Identification of suprathreshold voxels
The results of the MKDA analysis were reported earlier in an abbreviated form (Wager et al., 2008
) and are discussed and interpreted below in fuller detail in the context of the functional group analysis. Panels A–C in show the (unweighted) activation peaks from all the 437 CIMs plotted on the orbital, lateral, and medial surfaces on the brain (respectively). As can be seen, activations across studies are distributed throughout the cortex; to achieve significance in the MKDA analysis, any single voxel has to be consistently activated by over 4% of the contrasts in our metaanalysis (e.g. ~ 18 contrasts or more activating in the same location, depending on the study weights). Panels D–F in show regions that were consistently activated across neuroimaging studies as determined by our analysis. Yellow regions represent peak activation foci, FWER corrected at p
<.05. Other colored regions are FWER corrected for spatial extent at p
<.05 with primary alpha levels of .001 (orange), and .01 (pink). Slices corresponding to key regions are shown in . Stereotactic coordinates for the peak activation foci and the weighted percentage of activating CIMs in each contiguous corrected region (yellow in and ) are listed in . While many of these appear low in terms of absolute percentage of CIMs, there are sufficient numbers of reported activations in the same location to inspire confidence in their reliability.
Fig. 4 (A–C) Un-weighted peak activations from all 437 contrasts in our meta-analysis are plotted on the lateral, orbital, and medial surfaces on the brain, respectively. Activations across studies are distributed throughout the cortex, though clusters (more ...)
Fig. 5 (A) Unweighted peak activations from all the 437 contrasts in our meta-analysis are plotted on the subcortical surface. (B) Regions that were consistently activated across neuroimaging studies as determined by the meta-analysis are plotted on the subcortical (more ...)
First, and importantly, significant activations were found in a subset of frontal cortical regions. While individual studies reported activations spanning the lateral surface of the cortex ( and ), only a few activations were found to be consistent across all studies (). Significant activations in inferior frontal gyrus (IFG) bilaterally extend from the pars opercularis (Broca's area, BA 44) through pars triangularis (BA 45) and pars orbitalis on the inferior frontal convexity (BA 47) and into the frontal operculum (frOP), and are contiguous with activations in posterior OFC and the anterior insula (aIns; see , and for details).
Fig. 6 Detailed maps of orbitofrontal and visuotopic subregions. (A) Orbitofrontal and visuotopic subregions as well as significant activations are overlaid on the orbital surface. Orbitofrontal regions are as described by Ongur, Ferry, and Price (2003) as implemented (more ...)
On the medial surface (), activations were found in pre-SMA, dmPFC (BA 9 extending back to BA 32), and the cingulate cortex. Cingulate activations were largely limited to the rostral half of the ACC, corresponding to both the “affective” and “cognitive” zones (Bush et al., 2000
; Etkin et al., 2006
). Strikingly, these cingulate activations were clustered into three distinct foci, corresponding to rdACC (BA 24a/b, the so called “cognitive” zone in (Bush et al., 2000
), pgACC (BA24), and sgACC (corresponding to the so-called “affective” zone; See ).
Activations were found in temporal, occipital, and parietal association cortices. Consistent activations were also observed in a right-lateralized area within posterior STS, and the medial and lateral anterior temporal cortex near the TPJ ( and ). Regions of medial temporal cortex bordering on vaIns and parahippocampal cortex were consistently activated as well. Occipital activations were surprisingly relatively well localized to visual areas along the ventral stream from V1 to V8, and in MT+ (see for details). Significant activations were also found in a region in posterior cingulate (PCC). These are discussed in the context of the group analyses, below.
shows the unweighted activations from all the 437 CIMs plotted on the subcortical surface. show regions that were consistently activated across neuroimaging studies plotted on the same surface. Large regions of activation were observed in or around the amygdala (both dorsal and ventral; ), extending into the ventral Striatum (vStr; ), pallidum, nucleus accumbens, hippocampus (HCMP), and the basal forebrain (possibly encompassing sites of cholinergic nuclei). Notably, significant activations in the HCMP were found only in those areas in anterior HCMP that were contiguous to activations in the amygdala. In the brainstem, consistent activations were found in specific, mostly dorsal nuclei, which correspond to findings in animal studies. As shown in the slice in , PAG and SN were consistently activated, as was the rostral pons (), although lower brainstem centers in the pons and medulla were not consistently activated. Consistently activated diencephalic regions included the hypothalamus. Finally, while in many studies cerebellar activations are not reported (and therefore activations might be under-represented in this analysis), consistent activations were found in both lateral and deep nuclei of the cerebellum (CB; ). Taken together, these results suggest that – like animal studies – human neuroimaging studies do reliably activate subcortical regions such as the Hy or PAG.
