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The use of a battery of pain models to detect analgesic properties of compounds: a two-part four-way crossover study
Okkerse, P.; Amerongen, G. van; Kam, M.L. de; Stevens, J.; Butt, R.P.; Gurrell, R.; ... ; Groeneveld, G.J. 2017
The use of a battery of pain models to detect analgesic properties of compounds: a two-part four-way crossover study
Article / Letter to editor
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Biomarkers, Designs, and Interpretations of Resting-State fMRI in Translational Pharmacological Research: A Review of State-of-the-Art, Challenges, and Opportunities for Studying Brain Chemistry
Khalili-Mahani, N.; Rombouts, S.A.R.B.; Osch, M.J.P. van; Duff, E.P.; Carbonell, F.; Nickerson, L.D.; ... ; Gerven, J.M. van 2017
Biomarkers, Designs, and Interpretations of Resting-State fMRI in Translational Pharmacological Research: A Review of State-of-the-Art, Challenges, and Opportunities for Studying Brain Chemistry
Article / Letter to editor
open access
Biomarkers, Designs, and Interpretations of Resting-State fMRI in Translational Pharmacological Research: A Review of State-of-the-Art, Challenges, and Opportunities for Studying Brain Chemistry
Khalili-Mahani, N.; Rombouts, S.A.R.B.; Osch, M.J.P. van; Duff, E.P.; Carbonell, F.; Nickerson, L.D.; ... ; Gerven, J.M. van 2017
Biomarkers, Designs, and Interpretations of Resting-State fMRI in Translational Pharmacological Research: A Review of State-of-the-Art, Challenges, and Opportunities for Studying Brain Chemistry
Article / Letter to editor
open access
A decade of research and development in resting‐state functional MRI (RSfMRI) has opened new translational and clinical research frontiers. This review aims to bridge between technical and clinical... Show moreA decade of research and development in resting‐state functional MRI (RSfMRI) has opened new translational and clinical research frontiers. This review aims to bridge between technical and clinical researchers who seek reliable neuroimaging biomarkers for studying drug interactions with the brain. About 85 pharma‐RSfMRI studies using BOLD signal (75% of all) or arterial spin labeling (ASL) were surveyed to investigate the acute effects of psychoactive drugs. Experimental designs and objectives include drug fingerprinting dose‐response evaluation, biomarker validation and calibration, and translational studies. Common biomarkers in these studies include functional connectivity, graph metrics, cerebral blood flow and the amplitude and spectrum of BOLD fluctuations. Overall, RSfMRI‐derived biomarkers seem to be sensitive to spatiotemporal dynamics of drug interactions with the brain. However, drugs cause both central and peripheral effects, thus exacerbate difficulties related to biological confounds, structured noise from motion and physiological confounds, as well as modeling and inference testing. Currently, these issues are not well explored, and heterogeneities in experimental design, data acquisition and preprocessing make comparative or meta‐analysis of existing reports impossible. A unifying collaborative framework for data‐sharing and data‐mining is thus necessary for investigating the commonalities and differences in biomarker sensitivity and specificity, and establishing guidelines. Multimodal datasets including sham‐placebo or active control sessions and repeated measurements of various psychometric, physiological, metabolic and neuroimaging phenotypes are essential for pharmacokinetic/pharmacodynamic modeling and interpretation of the findings. We provide a list of basic minimum and advanced options that can be considered in design and analyses of future pharma‐RSfMRI studies. Hum Brain Mapp 38:2276–2325, 2017. © 2017 Wiley Periodicals, Inc. Show less
Model-based exposure-response analysis to quantify age related differences in the response to scopolamine in healthy subjects.
Alvarez-Jimenez, R.; Groeneveld, G.J.; Gerven, J.M. van; Goulooze, S.C.; Baakman, A.C.; Hay, J.L.; Stevens, J. 2016
Model-based exposure-response analysis to quantify age related differences in the response to scopolamine in healthy subjects.
