)
Journal of Clinical and Experimental Neuropsychology, 2013
Patients with mild cognitive impairment (MCI) do not always convert to dementia. In such cases, a... more Patients with mild cognitive impairment (MCI) do not always convert to dementia. In such cases, abnormal neuropsychological test results may not validly reflect cognitive symptoms due to brain disease, and the usual brain-behavior relationships may be absent. This study examined symptom validity in a memory clinic sample and its effect on the associations between hippocampal volume and memory performance. Eleven of 170 consecutive patients (6.5%; 13% of patients younger than 65 years) referred to memory clinics showed noncredible performance on symptom validity tests (SVTs, viz. Word Memory Test and Test of Memory Malingering). They were compared to a demographically matched group (n = 57) selected from the remaining patients. Hippocampal volume, measured by an automated volumetric method (Freesurfer), was correlated with scores on six verbal memory tests. The median correlation was r = .49 in the matched group. However, the relation was absent (median r = -.11) in patients who failed SVTs. Memory clinic samples may include patients who show noncredible performance, which invalidates their MCI diagnosis. This underscores the importance of applying SVTs in evaluating patients with cognitive complaints that may signify a predementia stage, especially when these patients are relatively young.
The purpose of the current study was to validate the change in thoracic impedance (dZ) derived re... more The purpose of the current study was to validate the change in thoracic impedance (dZ) derived respiratory signal obtained from four spot electrodes against incidental spirometry. Additionally, a similar validation was performed for a dual respiratory belts signal to compare the relative merit of both methods. Participants were 38 healthy adult subjects (half male, half female). Cross-method comparisons were performed at three (paced) respiration frequencies in sitting, supine and standing postures. Multilevel regression was used to examine the within- and between-subjects structure of the relationship between spirometric volume and the respiratory amplitude signals obtained from either dZ or respiratory belts. Both dZ derived respiratory rate and dual belts derived respiratory rate accurately reflected the pacing frequencies. For both methods, fixed factors indicated acceptable but posture-specific regression on spirometric volume. However, random factors indicated large individual differences, which was supported by variability of gain analyses. It was concluded that both the dZ and dual belts methods can be used for measurement of respiratory rate and within-subjects, posture-specific, changes in respiratory volume. The need for frequent subject-specific and posture-specific calibration combined with relatively large measurement errors may strongly limit the usefulness of both methods to assess absolute tidal volume and minute ventilation in ambulatory designs.
Objective: To explore the reactivity of the theta and alpha rhythms during visuo-spatial working ... more Objective: To explore the reactivity of the theta and alpha rhythms during visuo-spatial working memory. Methods: One hundred and seventy-four subjects performed a delayed response task. They had to remember the spatial location of a target stimulus on a computer screen for a 1 or a 4 s retention interval. The target either remained visible throughout the entire interval (sensory trials) or disappeared after 150 ms (memory trials). Changes in induced band power (IBP) in the electroencephalogram (EEG) were analyzed in 4 narrow, individually adjusted frequency bands between 4 and 12 Hz.
Although involvement of the cerebello-thalamo-cortical network has often been suggested in essent... more Although involvement of the cerebello-thalamo-cortical network has often been suggested in essential tremor, the source of oscillatory activity remains largely unknown. To elucidate mechanisms of tremor generation, it is of crucial importance to study the dynamics within the cerebello-thalamo-cortical network. Using a combination of electromyography and functional magnetic resonance imaging, it is possible to record the peripheral manifestation of tremor simultaneously with brain activity related to tremor generation. Our first aim was to study the intrinsic activity of regions within the cerebello-thalamo-cortical network using dynamic causal modelling to estimate effective connectivity driven by the concurrently recorded tremor signal. Our second aim was to objectify how the functional integrity of the cerebello-thalamo-cortical network is affected in essential tremor. We investigated the functional connectivity between cerebellar and cortical motor regions showing activations dur...