Functional groups associated with emotion and affect
We identified six groups of regions that were consistently co-activated across studies of emotion and affect – each group is discussed below followed by a discussion of the connections between them. The functional groups are depicted in 3D rendering on the single-subject brain in ; Clockwise from the bottom left, the Lateral Occipital/Visual Association group
(, in yellow) includes cortical regions in the right and left lateral occipital gyrus and right occipital/temporal cortex, and CB (contiguous with inferior temporal cortex). Closely related is the Medial Posterior group
(Panel B, in magenta), which includes V1 (Primary Visual cortex) and PCC. The Cognitive/Motor group
(Panel C, in light blue) includes the right frOP, bilateral IFG, and the preSMA/left middle frontal gyrus. The Cognitive/Motor group
connects along multiple association routes to the Lateral Paralimbic group
(Panel D, in green), which includes the vStr, vpIns, daIns, vaIns/posterior orbital gyrus, and temporal pole. We also identified a Medial PFC group
(Panel E, in dark blue), which includes rostral–dorsal and pregenual subsection of the anterior cingulate cortex as well as dmPFC. Both the Lateral Paralimbic group and the Medial PFC group
importantly connects to the Core Limbic group
(F, in red), which includes the amygdala/left HCMP, thalamus extending into PAG, additional areas of ventral striatum, and lateral Hy. This functional group includes areas typically considered to be critical for affective behavior in animals (Bandler and Shipley, 1994
; Berridge, 1999
; LeDoux, 2000
; Panksepp, 1998
) and therefore provides a crucial link between animal and human studies. Panel G shows the co-activation patterns between these functional groups (for details, see the next section and the figure legend). lists the regions found in the MKDA analysis as well as their group affiliation.
Fig. 7 (A–F) The six functional groups revealed by our multivariate analysis are depicted in 3D rendering on the single-subject brain. Regions in each group are rendered in a unique color. (G) To visualize the relationships among the regions in each (more ...)
Regions and their Functional Group Affiliation
Lateral Occipital/Visual Association group and Medial Posterior group
Regions in these functional groups () are closely connected structurally, as well as functionally, and are likely to play a joint role in visual processing and attention to emotional stimuli; we therefore discuss their functional roles together.
The first important observation here is that consistent activations in visual areas were found. 75% of the studies included in this meta-analysis used visual stimuli to elicit emotions, and we examined whether visual activations were limited largely to these studies. Of the 28 studies (producing 37 contrasts) that activated in the V1 region described in our analysis, 26 used visual stimuli; only 2 studies activating in this area used other methods (olfactory stimuli, e.g. Royet et al., 2001
; Zatorre et al., 2000
). All of the visually induced emotion studies compared emotional conditions with comparable neutral control conditions. Thus, the localization of increased visual activation to V1, V4, and V8 (as seen in ) suggests that both early and late visual processing (primarily in the ventral stream) is enhanced in emotion when compared to neutral control conditions.
One possible explanation for this finding is that emotionally evocative stimuli are more visually complex or systematically differ from neutral stimuli in their perceptual characteristics. This alternative cannot be definitively ruled out, although most emotion studies compare affective and neutral stimuli matched fairly well on perceptual characteristics (Taylor et al., 2000
). A second possibility, supported by the neuroanatomical evidence, is that projections from limbic circuitry enhance activation in the ventral stream when viewing emotional content (for a discussion, see Duncan and Barrett, 2007
). According to this alternative, the affective salience of a stimulus directly influences visual activity. This interpretation is supported by several lines of evidence: a) recent electrophysiology work shows reward-timing prediction by neurons in V1 (Shuler and Bear, 2006
); b) recent ERP work shows that the C1 potential, associated with primary visual cortex, can be influenced by prior conditioning with affective International Affective Picture System (IAPS) images (Stolarova et al., 2006
); c) anatomical studies show direct projections from amygdala to V1 (Freese and Amaral, 2005
); and d) a neuroimaging study showed that amygdala-damaged patients show reduced visual cortical responses to emotional faces (Vuilleumier et al., 2004
). Consistent with this hypothesis, we found that V1 was directly associated and co-activated with the region encompassing vStr, GP, and the right amygdala, as can be seen in . Either by this means, or because of top–down, goal related influences (e.g., due to differential eye fixation patterns when viewing emotional stimuli; van Reekum et al., 2007
), evocative stimuli may elicit different patterns of fixation during viewing and consequently different visual activation.
Activations in TPJ and STS are often implicated in Theory of Mind (Saxe and Kanwisher, 2003
) and in intentional action, respectively (Saxe et al., 2004
). The inclusion of these areas in a posterior–cortical functional group consisting of occipital regions may reflect the frequent use of “social” visual stimuli to evoke emotions (e.g. faces or IAPS images featuring people, used in over 50% of the studies in the meta-analysis, and in the vast majority of those activating regions in this functional group, as illustrated above). However, this area is more generally considered multimodal association cortex (Kandel et al., 2000
; Macaluso and Driver, 2001
), and it may play a more general role in high-level visual processing. In studies of attention, similar activations result from salient changes in visual information or attention (Corbetta and Shulman, 2002
); a common theme may be making inferences and processing the conceptual relevance of visual elements.
