Functional activity mapping of the mesial hemispheric wall during anticipation of pain Carlo A. Porro, a, * Valentina Cettolo, a Maria Pia Francescato, a and Patrizia Baraldi b a Dipartimento Scienze e Tecnologie Biomediche, Universita ´ di Udine, I-33100 Udine, Italy b Dipartimento Scienze Biomediche, Universita ´ di Modena e Reggio Emilia, I-41100 Modena, Italy Received 13 November 2002; revised 7 March 2003; accepted 18 March 2003 Abstract The relative contributions of autonomic arousal and of cognitive processing to cortical activity during anticipation of pain, and the role of changes in thalamic outflow, are still largely unknown. To address these issues, we investigated with functional magnetic resonance imaging (fMRI) the activity of the contralateral mesial hemispheric wall in 56 healthy volunteers while they expected the stimulation of one foot, which could be either painful or innocuous. The waiting period was characterized by emotional arousal, a moderate rise in heart rate, and by increases in mean fMRI signals in the medial thalamus, mid- and posterior cingulate cortex, and in the putative foot area of the primary somatosensory and motor cortex. The same brain regions, excepting posterior cingulate, were also activated by somatosensory stimulation. We identified by cross-correlation analysis a cluster population whose fMRI signal time course was related to the mean heart rate (HR) profile, showing selective changes of activity during the waiting period. Positively correlated clusters were found mainly in sensorimotor areas, mid- and posterior cingulate, and dorsomedial prefrontal cortex. Negatively correlated clusters predominated in the perigenual anterior cingulate and ventromedial prefrontal cortex. HR clusters had different characteristics from, and showed limited spatial overlap with, clusters whose fMRI signals were related to the psychophysical pain intensity profile; however, both cluster populations were affected by anticipation. These findings unravel a complex pattern of brain activity during uncertain anticipation of noxious input, likely related both to changes in the level of arousal and to cognitive modulation of the pain system. © 2003 Elsevier Science (USA). All rights reserved. Keywords: Anticipation of pain; Aro `usal; Thalamus; Cerebral cortex; Functional magnetic resonance imaging Introduction Our ability to mentally represent perceptual or motor events and to anticipate the consequences of environmental stimuli is a fundamental aspect of consciousness and offers unique adaptive advantages. Considerable interest is now focused on brain mechanisms underlying anticipation of pain, an issue that has important theoretical and practical implications (Price, 1999). Cognitive appraisal of impending pain may differentially modulate brain activity depending on previous experience and available information on the kind of stimulus. This has been shown in a positron emission tomography (PET) study by Hsieh et al. (1999). When subjects anticipated an un- known painful event, increased regional blood flow levels were found in the ventromedial prefrontal cortex (approxi- mately corresponding to Brodmann area 12), in the anterior (area 32'/9) and posterior (area 24') portions of the midcin- gulate cortex (see Vogt et al., 1995, 2003), and in the periaqueductal gray matter. By contrast, blood flow de- creased in areas 12 and 24' during anticipation of a pre- trained known but unavoidable pain. These opposite pat- terns of brain activity paralleled different responses on the behavioral level—apprehension and directing attention to- ward the unknown stimulus, or diverging attention from the known source of distress. The relationships between anticipation- and somatosen- sory-related activity in the human cortex have been inves- * Corresponding author. Dip. Scienze e Tecnologie Biomediche, Univ. di Udine, P.le Kolbe 4, I-33100 Udine, Italy. Fax: +39-0432-494301. E-mail address: cporro@makek.dstb.uniud.it (C.A. Porro). NeuroImage 19 (2003) 1738 –1747 www.elsevier.com/locate/ynimg 1053-8119/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S1053-8119(03)00184-8