Although involvement of the cerebello-thalamo-cortical network has often been suggested in essent... more Although involvement of the cerebello-thalamo-cortical network has often been suggested in essential tremor, the source of oscillatory activity remains largely unknown. To elucidate mechanisms of tremor generation, it is of crucial importance to study the dynamics within the cerebello-thalamo-cortical network. Using a combination of electromyography and functional magnetic resonance imaging, it is possible to record the peripheral manifestation of tremor simultaneously with brain activity related to tremor generation. Our first aim was to study the intrinsic activity of regions within the cerebello-thalamo-cortical network using dynamic causal modelling to estimate effective connectivity driven by the concurrently recorded tremor signal. Our second aim was to objectify how the functional integrity of the cerebello-thalamo-cortical network is affected in essential tremor. We investigated the functional connectivity between cerebellar and cortical motor regions showing activations during a motor task. Twenty-two essential tremor patients and 22 healthy controls were analysed. For the effective connectivity analysis, a network of tremor-signal related regions was constructed, consisting of the left primary motor cortex, premotor cortex, supplementary motor area, left thalamus, and right cerebellar motor regions lobule V and lobule VIII. A measure of variation in tremor severity over time, derived from the electromyogram, was included as modulatory input on intrinsic connections and on the extrinsic cerebello-thalamic connections, giving a total of 128 models. Bayesian model selection and random effects Bayesian model averaging were used. Separate seed-based functional connectivity analyses for the left primary motor cortex, left supplementary motor area and right cerebellar lobules IV, V, VI and VIII were performed. We report two novel findings that support an important role for the cerebellar system in the pathophysiology of essential tremor. First, in the effective connectivity analysis, tremor variation during the motor task has an excitatory effect on both the extrinsic connection from cerebellar lobule V to the thalamus, and the intrinsic activity of cerebellar lobule V and thalamus. Second, the functional integrity of the motor network is affected in essential tremor, with a decrease in functional connectivity between cortical and cerebellar motor regions. This decrease in functional connectivity, related to the motor task, correlates with an increase in clinical tremor severity. Interestingly, increased functional connectivity between right cerebellar lobules I-IV and the left thalamus correlates with an increase in clinical tremor severity. In conclusion, our findings suggest that cerebello-dentato-thalamic activity and cerebello-cortical connectivity is disturbed in essential tremor, supporting previous evidence of functional cerebellar changes in essential tremor.
Journal of Neurology, Neurosurgery & Psychiatry, 2012
Various studies have shown that ecstasy (3,4-methylenedioxymethamphetamine) users display signifi... more Various studies have shown that ecstasy (3,4-methylenedioxymethamphetamine) users display significant memory impairments, whereas their performance on other cognitive tests is generally normal. The hippocampus plays an essential role in short-term memory. There are, however, no structural human data on the effects of ecstasy on the hippocampus. The objective of this study was to investigate whether the hippocampal volume of chronic ecstasy users is reduced when compared with healthy polydrug-using controls, as an indicator of hippocampal damage. The hippocampus was manually outlined in volumetric MRI scans in 10 male ecstasy users (mean age 25.4 years) and seven healthy age- and gender-matched control subjects (21.3 years). Other than the use of ecstasy, there were no statistically significant differences between both groups in exposure to other drugs of abuse and alcohol. The ecstasy users were on average drug-free for more than 2 months and had used on average 281 tablets over the past six and a half years. The hippocampal volume in the ecstasy using group was on average 10.5% smaller than the hippocampal volume in the control group (p=0.032). These data provide preliminary evidence that ecstasy users may be prone to incurring hippocampal damage, in line with previous reports of acute hippocampal sclerosis and subsequent atrophy in chronic users of this drug.
Objective: To examine brain activation patterns during verbal fluency performance in patients wit... more Objective: To examine brain activation patterns during verbal fluency performance in patients with progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS). Methods: fMRI was used to examine the blood oxygen level–dependent response during letter and category fluency performance in 18 patients with PMA, 21 patients with ALS, and 17 healthy control subjects, matched for age and education. fMRI results are reported at p , 0.05, family-wise error (FWE)-corrected for multiple comparisons. We analyzed effects of performance, age-related white matter changes (ARWMC), and regional brain volumes; all participants underwent neuropsychological investigation. Results: Disease duration of patients with PMA (mean 26.0 months, SD 13.6) and ALS (22.2 months, SD 11.4) was comparable. Patients with PMA and ALS had mild to moderate disease severity and showed impaired letter fluency compared with controls. Between-group analysis showed a main effect of group in the left inferior frontal gyrus (IFG, Brodmann area 45) during letter fluency, which was unaffected by performance, ARWMC, and IFG volume: patients with PMA showed lower activation than controls but higher than that of patients with ALS (ALS , PMA , healthy controls; p FWE 5 0.035; z score 4.11; cluster size 5 11). A more caudal region in the IFG showed lower activation in patients with PMA than controls during letter fluency performance (post hoc test; p FWE 5 0.026). No activation differences were observed during the category fluency task.