Although the precise function of PCC in emotion remains unclear, several roles have been proposed. It may play a role in memory-guided representation of context important for conceptual processing in emotion (Maddock, 1999
; Mantani et al., 2005
; Minoshima et al., 1997
) or in allocating spatial attention (Mesulam et al., 2001
; Small et al., 2003
). Also, along with activations in vmPFC and dmPFC, activation of PCC might be a part of the resting state or “default” network, which appears to mediate associative, internally-generated thought processes (Greicius et al., 2003
; Gusnard and Raichle, 2001
), suggesting a role for self-directed attention in emotional events. Consistently, activation in PCC has shown linear increases with self-relevance (Moran et al., 2006
), and recent TMS work has shown that PCC is essential for episodic memory retrieval of self-representations (but not for other-representations; Lou et al., 2004
). However, an alternative interpretation given the resting state activity pattern attributed to the PCC is that activations in contrasts comparing emotional conditions with control conditions may in fact reflect lower levels of deactivations in the emotion condition compared to the control condition.
Given several potential major roles for PCC (discussed above), the co-activation results support the visual attention hypothesis, although further research is needed to disambiguate the affective functions of the PCC. This need is underscored by the apparent importance of PCC in this functional group analysis; as seen in , the PCC serves as a “relay-station” to other functional groups, as it directly connects to the dmPFC and pgACC in the Medial PFC group (which is consistent with the default network), and to the vStr, midIns, and HCMP in the Lateral Paralimbic group.
The consistent cerebellar activation we observed might be related to increased demands on motor planning during affective and emotional states, but there is accumulating evidence for a more direct cerebellar role in emotion-related processing more generally. Electrical stimulation of deep cerebellar nuclei in humans has been shown to induce activity in mesolimbic affect-related areas (Heath et al., 1978
) and, in some cases, to elicit states of profound rage (Heath et al., 1974
). Conversely, CB damage often leads to emotion dysregulation, characterized by fluctuations between flattened affect and inappropriate social behaviors (Schmahmann and Sherman, 1998
) reminiscent of social and emotional deficits with OFC damage. The CB is connected with specific prefrontal regions in topographically mapped reciprocal circuits (Middleton and Strick, 1994
) and with “limbic” regions, including the Hy (Haines and Dietrichs, 1984
), OFC, dmPFC, portions of IFG, and inferior frontal convexity (BA 46/12) (Middleton and Strick, 2001
). Cerebellar efferents to these areas pass largely through DM in the thalamus, which we also find is consistently activated in human emotion. One hypothesis is that the CB might contribute to the processing of situational context (Schmahmann and Sherman, 1998
) as part of a complex pattern-recognition system (Albus, 1971
). However, it is also possible that the inclusion of the superior cerebellum in this functional group is an artifact due to inconsistent spatial normalization across studies, as warping procedures typically behave poorly in this region (Diedrichsen, 2006
). Thus, the connectivity with occipital regions may be driven by peaks that actually lie within the inferior temporal–occipital cortex. Nevertheless, this does not preclude the notion that the superior lateral neocerebellum may be consistently activated in studies of emotion and affect.
Like the two functional groups discussed above, activation of this functional group (, in light blue) is most likely not specific to emotion, consistent with the idea that emotions are mental events constructed from a number of component cognitive, affective, perceptual, and motor processes (Barrett, 2006b
; Barrett et al., 2007b
). The group consists of pre-SMA, bilateral IFG, and frOP. The pre-SMA is thought to underlie representation of intentional action (Lau et al., 2004
), or in related conceptions, energization of cognitive systems to orient and respond based on internal cues (Stuss and Alexander, 2007
). Both the IFG and the frOP have been previously reported not only in many studies of emotion, but also in neuroimaging studies of response inhibition and selection, task switching, and working memory (Aron et al., 2003
; Badre et al., 2005
; Gabrieli et al., 1998
; Martin and Chao, 2001
; Poldrack et al., 1999
; Wager et al., 2005
; Wagner et al., 2001
). The right IFG and right frOP in particular are hypothesized to be parts of a ventral frontoparietal network of attention to sensory stimuli of potential behavioral significance (Corbetta and Shulman, 2002
) and have been specifically implicated in manipulation of information in working memory (Wager and Smith, 2003
) and in response inhibition across domains (Aron et al., 2004a
; Nee et al., 2007
). A general role for BA 44/45 and the operculum might be context-based selection among competing stimulus–response mappings or sets (Thompson-Schill et al., 1997
), with left specialization for semantic and right specialization for late-stage response selection (Nee et al., 2007
Though the precise information-processing roles of the regions in this functional group may be dissociable, meta-analyses have shown that activation of all regions—pre-SMA, IFG, and frOP—is a consistent feature of cognitive control operations (Nee et al., 2007
; Wager et al., 2004a
; Wager and Smith, 2003
). Prior studies of functional connectivity have also shown that bilateral vlPFC/ frOP and preSMA form a functional network during cognitive control tasks (Wager et al., 2005
). Given this evidence for functional integration in cognitive tasks and the functional roles discussed above—namely, the role of IFG/frOP in attention for action (Corbetta and Shulman, 2002
), right IFG in response inhibition (Nee et al., 2007
), and preSMA in selection for action—this functional group is likely to play an important role in context-appropriate selection of actions and attention for action.
