The effect of hypercapnia on the neural and hemodynamic responses to somatosensory stimulation Myles Jones, * Jason Berwick, Nicola Hewson-Stoate, Carlos Gias, and John Mayhew The Centre for Signal Processing in Neuroimaging and Systems Neuroscience (SPINSN), Department of Psychology, University of Sheffield, Western Bank, Sheffield S10 2TP, UK Received 12 November 2004; revised 17 March 2005; accepted 28 April 2005 Available online 22 June 2005 Modern non-invasive imaging techniques utilize the coupling between neural activity and changes in blood flow, volume and oxygenation to map the functional architecture of the human brain. An understanding of how the hemodynamic response is influenced by pre-stimulus baseline perfusion is important for the interpretation of imaging data. To address this issue, the present study measured hemodynamics with optical imaging spectroscopy and laser Doppler flowmetry, while multi- channel electrophysiology was used to record local field potentials (LFP) and multi-unit activity (MUA). The response to whisker stimulation in rodent barrel cortex was recorded during baseline (normocapnia) and elevated perfusion rates produced by two levels of hypercapnia (5 and 10%). With the exception of the Fwashout_ of deoxyhemoglobin, which was attenuated, all aspects of the neural and hemodynamic response to whisker stimulation were similar during 5% hypercapnia to those evoked during normocapnia. In contrast, 10% hypercapnia produced cortical arousal and a reduction in both the current sink and MUA elicited by stimulation. Blood flow and volume responses were reduced by a similar magnitude to that observed in the current sink. The deoxyhemoglobin Fwashout_, however, was attenu- ated to a greater degree than could be expected from the neural activity. These data suggest that imaging techniques based on perfusion or blood volume changes may be more robust to shifts in baseline than those based on the dilution of deoxyhemoglobin, such as conventional BOLD fMRI. D 2005 Elsevier Inc. All rights reserved. Keywords: Hypercapnia; Hemodynamic responses; Deoxyhemoglobin; fMRI, Optical imaging; Barrel cortex Introduction The changes in blood flow, volume and oxygenation that accompany changes in neural activity are collectively referred to as the hemodynamic response. The relationship between cerebral hemodynamics and neural activity is of interest to cognitive neuroscience as non-invasive functional neuroimaging techniques such as blood oxygen dependent (BOLD) functional magnetic resonance imaging (fMRI) use hemodynamic surrogates of neural activity to infer the loci and magnitude of brain activity. The present paper addresses whether neurovascular coupling remains constant at different baseline perfusion rates. This is an important issue for functional imaging as the levels of both exogenous (e.g., nicotine, caffeine, alcohol) and endogenous substances (e.g., estrogen) in human subjects may alter global brain perfusion (Cohen et al., 2002). More importantly, as imaging experiments become more sophisticated, cognitive (Mattay et al., 2003) and neural manipulations (Bentley et al., 2004) are achieved by the administration of pharmacological agents that may also have additional independent effects on baseline perfusion. If changes in baseline perfusion cause modulation of stimulus-induced hemody- namics irrespective of neural activity (Kemna et al., 2001), then these changes may be incorrectly attributed to differences in the amount of evoked neural activity. To address this issue in the laboratory, baseline cerebral blood flow (CBF) is typically altered by changing the fraction of inspired carbon dioxide (Grubb et al., 1974). However, whether the hemodynamic response to neural activity is altered following such manipulations is a moot point (Ances et al., 2001b; Cohen et al., 2002; Corfield et al., 2001; Kemna et al., 2001). Previous studies have measured either a single aspect of hemodynamics (e.g., CBF) or the BOLD fMRI response itself. As the BOLD signal is based on deoxyhemoglobin content, it varies with changes in blood flow, volume and oxygen consump- tion. It may be the case that some aspects of the hemodynamic response may be more susceptible to baseline shifts than others (Brown et al., 2003) making data from different studies difficult to reconcile. However, even with regard to a single aspect of the hemodynamic response (e.g., CBF), some authors report similar magnitude of stimulus-elicited responses at a wide range of baseline flow rates (Ances et al., 2001b; Maximilian et al., 1980) while others report a drastic reduction (Kemna et al., 2001). A further difficulty could arise in assuming that stimulus-induced neural activity is of identical magnitude at different levels of arterial CO 2 . There is some evidence to suggest that both the 1053-8119/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2005.04.036 * Corresponding author. Fax: +44 114 276 6515. E-mail address: m.jones@sheffield.ac.uk (M. Jones). Available online on ScienceDirect (www.sciencedirect.com). www.elsevier.com/locate/ynimg NeuroImage 27 (2005) 609 – 623