Individual variability in brain representations of pain.

Characterizing cerebral contributions to individual variability in pain processing is crucial for personalized pain medicine, but has yet to be done. In the present study, we address this problem by identifying brain regions with high versus low interindividual variability in their relationship with pain. We trained idiographic pain-predictive models with 13 single-trial functional MRI datasets (n = 404, discovery set) and quantified voxel-level importance for individualized pain prediction. With 21 regions identified as important pain predictors, we examined the interindividual variability of local pain-predictive weights in these regions. Higher-order transmodal regions, such as ventromedial and ventrolateral prefrontal cortices, showed larger individual variability, whereas unimodal regions, such as somatomotor cortices, showed more stable pain representations across individuals. We replicated this result in an independent dataset (n = 124). Overall, our study identifies cerebral sources of individual differences in pain processing, providing potential targets for personalized assessment and treatment of pain.

Distinct brain systems mediate the effects of nociceptive input and self-regulation on pain.

Cognitive self-regulation can strongly modulate pain and emotion. However, it is unclear whether self-regulation primarily influences primary nociceptive and affective processes or evaluative ones. In this study, participants engaged in self-regulation to increase or decrease pain while experiencing multiple levels of painful heat during functional magnetic resonance imaging (fMRI) imaging. Both heat intensity and self-regulation strongly influenced reported pain, but they did so via two distinct brain pathways. The effects of stimulus intensity were mediated by the neurologic pain signature (NPS), an a priori distributed brain network shown to predict physical pain with over 90% sensitivity and specificity across four studies. Self-regulation did not influence NPS responses; instead, its effects were mediated through functional connections between the nucleus accumbens and ventromedial prefrontal cortex. This pathway was unresponsive to noxious input, and has been broadly implicated in valuation, emotional appraisal, and functional outcomes in pain and other types of affective processes. These findings provide evidence that pain reports are associated with two dissociable functional systems: nociceptive/affective aspects mediated by the NPS, and evaluative/functional aspects mediated by a fronto-striatal system.

Cognitive reappraisal of emotion: a meta-analysis of human neuroimaging studies.

In recent years, an explosion of neuroimaging studies has examined cognitive reappraisal, an emotion regulation strategy that involves changing the way one thinks about a stimulus in order to change its affective impact. Existing models broadly agree that reappraisal recruits frontal and parietal control regions to modulate emotional responding in the amygdala, but they offer competing visions of how this is accomplished. One view holds that control regions engage ventromedial prefrontal cortex (vmPFC), an area associated with fear extinction, that in turn modulates amygdala responses. An alternative view is that control regions modulate semantic representations in lateral temporal cortex that indirectly influence emotion-related responses in the amygdala. Furthermore, while previous work has emphasized the amygdala, whether reappraisal influences other regions implicated in emotional responding remains unknown. To resolve these questions, we performed a meta-analysis of 48 neuroimaging studies of reappraisal, most involving downregulation of negative affect. Reappraisal consistently 1) activated cognitive control regions and lateral temporal cortex, but not vmPFC, and 2) modulated the bilateral amygdala, but no other brain regions. This suggests that reappraisal involves the use of cognitive control to modulate semantic representations of an emotional stimulus, and these altered representations in turn attenuate activity in the amygdala.

Identification of discrete functional subregions of the human periaqueductal gray.

The midbrain periaqueductal gray (PAG) region is organized into distinct subregions that coordinate survival-related responses during threat and stress [Bandler R, Keay KA, Floyd N, Price J (2000) Brain Res 53 (1):95-104]. To examine PAG function in humans, researchers have relied primarily on functional MRI (fMRI), but technological and methodological limitations have prevented researchers from localizing responses to different PAG subregions. We used high-field strength (7-T) fMRI techniques to image the PAG at high resolution (0.75 mm isotropic), which was critical for dissociating the PAG from the greater signal variability in the aqueduct. Activation while participants were exposed to emotionally aversive images segregated into subregions of the PAG along both dorsal/ventral and rostral/caudal axes. In the rostral PAG, activity was localized to lateral and dorsomedial subregions. In caudal PAG, activity was localized to the ventrolateral region. This shifting pattern of activity from dorsal to ventral PAG along the rostrocaudal axis mirrors structural and functional neurobiological observations in nonhuman animals. Activity in lateral and ventrolateral subregions also grouped with distinct emotional experiences (e.g., anger and sadness) in a factor analysis, suggesting that each subregion participates in distinct functional circuitry. This study establishes the use of high-field strength fMRI as a promising technique for revealing the functional architecture of the PAG. The techniques developed here also may be extended to investigate the functional roles of other brainstem nuclei.

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 data sets, half featuring pain stimulation and half negative image viewing. In sum, these data sets 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.