In emotion-related phenomena, these frontal–lateral region may be important for the information selection that is integral to analysis of meaning of emotional input, such as that associated with appraisal or conceptual categorization and labeling of affect, (Lieberman et al., 2007
) and in shaping subsequent behavior and physiological responses via projections to subcortical areas such as the PAG (An et al., 1998
). In support of this notion, emotion- and pain-related activity in IFG and the operculum is modified by manipulations of the context in which affective stimuli are presented, such as when pain expectations are changed (Benedetti et al., 2005
; Kong et al., 2006
; Wager et al., 2004b
). Activity in these areas is also modified by voluntary regulation of emotional responses, such as when participants are asked to use cognitive strategies to reduce or increase negative emotion, (Johnstone et al., 2007
; Ochsner et al., 2002
). Further, in emotion regulation, the IFG was found to be inversely correlated with amygdala via mPFC, a relationship that is disrupted in depression (Johnstone et al., 2007
Lateral Paralimbic group
This functional group is likely to play an important role in motivation. Both the OFC (including posterior orbital gyrus) and the vStr are thought to contribute to valuation of stimuli in general and rewards in particular. Specifically, vStr, is sensitive to both reward and punishment (Delgado et al., 2000
) and has been implicated in reward prediction (O'Doherty et al., 2004
). Similarly, OFC is sensititve to both rewards and punishment (Kringelbach and Rolls, 2004
; O'Doherty et al., 2001
), and is capable of reward discrimination, valuation, and prediction in both animals and humans (Gottfried et al., 2003
; Schultz et al., 2000
). Sub regions of the OFC activated in this meta-analysis () as well as the insula are thought to belong to the Orbital Sensory network proposed by Ongur & Price and are known to receive olfactory, visceral, and gustatory inputs (Ongur and Price, 2000
). Importantly, these OFC sub-regions are neuroanatomically interconnected with the amygdala and vStr (Ongur and Price, 2000
), connections that are also evident in the group analysis (). Consistently, one possible role for the OFC is to facilitate associative flexibility that is coded in such subcortical structures (for discussion, see Barrett et al., 2007c
In a recent meta-analysis of insula activation across studies of pain, emotion, attention shifting, and working memory (Wager and Barrett, 2004
). vaIns was associated relatively specifically with emotion, particularly emotion elicited by autobiographical memory retrieval, which is likely to elicit relatively strong experienced emotion. By contrast, daIns was activated primarily by pain and cognitive response selection tasks that require motivated selection for action. Based on these findings, the authors proposed a continuum from vIns, which is most closely connected to brainstem and other core limbic regions and is functionally related to emotional and affective sensory experience, through dIns and frOP, which are more heavily interconnected with lateral frontal cognitive and motor systems. The present results provide some support for this view: the daIns region appears to form a bridge between the pre-SMA and the vaIns (). The ventral insular regions, but not the dorsal ones, connect directly to the “core limbic” regions of ventral Thal, Hy, PAG, and vStr.
Lastly, activity in right daIns has been associated with interoception, or representation of bodily responses (Craig, 2002
; Critchley et al., 2004
), which contribute to both broad and specific affective states. Therefore, it is likely that this functional group has a role in evaluating “bottom–up” internal as well as external affective signals and integrating them into motivational states with associated goals. Indeed, the close links between this group and both the Cognitive/Motor group
and the Medial PFC group
further emphasizes its integrative role with cognitive inputs processed in medial and lateral prefrontal cortex.
Interestingly, the HCMP was part of early definitions of the limbic system (Maclean, 1949
; Papez, 1937
) and was a focus of early human brain stimulation work on emotion (Sem-Jacobsen, 1968
), but its role in emotion has not been emphasized as much recently because of a lack of obvious emotional deficits in animals with hippocampal lesions (but cf. Gray and McNaughton, 2000
; Maren et al., 1997
). Activation in HCMP suggests that memory retrieval might play a role in emotion. Further, the concurrent activation of PCC, MTL, and mPFC might represent elements of a memory retrieval circuit that has been previously identified (Vincent et al., 2006
) that could interact with the frontal information selection and appraisal circuit of IFG/dmPFC.
