Focused attention typically enhances neural nociceptive responses, reflected electroencephalographically as increased amplitude of pain-evoked event-related potentials (ERPs). Additionally, pain-evoked ERPs are attenuated by hypertension and baroreceptor activity, through as yet unclear mechanisms. There is indirect evidence that these two effects may interact, suggesting that baroreceptor-related modulation of nociception is more than a low-level gating phenomenon. To address this hypothesis, we explored in a group of healthy participants the combined effects of cue-induced expectancy and baroreceptor activity on the amplitude of pain-evoked ERPs. Brief nociceptive skin stimuli were delivered during a simple visual task; half were preceded by a visual forewarning cue, and half were unpredictable. Nociceptive stimuli were timed to coincide either with systole (maximum activation of cardiac baroreceptors) or with diastole (minimum baroreceptor activation). We observed a strong interaction between expectancy and cardiac timing for the amplitude of the P2 ERP component; no effects were observed for the N2 component. Cued stimuli were associated with larger P2 amplitude, but this effect was abolished for stimuli presented during baroreceptor activation. No cardiac timing effect was observed for un-cued stimuli. Taken together, these findings suggest a close integration of cognitive–affective aspects of expectancy and baroreceptor influences on pain, and as such may cast further light on mechanisms underlying mental and physiological contributions to clinical pain.
Pain expectation mobilises attentional resources toward relevant external and internal stimuli facilitating adaptive behavioral and physiological responses. Attention modulates both subjective experience [5] and neural correlates [42] of pain, directing attention toward pain, relative to non direction or distraction, and increases pain-evoked ERP amplitudes [8], [34], [50], [75] and [76]. Similarly, both hypnotic suggestion and expectations about pain modulate electroencephalographic [17] and functional imaging indices of nociceptive processing [41] and [68]. Thus the neural responses that track subjective pain [14], [18] and [43] do not simply reproduce energy delivered by nociceptive stimuli, but are shaped by cognitive and affective processes [41] and [55].
Nociceptive processing is also influenced by visceral state. Even within the short timeframe of the cardiac cycle, nociceptive stimuli can be attenuated by discharge of cardiac and arterial baroreceptors, activated naturally at systole by phasic ejection of blood from the heart [3], [13] and [35]. Experimentally, increasing baroreceptor discharge through artificial stimulation (phase related external suction, PRES, over the neck in the carotid region [23], [27] and [59]) typically reduces subjective pain ratings [4], [11], [22], [45] and [54], without necessarily affecting pain detection thresholds [22] and [45]. Baroreceptor activity similarly modulates neural signatures of pain processing: PRES, coupled to baroreceptor activation occurring naturally during cardiac systole, engenders a negative shift in pain-evoked ERPs [60], and timing nociceptive stimuli in relation to natural systolic baroreceptor discharge influences the amplitude of the N2 and P2 components of pain-evoked ERPs [4], [11], [26] and [54]. Baroreceptor discharge also influences skeletomotor [59] and autonomic reflexes to nociceptive stimulation, inhibiting activity in sympathetic nerves supplying skeletal muscles (muscle sympathetic nerve activity; MSNA) [19], an effect associated with attenuated blood pressure responses to pain [20], [21], [39] and [72]. Thus nociceptive processing can be modulated by baroreceptor activation, as evidenced by alterations in subjective reports, pain-evoked potential amplitudes and autonomic reactions.
Influential theories suggest a central role of visceral afferent information in emotion and motivation [15], [16] and [58], yet it is unclear if baroreceptor influences extend beyond cardiovascular homoeostasis or low-level sensory gating. Nociceptive processing provides a unique window to explore how baroreceptor activity might interact with cognitive and motivational functions. Of direct relevance is the observation by Donadio and co-workers that infrequent nociceptive stimuli presented during baroreceptor discharge have the greatest selective impact on autonomic reactions (enhancing MSNA inhibition without altering sympathetic skin responses). Moreover, MSNA inhibition rapidly habituates if stimuli are repeated over five consecutive cardiac cycles [20]. One interpretation is that the initial nociceptive stimulus carries attentional salience, amplifying baroreceptor inhibition of MSNA, but subsequent stimuli lose salience and have diminished baroreceptor-related effects. Alternatively, the effect may emerge from refractory characteristics of homoeostatic neurons that specifically fatigue MSNA inhibition across consecutive cardiac cycles.
The current study, extending earlier neuroimaging work [39], was motivated to examine the interaction between attentional salience and phasic visceral effects in nociception. We modulated expectancy by embedding nociceptive stimuli within a visual task, to dissect attentional and baroreceptor influences. We hypothesized that if expectancy and attention, rather than physiological habituation, modulate the baroreceptor gating of pain responses [20], then the baroreceptor influence on the pain-evoked ERPs would be different between expected and unexpected pain, suggesting that attentional effects on central nociception are mechanistically dependent on visceral state.