Article / Letter to editor
closed access
AIM Subjects with increasing age are more sensitive to the effects of the anti-muscarinic agent scopolamine, which is used (among other indications) to induce temporary cognitive dysfunction in... Show moreAIM Subjects with increasing age are more sensitive to the effects of the anti-muscarinic agent scopolamine, which is used (among other indications) to induce temporary cognitive dysfunction in early phase drug studies with cognition enhancing compounds. The enhanced sensitivity has always been attributed to incipient cholinergic neuronal dysfunction, as a part of the normal aging process. The aim of the study was to correlate age-dependent pharmacodynamic neuro-physiologic effects of scopolamine after correcting for differences in individual exposure. METHODS We applied a pharmacokinetic and pharmacodynamic modelling approach to describe individual exposure and neurocognitive effects of intravenous scopolamine administration in healthy subjects. RESULTS A two-compartment linear kinetics model best described the plasma concentrations of scopolamine. The estimated scopolamine population mean apparent central and peripheral volume of distribution was 2.66 ± 1.050 l and 62.10 ± 10.100 l, respectively and the clearance was 1.09 ± 0.096 l min(-1) . Age was not related to a decrease of performance in the tests following scopolamine administration in older subjects. Only the saccadic peak velocity showed a positive correlation between age and sensitivity to scopolamine. Age was, however, correlated at baseline with an estimated slower reaction time while performing the cognitive tests and to higher global δ and frontal θ frequency bands measured with the surface EEG. CONCLUSIONS Most of the differences in response to scopolamine administration between young and older subjects could be explained by pharmacokinetic differences (lower clearance) and not to an enhanced sensitivity when corrected for exposure levels. Show less
Spatial heterogeneity of the relation between resting-state connectivity and blood flow: An important consideration for pharmacological studies
Khalili-Mahani, N.; Osch, M.J. van; Rooij, M. de; Beckmann, C.F.; Buchem, M.A. van; Dahan, A.; ... ; Rombouts, S.A.R.B. 2014
Spatial heterogeneity of the relation between resting-state connectivity and blood flow: An important consideration for pharmacological studies
Article / Letter to editor
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Tolerability, Pharmacokinetics, and Pharmacodynamics of Single-Dose Almorexant, an Orexin Receptor Antagonist, in Healthy Elderly Subjects
Hoever, P.; Hay, J.; Rad, M.; Cavallaro, M.; Gerven, J.M. van; Dingemanse, J. 2013
Tolerability, Pharmacokinetics, and Pharmacodynamics of Single-Dose Almorexant, an Orexin Receptor Antagonist, in Healthy Elderly Subjects
Article / Letter to editor
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Spatial heterogeneity of the relation between resting-state connectivity and blood flow: An important consideration for pharmacological studies
Khalili-Mahani, N.; Osch, M.J. van; Rooij, M. de; Beckmann, C.F.; Buchem, M.A. van; Dahan, A.; ... ; Rombouts, S.A.R.B. 2012
Spatial heterogeneity of the relation between resting-state connectivity and blood flow: An important consideration for pharmacological studies
Article / Letter to editor
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Resting state fMRI (RSfMRI) and arterial spin labeling (ASL) provide the field of pharmacological Neuroimaging tool for investigating states of brain activity in terms of functional connectivity or... Show moreResting state fMRI (RSfMRI) and arterial spin labeling (ASL) provide the field of pharmacological Neuroimaging tool for investigating states of brain activity in terms of functional connectivity or cerebral blood flow (CBF). Functional connectivity reflects the degree of synchrony or correlation of spontaneous fluctuations-mostly in the blood oxygen level dependent (BOLD) signal-across brain networks; but CBF reflects mean delivery of arterial blood to the brain tissue over time. The BOLD and CBF signals are linked to common neurovascular and hemodynamic mechanisms that necessitate increased oxygen transportation to the site of neuronal activation; however, the scale and the sources of variation in static CBF and spatiotemporal BOLD correlations are likely different. We tested this hypothesis by examining the relation between CBF and resting-state-network consistency (RSNC)-representing average intranetwork connectivity, determined from dual regression analysis with eight standard networks of interest (NOIs)-in a crossover placebo-controlled study of morphine and alcohol. Overall, we observed spatially heterogeneous relations between RSNC and CBF, and between the experimental factors (drug-by-time, time, drug and physiological rates) and each of these metrics. The drug-by-time effects on CBF were significant in all networks, but significant RSNC changes were limited to the sensorimotor, the executive/salience and the working memory networks. The post-hoc voxel-wise statistics revealed similar dissociations, perhaps suggesting differential sensitivity of RSNC and CBF to neuronal and vascular endpoints of drug actions. The spatial heterogeneity of RSNC/CBF relations encourages further investigation into the role of neuroreceptor distribution and cerebrovascular anatomy in predicting spontaneous fluctuations under drugs. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc. Show less
Dopamine Modulates Reward System Activity During Subconscious Processing of Sexual Stimuli
Oei, N.Y.L.; Rombouts, S.A.R.B.; Soeter, R.P.; Gerven, J.M. van; Both, S. 2012
Dopamine Modulates Reward System Activity During Subconscious Processing of Sexual Stimuli
Article / Letter to editor
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