Medial PFC group
This functional group, which encompasses the ACC subregions that were activated in this meta-analysis as well as dmPFC, is likely to play a role in both the generation and regulation of emotion. The regions in this functional group have been identified as a part of a medial visceromotor network (Ongur and Price, 2000
) and each region shows evidence for context-based generation and modulation of emotion. While the regions cluster into the same functional group in our analyses, there is evidence that their roles are related but may also be dissociable. In humans, activity in pgACC has classically been associated with resolution of conflict in emotional Stroop tasks (Bush et al., 2000
; Etkin et al., 2006
), but also correlated with heart rate during cognitively generated stress (Wager et al., 2006
) and motivated selection and/or maintenance of task goals (Summerfield et al., 2006
; Wager et al., 2005
). Further, pgACC shows increases in activity and opioid release with placebo treatment in pain (Petrovic et al., 2002
; Wager et al., 2004a
; Zubieta et al., 2005
). In addition, the rdACC has been directly implicated in the cognitive modulation of pain affect (Faymonville et al., 2000
; Rainville et al., 1997
; Wager et al., 2004b
Interestingly, a recent meta-analysis of anxiety disorders (Etkin and Wager, 2007
) showed rdACC to be hyperactive in patients with specific phobias (compared to controls), and in fear conditioning in nonclinical populations; the rdACC and mOFC/sgACC were also observed to be consistently hypoactive in PTSD patients compared to controls, suggesting a direct link between altered function in this region and dysregulation of affect. Importantly, the pgACC peak found in our analysis extends into this area of sgACC, which has been functionally implicated in depression in several ways. Namely, the sgACC has been found to be hypoactivate in depression Drevets et al., 2002
, and to be modulated by treatment with selective serotonin reuptake inhibitors (SSRIs; Drevets et al., 2002
; Mayberg et al., 2000
) as well as by deep brain stimulation in treatment-resistant depression (Mayberg et al., 2005
). Metabolic decreases in this area were related to clinical improvement in these studies, and may be mediated by connectivity to OFC, pgACC, hypothalamus, NAcc, and the amygdala/HCMP (Johansen-Berg et al., 2008
). In addition, regions of vmPFC (just anterior to sgACC) have been shown to inversely correlate with amygdala during successful emotion regulation. Additional findings that this inverse pattern predicts a more adaptive diurnal rhythm of circulating free cortisol in older adults and is absent in depressed individuals, further implicates medial frontal regions in affective functioning (Johnstone et al., 2007
; Urry et al., 2006
The functional contributions of mPFC have yet to be precisely determined, but recent research and theorizing suggests that these brain areas jointly contribute to making mental state attributions (for reviews, see Adolphs, 2001
; Blakemore et al., 2004
; Lane and McRae, 2004
) such as when a person makes judgments about the psychological states of another person, or monitors, introspects, or makes inferences about his or her own moment-to-moment feelings (also see Ochsner et al., 2004b
). Further, it has also been implicated in anticipation of pain (Porro et al., 2002
), with a potential role in generating second-order appraisals leading to secondary pain affect (Price, 2000
). Further, it has been suggested that the dorsal portions of mPFC are uniquely associated with the metacognitive ability to monitor, re-represent, or re-describe affective inputs, as occurs in cognitive generation of emotion and in emotion regulation (Ochsner and Gross, 2005
; Ochsner et al., 2004a
One surprising feature of these results is that while the Medial PFC group
is directly connected to both the Core Limbic group
and the Lateral Paralimbic group
, we did not observe direct functional connectivity between the Cognitive/Motor group
and the Medial PFC group
; rather, dorsal and posterior insular regions (in the Paralimbic group
; ) served as a bridge between the two groups. This suggests that the Medial PFC group
is more related to core affective responses than to cognitive–motor activity. Consistent with these findings, areas of the medial wall including pgACC, are known to have direct projections to the Hy and lower brainstem autonomic effectors (Saper, 1995
), have been related to visceromotor control (Vogt et al., 1992
), and to extinction of conditioned fear responses (Milad and Quirk, 2002
) in animal studies. Further, different subregions of mPFC appear to play different and perhaps opposing roles in the generation and regulation of hypothalamic–pituitary–adrenal “stress” responses (Sullivan and Gratton, 2002
). Taken together, it seems likely that this Medial PFC group
interfaces between cognitive context and core affect, and as some subregions may be more associated with cognitive representation and context-generated emotion (dmPFC), others may be more closely related to control over affective physiology (pgACC).
Core Limbic group
This functional group represents the closest parallel to findings in the animal literature. The PAG is thought to participate in regulation of autonomic responses related to the psychophysiology of emotion, and it is likely that in humans, like in animals, it serves as an integrative emotional center, receiving direct cortical inputs (e.g. mPFC, OFC, Ins), and projecting to the lower brainstem neuclei as well as to the hypothalamus. Further, it is known that dopaminergic neurons in SN fire in response to rewarding (Schultz et al., 1997
) and to simply salient events (Horvitz, 2000
), and recent work has shown that phasic firing of these neurons specifically indicates error in reward prediction in animals (Schultz and Dickinson, 2000
) as well as humans (Montague et al., 2004
). Similar responses were recorded in humans to cognitive feedback even in absence of reward (Aron et al., 2004b
). Lastly, SN projects to vStr, which is itself implicated in reward prediction (O'Doherty et al., 2004
). It is likely, therefore, that the SN and vStr play a role in appetitive learning and in response to salient events in the environment, including emotion-related stimuli and possibly emotional experience.
Significant activations were also found throughout the dorsal Thal, with maximal consistency in the central medial zone, around the “limbic” mediodorsal and centromedian nuclei (). The subnuclei of the thalamus are heavily connected in reciprocal circuits with much of the forebrain and provide avenues of communication among cortical regions (see Edelman and Tononi, 2001
, for review). As described above, consistent activations in the Hy in studies of emotion (69 contrasts, from 52 studies) is likely to reflect its role in regulation of stress responses, motivated behavior, and homeostatic processes, as well as its interaction with the autonomic nervous system and control of bodily states via the endocrine system.