To examine brain activation patterns during verbal fluency performance in patients with progressi... more To examine brain activation patterns during verbal fluency performance in patients with progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS). fMRI was used to examine the blood oxygen level-dependent response during letter and category fluency performance in 18 patients with PMA, 21 patients with ALS, and 17 healthy control subjects, matched for age and education. fMRI results are reported at p<0.05, family-wise error (FWE)-corrected for multiple comparisons. We analyzed effects of performance, age-related white matter changes (ARWMC), and regional brain volumes; all participants underwent neuropsychological investigation. Disease duration of patients with PMA (mean 26.0 months, SD 13.6) and ALS (22.2 months, SD 11.4) was comparable. Patients with PMA and ALS had mild to moderate disease severity and showed impaired letter fluency compared with controls. Between-group analysis showed a main effect of group in the left inferior frontal gyrus (IFG, Brodmann ar...
To define thresholds for detecting significant change in liver viscoelasticity with magnetic reso... more To define thresholds for detecting significant change in liver viscoelasticity with magnetic resonance (MR) elastography, both for whole-liver measurements and for voxel-wise measurements in relation to spatial resolution. This prospective study was approved by the institutional review board, and all participants provided written informed consent. Thirty participants (16 volunteers and 14 patients with hepatitis B or C; 18 men; median age, 30.4 years; age range, 18.9-58.6 years) underwent imaging twice while in the same position (intraimage reproducibility), after repositioning (within-day reproducibility), and 1-4 weeks later (between-weeks reproducibility). MR elastography parameters comprised elasticity, viscosity, attenuation parameter α, and propagation parameter β. Bland-Altman analysis was used to calculate repeatability indexes for each parameter. Analyses were performed in a region-of-interest and a voxel-by-voxel level. Voxel-wise results were calculated in relation to spatial resolution by applying Gaussian filtering to establish the optimal trade-off point between resolution and reproducibility. For elasticity, α, and β, within-day and between-weeks results were significantly lower than intraimage results (P ≤ .018 for all). Within-day and between-weeks results did not differ significantly. Over-time changes of more than 22.2% for elasticity, 26.3% for viscosity, 26.8% for α, and 10.1% for β represented thresholds for significant change. The optimal trade-off between spatial resolution and reproducibility was found at a filter size of 8-mm full width at half maximum (FWHM) for elasticity and propagation parameter β and at 16-mm FWHM for viscosity and attenuation parameter α. Repositioning causes a significant decrease in the reproducibility of MR elastography. The propagation parameter β is the most reliable parameter, with an over-time threshold for significant change of 10.1% and the ability to reproduce viscoelasticity up to a resolution of 8-mm FWHM. Online supplemental material is available for this article.
Arterial spin labeling (ASL) has undergone significant development since its inception, with a fo... more Arterial spin labeling (ASL) has undergone significant development since its inception, with a focus on improving standardization and reproducibility of its acquisition and quantification. In a community-wide effort towards robust and reproducible clinical ASL image processing, we developed the software package ExploreASL, allowing standardized analyses across centers and scanners. The procedures used in ExploreASL capitalize on published image processing advancements and address the challenges of multi-center datasets with scanner-specific processing and artifact reduction to limit patient exclusion. ExploreASL is self-contained, written in MATLAB and based on Statistical Parameter Mapping (SPM) and runs on multiple operating systems. The toolbox adheres to previously defined international standards for data structure, provenance, and best analysis practice. ExploreASL was iteratively refined and tested in the analysis of >10,000 ASL scans using different pulse-sequences in a va...
