PERIAQUEDUCTAL GRAY 1 Running head: PERIAQUEDUCTAL GRAY Common representation of pain and negative emotion in the midbrain periaqueductal gray

Human neuroimaging offers a powerful way to connect animal and human research on emotion, with profound implications for psychological science. However, the gulf between animal and human studies remains a formidable obstacle: Human studies typically focus on the cortex and a few subcortical regions such as the amygdala, whereas deeper structures such as the brainstem periaqueductal gray (PAG) play a key role in animal models. Here, we directly assessed the role of PAG in human affect by interleaving in a single fMRI session two conditions known to elicit strong emotional responses—physical pain and negative image viewing. Negative affect and PAG activity increased in both conditions. We next examined eight independent datasets, half featuring pain stimulation and half negative image viewing. In sum, these datasets comprised 198 additional participants. We found increased activity in PAG in all eight studies. Taken together, these findings suggest PAG is a key component of human affective responses. at U niersity of C orado on M arch 8, 2012 http://scaordjournals.org/ D ow nladed from PERIAQUEDUCTAL GRAY 4 Introduction Historically, much of what we know about mind, brain and behavior has come from electrophysiological and lesion methods in animals. In the last 15 years, fMRI has emerged as a noninvasive, human counterpart to these traditional approaches. This development greatly enhances the potential for animal and human research to directly inform one another, as homologies across species can be established based on similarities in brain function. Such work is crucial for understanding human brain function, as fMRI can provide only correlational measures of neural activity. Causal inference requires invasive and disruptive methods. While such methods are commonly used in animal research, in humans they are limited and rare. However, at present there exists a substantial gulf between human and animal work on affective processes, because human and animal studies focus largely on different brain structures. Human fMRI studies have focused primarily on the cerebral cortex and structures such as the amgydala, whereas animal models of emotion focus on deeper subcortical structures, often describing pathways connecting the brainstem to the periphery. Although there is some overlap in basal telencephalic structures such as the amygdala (LeDoux, 2007) and ventral striatum (Cardinal, Parkinson, Hall, & Everitt, 2002), key players in animal models of emotion, including the midbrain periaqueductal gray (PAG; Bandler & Shipley, 1994; Behbehani, 1995; Panksepp, 1998), hypothalamus (Sewards & Sewards, 2003), and other brainstem nuclei (Alcaro, Huber, & Panksepp, 2007), have been largely absent from models of emotion based on human neuroimaging. at U niersity of C orado on M arch 8, 2012 http://scaordjournals.org/ D ow nladed from PERIAQUEDUCTAL GRAY 5 One possible explanation for this discrepancy is that it reflects a true difference between species in the neural bases of emotion. A second possibility is that the human neuroimaging techniques lack sensitivity to reliably detect changes in small, ventral brain regions like those that are prominent in the animal literature. However, while the cortex and amygdala clearly play important roles in affective processes, a recent meta-analysis of human neuroimaging studies of emotion questioned their centrality to emotional experience, finding amygdala activations most reliably reflect salience detection and emotion perception, while rostral anterior cingulate and anterior insula participate extensively in cognitive processes likely unrelated to emotion (Wager, Barrett, et al., 2008). Furthermore, meta-analytic evidence suggests that human neuroimaging studies do indeed reliably detect emotion-related activity in the brainstem and hypothalamus (Kober et al., 2008; Wager, Barrett, et al., 2008). Taken together, previous research suggests that the neural architecture of human emotion may more closely resemble that observed in animal research, and regions such as the brainstem and hypothalamus can be reliably imaged using standard neuroimaging techniques. In the present research, we chose to focus on the midbrain PAG, an area thought to be central in driving emotional experience and physiology in non-human animals, particularly in response to threat (Bandler & Carrive, 1988; Cezario, Ribeiro-Barbosa, Baldo, & Canteras, 2008), as part of the motivational drive for hunting and foraging (Sukikara, Mota-Ortiz, Baldo, Felicio, & Canteras, 2010) and during sexual and maternal behaviors (Salzberg, Lonstein, & Stern, 2002). Across these diverse affective and motivational circumstances, PAG may serve to flexibly coordinate the common and distinct at U niersity of C orado on M arch 8, 2012 http://scaordjournals.org/ D ow nladed from PERIAQUEDUCTAL GRAY 6 brain regions needed to implement an appropriate set of behavioral, physiological, and experiential responses (Bandler & Shipley, 1994; Behbehani, 1995; Panksepp, 1998). In spite of this considerable animal literature suggesting PAG involvement in affective and motivational processes beyond nociception, the human neuroimaging literature on emotion seldom has discussed PAG (for exceptions, see: Damasio et al., 2000; Del-Ben & Graeff, 2009; Linnman, Moulton, Barmettler, Becerra, & Borsook, 2011; Mobbs et al., 2009; Mobbs et al., 2007; Mobbs et al., 2010; Wager et al., 2009). However, a growing literature on PAG activity related to physical pain—a strong elicitor of negative affect— suggests that PAG can be reliably imaged with current standard fMRI sequences (Kong et al., 2010; Linnman et al., 2011; Schoell et al., 2010; Wager et al., 2004). While it is not clear if this PAG activity is directly related to the emotional aspect of pain, recent meta-analyses of human neuroimaging studies found consistent activation of PAG during negative emotional processing unrelated to nociception (Kober et al., 2008; Wager, Barrett, et al., 2008), suggesting the limited discussion of PAG in the human emotion literature may not reflect a true functional difference between species. To address this issue, we first conducted an experiment that interleaved phasic heat stimulation and presentation of aversive photographs during a single fMRI session. We chose physical pain and negative image viewing because we have found both reliably increase negative affect. We hypothesized that PAG activity would be greater during both pain and negative image viewing, consistent with animal data demonstrating a broad role for PAG in negative emotion. While pain is an inherently aversive primary reinforcer, images typically require conceptual, social, or memory-guided interpretation in order to at U niersity of C orado on M arch 8, 2012 http://scaordjournals.org/ D ow nladed from PERIAQUEDUCTAL GRAY 7 evoke emotion. Thus, this study also explores whether PAG is activated even when affective responses are largely conceptually driven, a possibility not easily tested in animal models. To provide additional, independent tests of our hypothesis, we next examined the area of PAG overlap in eight additional datasets, four of which featured high and low pain and four of which featured negative and neutral images. Altogether, these independent datasets comprised 198 additional participants. Despite heterogeneity in the experimental designs, participant demographics, analysis techniques, and MRI magnets used, we hypothesized we would observe increased activity in PAG in all eight studies. Taken together, these findings would suggest PAG is a core region involved in human emotion. Methods Participants The initial study included 16 participants (5 women; ages 18-45, M(SD) =