While the amygdala is consistently activated in neuroimaging studies of emotion, its role in emotion generation or experience is not clear, as findings in individual studies are somewhat inconsistent. One possibility is that the amygdala may set the stage for, but not be intrinsic to the implementation of, emotion experience (Barrett et al., 2007a
). Some of the discrepancy in findings may also stem from the highly differentiated structure of the amygdala; it is organized into three sub-complexes, the basolateral, cortico-medial, and central, which are further comprised of over 20 distinct nuclei, thought to perform distinct operations (Swanson and Petrovich, 1998
). Indeed, many roles have been proposed for the amygdala; some argue that the amygdala is critical to fear-related processing (LeDoux, 2000
), although two recent meta-analyses (Murphy et al., 2003
; Phan et al., 2002
) reported that only 40%–60% of the studies involving the experience or perception of fear showed increased amygdala activation (Barrett and Wager, 2006
). Moreover, neither is amygdala activity specific to the category “fear.” We previously reported that the most fear-related region in the amygdala (the superior amygdala) is just as responsive to disgust-related stimuli (Wager et al., 2008
). In individual studies as well, amygdala activation is found not only for fearful faces, but also for happy and angry faces, compared to neutral faces (Breiter et al., 1996
; Whalen et al., 2001
, respectively). At the level of the single neuron, single cells in the primate's amygdala respond to stimuli that acquire both positive and negative value during conditioning (Paton et al., 2006
). Consistently, it has been suggested that amygdala activity has a general role in evaluation of affective significance (Phelps and Anderson, 1997
), as well as other roles in mediating emotional memory (LaBar and Cabeza, 2006
; Mather, 2007
), and as related to a general dispositional style (Davidson and Irwin, 1999
). Importantly, however, the human amygdala also responds to novelty (Wright et al., 2006
) and habituates quickly once the stimulus acquires a clear and certain predictive value (Fischer et al., 2003
), which is consistent with an alternate view that the amygdala tags stimuli of unknown or uncertain predictive value to increase attention, so that more can be learned about their value on the next encounter or trial (Barrett et al., 2007a
Connections Among Functional Groups
Once we identified the six functional groups most associated with emotion, we examined patterns of co-activation among these groups across studies, testing for co-activation between areas within groups. To visualize the relationships among the regions in each functional group, displays both regions and co-activation lines on a “flattened” map of the connectivity space along the first two dimensions determined by NMDS (as described in the methods section), and with matching colors to the 3D groups. Points that are closer together on this map tend to have positive co-activation, and connected lines represent significant Tau-b (τ) association values between pairs of two regions (FDR corrected). Importantly, this map has been “pruned” such that the relationships depicted by these lines represent only those functional relationships between regions that were not completely mediated by any other region.
As can be seen from the “pruned” flattened map, there appears to be a strong relationship between the Medial PFC group and the Core Limbic group. Medial PFC group regions such as dmPFC and pgACC are directly coactivated with PAG/Thal and vStr/Amygdala, respectively, both in the Core Limbic group. In addition, these two groups appear to be indirectly connected along multiple routes via the Lateral Paralimbic group (via regions such as the vpIns).
Frontal areas in the Cognitive/Motor group are also directly associated with areas in the Lateral Paralimbic group; in turn, these areas (e.g. vaIns) are directly related to areas in the Core Limbic group. Therefore, areas that are part of the Cognitive/Motor group such as frOP may be co-activated with brainstem areas such as PAG in the Core Limbic group, through coactivations in the Lateral Paralimbic group or through concurrent coactivations in both the Lateral Paralimbic and the Medial PFC group. This pattern of connectivity could indicate that while appraisals generated in the Medial PFC group directly influence activity in limbic regions, they also converge in insular regions with other core limbic inputs to influence more general motivational states, which could influence attention and selection of action in the Cognitive/Motor group.
Importantly, in further analyses of these associations (described in the next section), we chose to focus on frontal–posterior co-activations, as these are thought to be critical components of emotion-inducing appraisal in humans; we therefore tested frontalamygdala, frontal-PAG and frontal-Hy links. Positive findings would suggest the presence of anatomically specific cortical–limbic and cortical–brainstem pathways that may be tested in future individual neuroimaging studies.
Frontal interaction with amygdala
Recently, neuroimaging studies have highlighted fronto-amygdala interactions, especially because medial PFC regions are thought to be involved in regulation of amygdala responses to negative events. Several studies have reported negative correlations between amygdala and activity in both vmPFC (Johnstone et al., 2007
; Urry et al., 2006
) and lateral PFC (Lieberman et al., 2007
; Ochsner et al., 2002
). Both animal and human neuroimaging studies show mPFC is critical for fear extinction and modulating learned fear responses via amygdala (Gottfried and Dolan, 2004
; Milad and Quirk, 2002
; Phelps et al., 2004
). In PTSD, hypo-frontality is functionally associated with hyperactivity in amygdala (Etkin and Wager, 2007
). However, other studies have shown mPFC sub-regions relate positively to stress and negative emotion—e.g. in animals studies, stimulation of prelimbic cortex causes Hy increases and HPA axis activation and cortisol release (Sullivan and Gratton, 2002
). Therefore, it is of interest to know which frontal regions are most strongly co-activated with amygdala, whether different frontal regions co-activate with distinct amygdala sub-regions, whether these are the same frontal regions that co-activated with PAG and Hy, and whether any regions show negative co-activation (which would imply that activation of PFC region results in reduced probability of a study activating amygdala).