Journal of magnetic resonance imaging : JMRI, Jan 8, 2017
To compare registration strategies to align arterial spin labeling (ASL) with 3D T1-weighted (T1w... more To compare registration strategies to align arterial spin labeling (ASL) with 3D T1-weighted (T1w) images, with the goal of reducing the between-subject variability of cerebral blood flow (CBF) images. Multi-center 3T ASL data were collected at eight sites with four different sequences in the multi-center GENetic Frontotemporal dementia Initiative (GENFI) study. In a total of 48 healthy controls, we compared the following image registration options: (I) which images to use for registration (perfusion-weighted images [PWI] to the segmented gray matter (GM) probability map (pGM) (CBF-pGM) or M0 to T1w (M0-T1w); (II) which transformation to use (rigid-body or non-rigid); and (III) whether to mask or not (no masking, M0-based FMRIB software library Brain Extraction Tool [BET] masking). In addition to visual comparison, we quantified image similarity using the Pearson correlation coefficient (CC), and used the Mann-Whitney U rank sum test. CBF-pGM outperformed M0-T1w (CC improvement 47.2...
Stressors have been related to medically insufficiently explained or functional somatic symptoms ... more Stressors have been related to medically insufficiently explained or functional somatic symptoms (FSS). However, the underlying mechanism of this association is largely unclear. In the current study, we examined whether FSS are associated with different perceived stress and cardiac autonomic nervous system (ANS) levels during a standardized stressful situation, and whether these associations are symptom-specific. We examined 715 adolescents (16.1 years, 51.3% girls) from the Dutch cohort study Tracking Adolescents' Individual Lives Sample during the Groningen Social Stress Test (GSST). FSS were assessed by the Youth Self-Report, and clustered into a cluster of overtiredness, dizziness and musculoskeletal pain and a cluster of headache and gastrointestinal symptoms. Perceived stress levels (i.e. unpleasantness and arousal) were assessed by the Self-Assessment Manikin, and cardiac ANS activity by assessing heart rate variability (HRV-HF) and pre-ejection period (PEP). Perceived st...
International Journal of Psychophysiology Official Journal of the International Organization of Psychophysiology, Feb 1, 2006
The purpose of the current study was to validate the change in thoracic impedance (dZ) derived re... more The purpose of the current study was to validate the change in thoracic impedance (dZ) derived respiratory signal obtained from four spot electrodes against incidental spirometry. Additionally, a similar validation was performed for a dual respiratory belts signal to compare the relative merit of both methods. Participants were 38 healthy adult subjects (half male, half female). Cross-method comparisons were performed at three (paced) respiration frequencies in sitting, supine and standing postures. Multilevel regression was used to examine the within- and between-subjects structure of the relationship between spirometric volume and the respiratory amplitude signals obtained from either dZ or respiratory belts. Both dZ derived respiratory rate and dual belts derived respiratory rate accurately reflected the pacing frequencies. For both methods, fixed factors indicated acceptable but posture-specific regression on spirometric volume. However, random factors indicated large individual differences, which was supported by variability of gain analyses. It was concluded that both the dZ and dual belts methods can be used for measurement of respiratory rate and within-subjects, posture-specific, changes in respiratory volume. The need for frequent subject-specific and posture-specific calibration combined with relatively large measurement errors may strongly limit the usefulness of both methods to assess absolute tidal volume and minute ventilation in ambulatory designs.
Dedicated pairs of isometric wrist flexion tasks, with and without visual feedback of the exerted... more Dedicated pairs of isometric wrist flexion tasks, with and without visual feedback of the exerted torque, were designed to target activation of the CBL and BG in healthy subjects during functional magnetic resonance imaging (fMRI). Selective activation of the cerebellum (CBL) and basal ganglia (BG), often implicated in movement disorders such as tremor and dystonia, may help identify pathological changes and expedite diagnosis. A prototyped MR-compatible wrist torque measurement device, free of magnetic and conductive materials, allowed safe execution of tasks during fMRI without causing artifacts. A significant increase of activity in CBL and BG was found in healthy volunteers during a constant torque task with visual feedback compared to a constant torque task without visual feedback. This study shows that specific pairs of motor tasks using MR-compatible equipment at the wrist allow for targeted activation of CBL and BG, paving a new way for research into the pathophysiology of movement disorders.
