Table 2.

Methodological strategies to check for neurovascular confounding in pharmacological-functional imaging studies.

	Example references
Global physiological–psychological indices
Systemic physiological measurements – pulse, blood pressure: compare between sessions; or include as regressors of no interest	Kukolja et al. (2009)
Subjective scores (e.g. Bond and Lader, 1974) – as for physiological parameters	Thiel et al. (2001)
Co-administration of drug that counteracts extracerebral cardiovascular side-effects, e.g. glycopyrrolate with centrally acting cholinesterase inhibitor	Furey et al. (2000a)
Mean rCBF/BOLD values
Grand mean rCBF or BOLD values – over whole brain per session; compare between sessions and/or correct (scaling)	Grasby et al. (1995); most fMRI studies
Global mean BOLD values – over whole brain per scan; include as regressor of no interest or correct (scaling)	Thiel et al. (2001)
High-pass filtering – removes gradual changes in response, e.g. due to declining drug levels	Most fMRI studies
Voxel-level session effect; compare across conditions	Bentley et al. (2004)
Drug × condition interactions
Dissociations: identify interactions with similar activation levels between conditions under placebo (e.g. placebo: A – low; B – low; drug: A – low; B – high)	Bentley et al. (2004)
Cross-over: identify interactions in which drug causes an opposite pattern of responses across conditions (i.e. placebo: A – high; B – low; drug: A – low; B – high)	Hahn et al. (2007), Kukolja et al. (2009)
Cross-over re-mapping: e.g. where drug modulates differential responses to two arbitrary stimuli whose cognitive significance reverses in half of subjects	Thiel et al. (2002a)
Region-specific interactions, e.g. task-specific drug interaction in parietal but not occipital cortex despite similar activation levels under placebo	Thiel et al. (2001), Sperling et al. (2002)
Behavioral correlations
Correlation of drug-induced activation change and behavioural measure of interest suggests drug effect on neural activity, especially if scan and behavioural measure separated in time	Furey et al. (2000b), Bentley et al. (2009)
Alternative analytic methods
Modelling multiple basis functions for BOLD response	Rombouts et al. (2005)
Measurement of BOLD phase relationship only with respect to alternating visual stimulus	Silver et al. (2008)
Fractal complexity (Hurst exponent, H) and inter-regional correlations of resting-state fMRI time-series	Wink et al. (2006), Suckling et al. (2008)
Inter-regional correlations of event-related fMRI (functional connectivity)	Jacobsen et al. (2004), Kobiella et al. (2011)
Measurement of BOLD and rCBF
Use of arterial-spin labelling in addition to T2* MRI sequences	Hahn et al. (2009)