To that end, we selected parcels that corresponded to the basolateral complex and the superior amygdala (corresponding to centro-medial complex, the superficial amygdala, and the central nucleus) bilaterally using the SPM Anatomy Toolbox (V15) as a guide (Eickhoff et al., 2006
). shows the regions depicted in the toolbox; shows the parcels that were found in this meta-analysis. Once we identified four distinct parcels—namely, Right BasoLateral (RBL), Left BasoLateral (LBL), Right Superior Amygdala (RSA), and Left Superior Amygdala (LSA)—we looked for any individual frontal regions that were co-activated with each of the amygdala sub-regions, by re-computing Tau-b (τ) associations for each frontal–amygdala pair of regions. Results were FDR corrected, and are shown in .
Fig. 8 (A) Amygdala sub-regions specified in the SPM Anatomical Toolbox. The Basolateral Amygdala (BL) is depicted in magenta; the Centro-Medial complex (CM) is depicted in blue; the Superficial Amygdala (SF) is depicted in cyan. (B) Amygdala sub-regions identified (more ...)
Several frontal regions were significantly co-activated with amygdala sub-regions, especially along the medial wall, and ventral areas showed more frequent associations with amygdala than dorsal. The most strongly connected regions (in the sense that they correlated significantly with multiple amygdala sub-regions) were pgACC (), rdACC (), and right frOP (), which are consistent with the literature discussed above. More specifically, dmPFC was co-activated only with one amygdala sub-region, LSA3
, the right frOP was co-activated with LBL, RSA, and LSA (but not the RBL)4
, the rdACC was co-activated with RBL, RSA, and LSA (but not LBL).5
Finally, the pgACC was co-activated with RBL, RSA, LSA (but not LBL).6
These results illustrate that each of the frontal regions has a unique pattern of co-activation with amygdala sub-regions in this analysis, and that amygdala sub-regions have unique patterns of co-activation with frontal regions. Indeed, the only amygdala sub-region that showed strong association with all frontal regions in this analysis is the LSA; this is consistent with previous meta-analyses of emotion that found amygdala activation to be left-lateralized and superior (Wager et al., 2003
However, while the regions identified were consistent with our predictions, we did not find any inverse co-activation between any frontal regions and amygdala. This may be attributed to the absence of emotion regulation studies from this meta-analysis. It is possible that such an inverse functional relationship is expressed when emotional experience is influenced by context or processes of valuation, rather than valence per se (Wager et al., 2003
). Lastly, as we show below, mPFC regions are also functionally associated with PAG/Hy activity, although there is evidence for a different pattern within mFPC.
Frontal interaction with PAG and Hy
In animal models of emotion, the PAG and Hy are considered both central and critical. While they have been shown to mediate physiological effects of emotion and stress through the HPA axis and autonomic nervous system, whether they broadly mediate the instantiation of emotional states is unknown. For example, Mobbs et al. (2007)
recently reported PAG activation in conditions of proximal threat, along with correlations between PAG activity and the experience of dread, suggesting parallelism between human and animal responses to threat. Consistent with these findings we find the cluster encompassing PAG and Thal and a region centered on Hy activated consistently in a range of emotion conditions, including those in experimental imaging studies by cognitive factors (memory for emotional events, cognitively mediated threat, etc.). Therefore, although PAG and Hy may serve similar functional roles in animals and humans, cortical generators of PAG and Hy responses are likely to be different in humans and animals. This potential difference underscores the need to identify those cortical correlates of PAG and HY in humans, especially in PFC.
Functional co-activation with PAG and Hy
The group analyses discussed above shows that areas in medial PFC are functionally positioned in close proximity to subcortical brainstem limbic structures, such as PAG and Hy, while lateral PFC regions in the Cognitive/Motor group
were only associated with these subcortical structures through areas in the Lateral Paralimbic group
. However, regions such as lateral PFC figure prominently in some theories of cognitive generation and control of emotion (Ochsner and Gross, 2005
; Wager, 2005
). Therefore, we first looked for any individual frontal regions that were co-activated with PAG and Hy. Results are shown in . Right frOP, rdACC, and dmPFC are co-activated with the Core Limbic group
region encompassing the Thal and PAG.7
Importantly, this is a subset of the regions that were co-activated with amygdala. However, only two of these three regions were also connected with multiple amygdala structures (namely, rdACC and frOP). Conversely, and as shown in , dmPFC is the only frontal region co-activated with Hy in our analysis.8
Fig. 9 Co-activation of frontal and subcortical regions. (A) Frontal cortical regions that are co-activated with PAG. Color of activated areas indicate the network to which they belong — dark blue for the mPFC network (dmPFC, rdACC), light blue for the (more ...)