Essential tremor (ET) is one of the most common hyperkinetic movement disorders. Previous researc... more Essential tremor (ET) is one of the most common hyperkinetic movement disorders. Previous research into the pathophysiology of ET suggested underlying cerebellar abnormalities. In this study, we added electromyography as an index of tremor intensity to functional Magnetic Resonance Imaging (EMG-fMRI) to study a group of ET patients selected according to strict criteria to achieve maximal homogeneity. With this approach we expected to improve upon the localization of the bilateral cerebellar abnormalities found in earlier fMRI studies. We included 21 propranolol sensitive patients, who were not using other tremor medication, with a definite diagnosis of ET defined by the Tremor Investigation Group. Simultaneous EMG-fMRI recordings were performed while patients were off tremor medication. Patients performed unilateral right hand and arm extension, inducing tremor, alternated with relaxation (rest). Twenty-one healthy, age- and sex-matched participants mimicked tremor during right arm extension. EMG power variability at the individual tremor frequency as a measure of tremor intensity variability was used as a regressor, mathematically independent of the block regressor, in the general linear model used for fMRI analysis, to find specific tremor-related activations. Block-related activations were found in the classical upper-limb motor network, both for ET patients and healthy participants in motor, premotor and supplementary motor areas. In ET patients, we found tremor-related activations bilaterally in the cerebellum: in left lobules V, VI, VIIb and IX and in right lobules V, VI, VIIIa and b, and in the brainstem. In healthy controls we found simulated tremor-related activations in right cerebellar lobule V. Our results expand on previous findings of bilateral cerebellar involvement in ET. We have identified specific areas in the bilateral somatomotor regions of the cerebellum: lobules V, VI and VIII.
Glucagon-like peptide-1 (GLP-1) affects appetite, supposedly mediated via the central nervous sys... more Glucagon-like peptide-1 (GLP-1) affects appetite, supposedly mediated via the central nervous system (CNS). We investigate if modulation of CNS responses to palatable food consumption may be a mechanism by which GLP-1 contributes to the central regulation of feeding. Using functional-MRI, we determined effects of endogenous GLP-1 and treatment with the GLP-1 analogue liraglutide on CNS activation to chocolate milk receipt. Study 1 included 20 healthy lean individuals and 20 obese patients with type 2 diabetes (T2DM). Scans were performed on two occasions: during infusion of the GLP-1 receptor antagonist exendin9-39 (blocking actions of endogenous GLP-1), and during placebo infusion. Study 2 was a randomised, cross-over intervention study in 20 T2DM patients, comparing treatment with liraglutide to insulin, after 10-days and 12-weeks. Compared to lean individuals, T2DM patients showed reduced activation to chocolate milk in right insula (P=0.04). In lean individuals, blockade of endo...
Science gateways provide user interfaces and highlevel services to access and manage applications... more Science gateways provide user interfaces and highlevel services to access and manage applications and data collections on distributed resources. They facilitate users to perform data analysis on distributed computing infrastructures (DCIs) without getting involved into the technical details. The e-BioInfra Gateway is a science gateway for biomedical data analysis on a national grid infrastructure, which has been successfully adopted for neuroscience research. Necessary improvements in this gateway motivated the design of a new next generation of e-BioInfra Gateway. In this paper we describe the motivation, requirements and design of this new gateway, which is based on the WS-PGRADE/gUSE SG framework, allowing for support for other types of DCIs. The new gateway has additional generic data and meta-data management facilities to access and manage (biomedical) data servers, and to provide an integrated and datacentric user interaction. Its first prototype is implemented and deployed for the computational neuroscience research community of the Academic
Background: Functional MRI combined with electromyography (EMG-fMRI) is a new technique to invest... more Background: Functional MRI combined with electromyography (EMG-fMRI) is a new technique to investigate the functional association of movement to brain activations. Thalamic stereotactic surgery is effective in reducing tremor. However, while some patients have satisfying benefit, others have only partial or temporary relief. This could be due to suboptimal targeting in some cases. By identifying tremor-related areas, EMG-fMRI could provide more insight into the pathophysiology of tremor and be potentially useful in refining surgical targeting.