Functional imaging studies of emotion regulation: a synthetic review and evolving model of the cognitive control of emotion.

This paper reviews and synthesizes functional imaging research that over the past decade has begun to offer new insights into the brain mechanisms underlying emotion regulation. Toward that end, the first section of the paper outlines a model of the processes and neural systems involved in emotion generation and regulation. The second section surveys recent research supporting and elaborating the model, focusing primarily on studies of the most commonly investigated strategy, which is known as reappraisal. At its core, the model specifies how prefrontal and cingulate control systems modulate activity in perceptual, semantic, and affect systems as a function of one's regulatory goals, tactics, and the nature of the stimuli and emotions being regulated. This section also shows how the model can be generalized to understand the brain mechanisms underlying other emotion regulation strategies as well as a range of other allied phenomena. The third and last section considers directions for future research, including how basic models of emotion regulation can be translated to understand changes in emotion across the life span and in clinical disorders.

Distraction and placebo: two separate routes to pain control.

An explosion of recent research has studied whether placebo treatments influence health-related outcomes and their biological markers, but almost no research has examined the psychological processes required for placebo effects to occur. This study tested whether placebo treatment and cognitive distraction reduce pain through shared or independent processes. We tested the joint effects of performance of an executive working memory task and placebo treatment on thermal pain perception. An interactive effect of these two manipulations would constitute evidence for shared mechanisms, whereas additive effects would imply separate mechanisms. Participants (N = 33) reported reduced pain both when they performed the working memory task and when they received the placebo treatment, but the reductions were additive, a result indicating that the executive demands of the working memory task did not interfere with placebo analgesia. Furthermore, placebo analgesia did not impair task performance. Together, these data suggest that placebo analgesia does not depend on active redirection of attention and that expectancy and distraction can be combined to maximize pain relief.

A slice of pi : an exploratory neuroimaging study of digit encoding and retrieval in a superior memorist.

Subject PI demonstrated superior memory using a variant of a Method of Loci (MOL) technique to recite the first digits of the mathematical constant pi to more than 2(16) decimal places. We report preliminary behavioral, functional magnetic resonance imaging (fMRI), and brain volumetric data from PI. fMRI data collected while PI recited the first 540 digits of pi (i.e., during retrieval) revealed increased activity in medial frontal gyrus and dorsolateral prefrontal cortex. Encoding of a novel string of 100 random digits activated motor association areas, midline frontal regions, and visual association areas. Volumetric analyses indicated an increased volume of the right subgenual cingulate, a brain region implicated in emotion, mentalizing, and autonomic arousal. Wechsler Abbreviated Scale of Intelligence (WASI) testing indicated that PI is of average intelligence, and performance on mirror tracing, rotor pursuit, and the Silverman and Eals Location Memory Task revealed normal procedural and implicit memory. PI's performance on the Wechsler Memory Scale (WMS-III) revealed average general memory abilities (50th percentile), but superior working memory abilities (99th percentile). Surprisingly, PI's visual memory (WMS-III) for neutral faces and common events was remarkably poor (3rd percentile). PI's self-report indicates that imagining affective situations and high emotional content is critical for successful recall. We speculate that PI's reduced memory for neutral/non-emotional faces and common events, and the observed increase in volume of the right subgenual cingulate, may be related to extensive practice with memorizing highly emotional material.

Selective biasing of a specific bistable-figure percept involves fMRI signal changes in frontostriatal circuits: a step toward unlocking the neural correlates of top-down control and self-regulation.

Attention, suggestion, context and expectation can all exert top-down influence on bottom-up processes (e.g., stimulus-driven mechanisms). Identifying the functional neuroanatomy that subserves top-down influences on sensory information processing can unlock the neural substrates of how suggestion can modulate behavior. Using functional magnetic resonance imaging (fMRI), we scanned 10 healthy participants (five men) viewing five bistable figures. Participants received a directional cue to perceive a particular spatial orientation a few seconds before the bistable figure appeared. After presentation, participants pressed a button to indicate their locking into the one desired orientation of the two possible interpretations. Participants additionally performed tests of impulse control and sustained attention. Our findings reveal the role of specific frontostriatal structures in selecting a particular orientation for bistable figures, including dorsolateral prefrontal regions and the putamen. Additional contrasts further bolstered the role of the frontostriatal system in the top-down processing of competing visual perceptions. Separate correlations of behavioral variables with fMRI activations support the idea that the frontostriatal system may mediate attentional control when selecting among competing visual perceptions. These results may generalize to other psychological functions. With special relevance to clinical neuroscience and applications involving attention, expectation and suggestion (e.g., hypnosis), our results address the importance of frontostriatal circuitry in behavioral modulation.