Testing mediations in the DMPFC-PAG-Hy pathway
Because Hy and PAG/Thal were found to be co-activated in the functional groups analysis (both are part of the Core Limbic group), and because dmPFC was found to be the only frontal area co-activated with both regions in subsequent analysis, we focus on this relationship in the mediation analyses. We do not report mediation analyses involving amygdala here, because frontal connections with amygdala sub-regions were more numerous and less specific, making path modeling less informative and less reliable. summarize the two-way patterns of co-activation among the dmPFC, PAG, and Hy. summarize the three-way contingencies of dmPFC and Hy when PAG/Thal region is active and inactive, respectively. As can be seen from the tables, dmPFC and Hy are more likely to be active when PAG/Thal is active than when it is inactive.
To further our understanding of this relationship, we examined the neuroanatomical projections between these regions. Although the human–monkey homology is often not entirely clear, it is known that monkey PAG and Hy have massive bidirectional projections (Beitz, 1982
; Cameron et al., 1995
). Similarly, it had been suggested that the region of dmPFC homologous to the one we observed (superior dmPFC/BA9; e.g. Ongur and Price, 2000
) is connected via a unidirectional projection to PAG (An et al., 1998
; Mantyh, 1983
), and that the same area of dmPFC projects heavily to Hy as well (Ongur et al., 1998
; Ongur and Price, 2000
). Therefore, based on this and the activation and co-activation evidence presented above, we reasoned that dmPFC is part of an appraisal system involved in the cognitive generation of emotion. Consequently, we predicted a functional pathway in co-activation across studies from dmPFC through PAG to Hy, and tested this hypothesis using path analysis, first using the PAG/Thal region that was identified in the NMDS analysis, and then testing PAG and Thal parcels separately.
The functional regions in question are shown in in which the arrows illustrate the potential directionality of a top–down projection from dmPFC through PAG/Thal to Hy. The critical test of this model is of the indirect pathway between dmPFC and Hy, mediated by PAG (e.g. whether a pathway through PAG explains a significant amount of the co-activation between dmPFC and Hy). Importantly, this mediation is not a test of directional (i.e., causal) association; we believe that making directional inferences with confidence in this case requires manipulation of variables (Rubin, 1986
). However, the results of such analyses may serve to inform directional hypotheses, especially when coupled with examination of directionality of anatomical projections. Further, such results may serve to both inform and inspire future empirical work that could directly test the related hypotheses.
Fig. 10 Mediation model and analyses for the association between dmPFC, Hy, and PAG/Thal. (A) Visualization of the locations of regions tested in the model and their connectivity in the model tested. (B) PAG/Thal is a complete mediator of dmPFC–Hy co-activation. (more ...)
As shown in , dmPFC and Hy are positively co-activated (total effect c=0.13, SE=0.06, p<.01). However, in the mediation bootstrap test with the PAG/Thal entered into the model, the relationship was no longer significant (direct effect c' = 0.08, SE=0.05, ns). In addition, the test showed that PAG/Thal was co-activated with Hy controlling for dmPFC (b=0.28, SE=0.06, p<.001) and significantly mediated the dmPFC–Hy relationship (ab=0.05, SE=0.02, p<.01). Together, the results suggest that the PAG/Thal region was a complete mediator of dmPFC and Hy co-activation. shows the distributions of the variables as created during the bootstrapping procedure.
Additionally, as the PAG/Thal region identified in the NMDS analysis encompassed two anatomical regions, we performed a set of mediation analyses on each parcel separately, to investigate whether each one independently mediates the relationship between dmPFC and Hy. The Mediation results are presented in . As can be seen in , Thal alone was a complete mediator of the dmPFC–Hy association (ab=0.04, SE=0.02, p<.01; additional statistics are shown in ). As can be seen in , PAG alone was also a complete mediator of the dmPFC–Hy association (ab=0.05, SE=0.02, p<.01; additional statistics are shown in ). However, when both PAG and Thal were entered into the model as simultaneous mediators (), PAG was found to fully mediate the dmPFC–Hy relationship (abPAG= 0.05, SE=0.02, p<.01; c' = 0.08, SE=0.05, ns). Conversely, Thal was no longer a significant mediator (abThal=0.00, SE=0.01, ns) and the Thal–Hy association was no longer significant (bThal=0.01, SE=0.08, ns). This result implies that the co-activation of dmPFC and Hy is mediated by activation in PAG. Three-way contingency tables showing frequency as a function of activation status in the three regions are shown in . In summary, dmPFC was the only frontal region co-activated with both PAG and Hy. Further, PAG appears to be a mediator of dmPFC–Hy co-activation, as suggested by anatomical evidence, which in turn implies a functional pathway from specific portions of the medial frontal cortex (dmPFC) to brainstem and hypothalamic regions thought to be critical for effects of emotion on the body, and possibly for emotional experience as well. This functional pathway implies a role for dmPFC in cognitive generation of emotion, and may be tested in future studies of brain–physiology interactions related to emotion.
Fig. 11 Thal and PAG as separate mediators of the dmPFC–Hy co-activation. Abbreviations for path coefficients are as in . (A) Thal is a complete mediator of the dmPFC–Hy co-activation. (B) PAG is a complete mediator of the dmPFC–Hy (more ...)