The extent to which variation in posture and respiration can confound pre-ejection period and res... more The extent to which variation in posture and respiration can confound pre-ejection period and respiratory sinus arrhythmia (RSA) as indices of cardiac sympatho-vagal activity was examined. Within-subjects changes in these measures were assessed in 36 subjects during different postures and (paced) respiratory frequencies. Changes from supine to sitting to standing led to reduced RSA values and longer pre-ejection periods, reflecting the known decrease in vagal but not the increase of sympathetic activity. Multilevel path analysis showed that within-subjects changes in sympatho-vagal balance were faithfully reflected by changes in interbeat interval, but imperfectly by changes in RSA and pre-ejection period. It was concluded that pre-ejection period should be stratified for posture and RSA for respiratory frequency to reliably index changes in sympatho-vagal balance when these factors are prone to change (e.g., during 24-h ambulatory recording)
Journal of Clinical and Experimental Neuropsychology, 2013
Patients with mild cognitive impairment (MCI) do not always convert to dementia. In such cases, a... more Patients with mild cognitive impairment (MCI) do not always convert to dementia. In such cases, abnormal neuropsychological test results may not validly reflect cognitive symptoms due to brain disease, and the usual brain-behavior relationships may be absent. This study examined symptom validity in a memory clinic sample and its effect on the associations between hippocampal volume and memory performance. Eleven of 170 consecutive patients (6.5%; 13% of patients younger than 65 years) referred to memory clinics showed noncredible performance on symptom validity tests (SVTs, viz. Word Memory Test and Test of Memory Malingering). They were compared to a demographically matched group (n = 57) selected from the remaining patients. Hippocampal volume, measured by an automated volumetric method (Freesurfer), was correlated with scores on six verbal memory tests. The median correlation was r = .49 in the matched group. However, the relation was absent (median r = -.11) in patients who failed SVTs. Memory clinic samples may include patients who show noncredible performance, which invalidates their MCI diagnosis. This underscores the importance of applying SVTs in evaluating patients with cognitive complaints that may signify a predementia stage, especially when these patients are relatively young.
The purpose of the current study was to validate the change in thoracic impedance (dZ) derived re... more The purpose of the current study was to validate the change in thoracic impedance (dZ) derived respiratory signal obtained from four spot electrodes against incidental spirometry. Additionally, a similar validation was performed for a dual respiratory belts signal to compare the relative merit of both methods. Participants were 38 healthy adult subjects (half male, half female). Cross-method comparisons were performed at three (paced) respiration frequencies in sitting, supine and standing postures. Multilevel regression was used to examine the within- and between-subjects structure of the relationship between spirometric volume and the respiratory amplitude signals obtained from either dZ or respiratory belts. Both dZ derived respiratory rate and dual belts derived respiratory rate accurately reflected the pacing frequencies. For both methods, fixed factors indicated acceptable but posture-specific regression on spirometric volume. However, random factors indicated large individual differences, which was supported by variability of gain analyses. It was concluded that both the dZ and dual belts methods can be used for measurement of respiratory rate and within-subjects, posture-specific, changes in respiratory volume. The need for frequent subject-specific and posture-specific calibration combined with relatively large measurement errors may strongly limit the usefulness of both methods to assess absolute tidal volume and minute ventilation in ambulatory designs.
Objective: To explore the reactivity of the theta and alpha rhythms during visuo-spatial working ... more Objective: To explore the reactivity of the theta and alpha rhythms during visuo-spatial working memory. Methods: One hundred and seventy-four subjects performed a delayed response task. They had to remember the spatial location of a target stimulus on a computer screen for a 1 or a 4 s retention interval. The target either remained visible throughout the entire interval (sensory trials) or disappeared after 150 ms (memory trials). Changes in induced band power (IBP) in the electroencephalogram (EEG) were analyzed in 4 narrow, individually adjusted frequency bands between 4 and 12 Hz.
