Biomarker Solutions



Functional Magnetic Resonance Imaging

Functional magnetic resonance imaging (fMRI) is increasingly used in CNS drug research. As a functional biomarker, fMRI is frequently applied when it is the aim to detect local drug effects, particularly in subcortical circuits of the brain.

Perfusion imaging (Arterial Spin Labeling) also is of tremendous value, in particular to assess brain perfusion in elderly patients with (early) vascular dementia and to evaluated whether and how a particular drug affects brain perfusion. We offer:

  • Study set-up and fMRI data acquisition incl. QC/monitoring (and SOP for multicenter data acquisition)
  • fMRI task conditions: resting (default mode network), N-back, verbal memory, oddball, reward etc.
  • Data analysis: whole brain voxelwise, region-of-interest (ROI), seed-based functional connectivity and independent component analyses using the FSL/SPM8 software packages
  • Arterial Spin labeling (ASL): Pulsed ASL sequence with echoplanar readout and online calculation of CBF (cerebral blood flow) maps
  • Pharmaco-fMRI: established subanesthetic ketamine challenge, nicotine challenge
  • Reference data from N = 100 clinically stable schizophrenia patients and > N = 100 subjects with MCI (Mild Cognitive Impairment) are available (in addition to N = 1000 healthy control subjects)
  • Special offer: Simultaneous fMRI/EEG. e.g. for EEG-informed functional connectivity analyses without the need to define a priori an anatomical seed. For instance, EEG information (e.g. vigilance staging during the imaging session can be used for (partial) regression of the BOLD signal. Advantages: EEG together with fMRI increases sensitivity (e.g. to detect drug effects). EEG is a highly reliable measure, it stabilizes the obtained BOLD response measures (e.g. in default mode network analyses)

PharmfMRI: Comparative evaluation of subanesthetic ketamine effects on resting-state functional networks

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Study design: double-blind, randomized, placebo-controlled cross-over subanesthetic S-ketamine application in N=17 healthy male subjects.

Simultaneous fMRI/EEG: EEG-informed fMRI Analysis increases Sensitivity to detect Drug Effects

constant impulse vs. variable impulseGrand-averaged ERPs for the electrode pool

BOLD activation and deactivationNicotine effects on the BOLD response to target stimuli

A 1-mg nasal nicotine spray (0.5 mg each nostril) or placebo (pepper) spray was administered in a double-blind, placebo-controlled, within-subject, randomized, cross-over design. Simultaneous EEG-fMRI and behavioral data were recorded from 19 current smokers in response to an oddball-type visual choice RT task. Conventional general linear model analysis and single trial P300 (P3) amplitude informed general linear model analysis of the fMRI data were performed.

Upper left: (A) The conventional analysis where a constant impulse (same height and duration) is positioned at stimulus onset. (B) A variable impulse model where the height of the basis function is modified by single-trial P3 amplitude. When P3 amplitude was included in the model, this resulted in the height of the basis function being higher when P3 amplitude was larger. This reflects differences in the intensity of responses, as reflected in P3 amplitude. For both models, the input functions (onset time, event duration, and event intensity) were convolved with the gamma HRF, which blurs and delays the waveform to match the difference between the input function and the measured hemodynamic response.
Upper right: Grand-averaged ERPs for the electrode pool (Cz, Pz, CP1, CP2) in the placebo (black line) and nicotine (red line) conditions for the target (left side) and infrequent stimuli (right side). The central part of the figure shows stacked plots of single-trial responses to target stimuli for two representative participants, illustrating a consistent positivity around 350–400 msec poststimulus (P3).
Lower left: BOLD activation (target > baseline, red) and deactivation (target < baseline, blue) for the conventional analysis (second-level mixed-effects FLAME, n = 19, cluster-corrected threshold Z = 2.3, p = .05) for the placebo and nicotine conditions.
Lower right: Nicotine effects (nicotine > placebo) on the BOLD response to target stimuli (target > baseline) for both the conventional and P300 amplitude informed models (second-level mixed-effects FLAME, n = 19, cluster-corrected threshold Z = 2.3, p = .05).
Note:  Whereas in the conventional model (classic fMRI investigation) only little nicotine effects are observed, strong nicotine effects appear in the modern state-of-the-art EEG-informed fMRI analysis. This again supports the notion that the combination of EEG (high sensitivity to drug effects) combined with fMRI (superior spatial accuracy and resolution) can greatly improve  functional imaging in the context of drug trials.

Reference: Warbrick T, Mobascher A, Brinkmeyer J, Musso F, Stoecker T, Shah NJ, Fink GR, Winterer G. Nicotine effects on brain function during a visual oddball task: a comparison between conventional and EEG-informed fMRI analysis. J Cogn Neurosci. 2012 Aug;24(8):1682-94.

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