Although involvement of the cerebello-thalamo-cortical network has often been suggested in essent... more Although involvement of the cerebello-thalamo-cortical network has often been suggested in essential tremor, the source of oscillatory activity remains largely unknown. To elucidate mechanisms of tremor generation, it is of crucial importance to study the dynamics within the cerebello-thalamo-cortical network. Using a combination of electromyography and functional magnetic resonance imaging, it is possible to record the peripheral manifestation of tremor simultaneously with brain activity related to tremor generation. Our first aim was to study the intrinsic activity of regions within the cerebello-thalamo-cortical network using dynamic causal modelling to estimate effective connectivity driven by the concurrently recorded tremor signal. Our second aim was to objectify how the functional integrity of the cerebello-thalamo-cortical network is affected in essential tremor. We investigated the functional connectivity between cerebellar and cortical motor regions showing activations dur...
Although involvement of the cerebello-thalamo-cortical network has often been suggested in essent... more Although involvement of the cerebello-thalamo-cortical network has often been suggested in essential tremor, the source of oscillatory activity remains largely unknown. To elucidate mechanisms of tremor generation, it is of crucial importance to study the dynamics within the cerebello-thalamo-cortical network. Using a combination of electromyography and functional magnetic resonance imaging, it is possible to record the peripheral manifestation of tremor simultaneously with brain activity related to tremor generation. Our first aim was to study the intrinsic activity of regions within the cerebello-thalamo-cortical network using dynamic causal modelling to estimate effective connectivity driven by the concurrently recorded tremor signal. Our second aim was to objectify how the functional integrity of the cerebello-thalamo-cortical network is affected in essential tremor. We investigated the functional connectivity between cerebellar and cortical motor regions showing activations during a motor task. Twenty-two essential tremor patients and 22 healthy controls were analysed. For the effective connectivity analysis, a network of tremor-signal related regions was constructed, consisting of the left primary motor cortex, premotor cortex, supplementary motor area, left thalamus, and right cerebellar motor regions lobule V and lobule VIII. A measure of variation in tremor severity over time, derived from the electromyogram, was included as modulatory input on intrinsic connections and on the extrinsic cerebello-thalamic connections, giving a total of 128 models. Bayesian model selection and random effects Bayesian model averaging were used. Separate seed-based functional connectivity analyses for the left primary motor cortex, left supplementary motor area and right cerebellar lobules IV, V, VI and VIII were performed. We report two novel findings that support an important role for the cerebellar system in the pathophysiology of essential tremor. First, in the effective connectivity analysis, tremor variation during the motor task has an excitatory effect on both the extrinsic connection from cerebellar lobule V to the thalamus, and the intrinsic activity of cerebellar lobule V and thalamus. Second, the functional integrity of the motor network is affected in essential tremor, with a decrease in functional connectivity between cortical and cerebellar motor regions. This decrease in functional connectivity, related to the motor task, correlates with an increase in clinical tremor severity. Interestingly, increased functional connectivity between right cerebellar lobules I-IV and the left thalamus correlates with an increase in clinical tremor severity. In conclusion, our findings suggest that cerebello-dentato-thalamic activity and cerebello-cortical connectivity is disturbed in essential tremor, supporting previous evidence of functional cerebellar changes in essential tremor.
Journal of Neurology, Neurosurgery & Psychiatry, 2012
Various studies have shown that ecstasy (3,4-methylenedioxymethamphetamine) users display signifi... more Various studies have shown that ecstasy (3,4-methylenedioxymethamphetamine) users display significant memory impairments, whereas their performance on other cognitive tests is generally normal. The hippocampus plays an essential role in short-term memory. There are, however, no structural human data on the effects of ecstasy on the hippocampus. The objective of this study was to investigate whether the hippocampal volume of chronic ecstasy users is reduced when compared with healthy polydrug-using controls, as an indicator of hippocampal damage. The hippocampus was manually outlined in volumetric MRI scans in 10 male ecstasy users (mean age 25.4 years) and seven healthy age- and gender-matched control subjects (21.3 years). Other than the use of ecstasy, there were no statistically significant differences between both groups in exposure to other drugs of abuse and alcohol. The ecstasy users were on average drug-free for more than 2 months and had used on average 281 tablets over the past six and a half years. The hippocampal volume in the ecstasy using group was on average 10.5% smaller than the hippocampal volume in the control group (p=0.032). These data provide preliminary evidence that ecstasy users may be prone to incurring hippocampal damage, in line with previous reports of acute hippocampal sclerosis and subsequent atrophy in chronic users of this drug.
Objective: To examine brain activation patterns during verbal fluency performance in patients wit... more Objective: To examine brain activation patterns during verbal fluency performance in patients with progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS). Methods: fMRI was used to examine the blood oxygen level–dependent response during letter and category fluency performance in 18 patients with PMA, 21 patients with ALS, and 17 healthy control subjects, matched for age and education. fMRI results are reported at p , 0.05, family-wise error (FWE)-corrected for multiple comparisons. We analyzed effects of performance, age-related white matter changes (ARWMC), and regional brain volumes; all participants underwent neuropsychological investigation. Results: Disease duration of patients with PMA (mean 26.0 months, SD 13.6) and ALS (22.2 months, SD 11.4) was comparable. Patients with PMA and ALS had mild to moderate disease severity and showed impaired letter fluency compared with controls. Between-group analysis showed a main effect of group in the left inferior frontal gyrus (IFG, Brodmann area 45) during letter fluency, which was unaffected by performance, ARWMC, and IFG volume: patients with PMA showed lower activation than controls but higher than that of patients with ALS (ALS , PMA , healthy controls; p FWE 5 0.035; z score 4.11; cluster size 5 11). A more caudal region in the IFG showed lower activation in patients with PMA than controls during letter fluency performance (post hoc test; p FWE 5 0.026). No activation differences were observed during the category fluency task.
To examine brain activation patterns during verbal fluency performance in patients with progressi... more To examine brain activation patterns during verbal fluency performance in patients with progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS). fMRI was used to examine the blood oxygen level-dependent response during letter and category fluency performance in 18 patients with PMA, 21 patients with ALS, and 17 healthy control subjects, matched for age and education. fMRI results are reported at p<0.05, family-wise error (FWE)-corrected for multiple comparisons. We analyzed effects of performance, age-related white matter changes (ARWMC), and regional brain volumes; all participants underwent neuropsychological investigation. Disease duration of patients with PMA (mean 26.0 months, SD 13.6) and ALS (22.2 months, SD 11.4) was comparable. Patients with PMA and ALS had mild to moderate disease severity and showed impaired letter fluency compared with controls. Between-group analysis showed a main effect of group in the left inferior frontal gyrus (IFG, Brodmann ar...
To define thresholds for detecting significant change in liver viscoelasticity with magnetic reso... more To define thresholds for detecting significant change in liver viscoelasticity with magnetic resonance (MR) elastography, both for whole-liver measurements and for voxel-wise measurements in relation to spatial resolution. This prospective study was approved by the institutional review board, and all participants provided written informed consent. Thirty participants (16 volunteers and 14 patients with hepatitis B or C; 18 men; median age, 30.4 years; age range, 18.9-58.6 years) underwent imaging twice while in the same position (intraimage reproducibility), after repositioning (within-day reproducibility), and 1-4 weeks later (between-weeks reproducibility). MR elastography parameters comprised elasticity, viscosity, attenuation parameter α, and propagation parameter β. Bland-Altman analysis was used to calculate repeatability indexes for each parameter. Analyses were performed in a region-of-interest and a voxel-by-voxel level. Voxel-wise results were calculated in relation to spatial resolution by applying Gaussian filtering to establish the optimal trade-off point between resolution and reproducibility. For elasticity, α, and β, within-day and between-weeks results were significantly lower than intraimage results (P ≤ .018 for all). Within-day and between-weeks results did not differ significantly. Over-time changes of more than 22.2% for elasticity, 26.3% for viscosity, 26.8% for α, and 10.1% for β represented thresholds for significant change. The optimal trade-off between spatial resolution and reproducibility was found at a filter size of 8-mm full width at half maximum (FWHM) for elasticity and propagation parameter β and at 16-mm FWHM for viscosity and attenuation parameter α. Repositioning causes a significant decrease in the reproducibility of MR elastography. The propagation parameter β is the most reliable parameter, with an over-time threshold for significant change of 10.1% and the ability to reproduce viscoelasticity up to a resolution of 8-mm FWHM. Online supplemental material is available for this article.
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Papers by Paul Groot