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.

Mechanisms of placebo analgesia: A dual-process model informed by insights from cross-species comparisons.

Placebo treatments are pharmacologically inert, but are known to alleviate symptoms across a variety of clinical conditions. Associative learning and cognitive expectations both play important roles in placebo responses, however we are just beginning to understand how interactions between these processes lead to powerful effects. Here, we review the psychological principles underlying placebo effects and our current understanding of their brain bases, focusing on studies demonstrating both the importance of cognitive expectations and those that demonstrate expectancy-independent associative learning. To account for both forms of placebo analgesia, we propose a dual-process model in which flexible, contextually driven cognitive schemas and attributions guide associative learning processes that produce stable, long-term placebo effects. According to this model, the placebo-induction paradigms with the most powerful effects are those that combine reinforcement (e.g., the experience of reduced pain after placebo treatment) with suggestions and context cues that disambiguate learning by attributing perceived benefit to the placebo. Using this model as a conceptual scaffold, we review and compare neurobiological systems identified in both human studies of placebo analgesia and behavioral pain modulation in rodents. We identify substantial overlap between the circuits involved in human placebo analgesia and those that mediate multiple forms of context-based modulation of pain behavior in rodents, including forebrain-brainstem pathways and opioid and cannabinoid systems in particular. This overlap suggests that placebo effects are part of a set of adaptive mechanisms for shaping nociceptive signaling based on its information value and anticipated optimal response in a given behavioral context.

Partial Amelioration of Medial Visceromotor Network Dysfunction in Major Depression by Sertraline.

OBJECTIVES: Major depression is associated with reduced cardiac vagal control, most commonly indexed by heart rate variability. To examine the dynamics of this abnormality, we examined within-participant covariation over time between brain activity, cardiac vagal control, and depressive symptoms in depressed patients treated with sertraline and in healthy volunteers. METHODS: Patients with depression and nondepressed control participants were enrolled in a 12-week protocol. After Week 0 assessment, patients began treatment with sertraline. Neural activity and vagal control were measured for all participants at Weeks 0, 2, 6, and 12 using functional magnetic resonance imaging and synchronized electrocardiographic recordings. At each of the four assessments, a moving window analysis was used to estimate vagal control as assessed by respiratory sinus arrhythmia (RSA) from the electrocardiographic data, which was then regressed onto functional magnetic resonance imaging activity. RESULTS: At baseline, patients showed reduced blood oxygen level-dependent RSA covariation compared with controls within multiple a priori brain regions associated with vagal control, collectively described as the medial visceromotor network (MVN). Sertraline treatment led to a significant increase in brain-RSA covariation for patients compared with controls, despite a lack of improvement in mean RSA. CONCLUSIONS: These data suggest a partial normalization of MVN dysfunction in depression during sertraline treatment. Specifically, results indicate a partial recovery of MVN function. However, this recovery was insufficient to cause a significant change in RSA levels. These results may help to explain both improvements with and limitations of sertraline treatment of depression.

Conditioned placebo analgesia persists when subjects know they are receiving a placebo.

UNLABELLED: Belief in the effectiveness of a placebo treatment is widely thought to be critical for placebo analgesia. Many types of placebo responses--even those that depend on conditioning--appear to be mediated by expectations that are strengthened as treatment cues are reinforced with positive outcomes. However, placebo effects may occur even when participants are aware they are receiving a placebo. To address the question of whether conditioned placebo analgesia can persist in the absence of expectations, we studied the effects of long (4 days) versus short (1 day) conditioning to a placebo treatment. After an initial placebo test, a "reveal" manipulation convincingly demonstrated to participants that they had never received an active drug. Placebo analgesia persisted after the reveal in the long conditioning group only. These findings suggest that reinforcing treatment cues with positive outcomes can create placebo effects that are independent of reported expectations for pain relief. PERSPECTIVE: This article demonstrates a form of placebo analgesia that relies on prior conditioning rather than current expected pain relief. This highlights the importance of prior experience on pain relief and offers insight into the variability of placebo effects across individuals.

Sex differences in extinction recall in posttraumatic stress disorder: a pilot fMRI study.

Recent research has found that individuals with posttraumatic stress disorder (PTSD) exhibit an impaired memory of fear extinction compounded by deficient functional activation of key nodes of the fear network including the amygdala, hippocampus, ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortex (dACC). Research has shown these regions are sexually dimorphic and activate differentially in healthy men and women during fear learning tasks. To explore biological markers of sex differences following exposure to psychological trauma, we used a fear learning and extinction paradigm together with functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) to assess 31 individuals with PTSD (18 women; 13 men) and 25 matched trauma-exposed healthy control subjects (13 women; 12 men). Whereas no sex differences appeared within the trauma-exposed healthy control group, both psychophysiological and neural activation patterns within the PTSD group indicated deficient recall of extinction memory among men and not among women. Men with PTSD exhibited increased activation in the left rostral dACC during extinction recall compared with women with PTSD. These findings highlight the importance of tracking sex differences in fear extinction when characterizing the underlying neurobiological mechanisms of PTSD psychopathology.

Characterization and reduction of cardiac- and respiratory-induced noise as a function of the sampling rate (TR) in fMRI.

It has recently been shown that both high-frequency and low-frequency cardiac and respiratory noise sources exist throughout the entire brain and can cause significant signal changes in fMRI data. It is also known that the brainstem, basal forebrain and spinal cord areas are problematic for fMRI because of the magnitude of cardiac-induced pulsations at these locations. In this study, the physiological noise contributions in the lower brain areas (covering the brainstem and adjacent regions) are investigated and a novel method is presented for computing both low-frequency and high-frequency physiological regressors accurately for each subject. In particular, using a novel optimization algorithm that penalizes curvature (i.e. the second derivative) of the physiological hemodynamic response functions, the cardiac- and respiratory-related response functions are computed. The physiological noise variance is determined for each voxel and the frequency-aliasing property of the high-frequency cardiac waveform as a function of the repetition time (TR) is investigated. It is shown that for the brainstem and other brain areas associated with large pulsations of the cardiac rate, the temporal SNR associated with the low-frequency range of the BOLD response has maxima at subject-specific TRs. At these values, the high-frequency aliased cardiac rate can be eliminated by digital filtering without affecting the BOLD-related signal.

Memory search following valid and invalid abrupt-onset cues.

The impact of abrupt-onset cues on memory search was investigated, where the abrupt-onset cue was a valid (Experiment 1), random (Experiment 2), or irrelevant (Experiment 3) predictor of the location containing the test probe. In Experiment 4, the abrupt-onset cue either preceded or followed the test probe. Sternberg-like functions were obtained in Experiments 1 and 2, with the effects of the abrupt-onset cue localized primarily in the intercept rather than the slope. Experiment 3 demonstrated that a spatially separated and irrelevant abrupt-onset cue increased latency even when all memory probes occurred at the fixation point. In Experiment 4, the robust impact of an abrupt-onset cue vanished, regardless of stimulus onset asynchrony, when it followed the target. We concluded that abrupt-onset cues captured attention regardless of their predictability, manifested as a delaying of search. However, once attention was captured by the target, a subsequent abrupt-onset stimulus had no effect. These results were discussed in terms of diffuse attention and contingent capture models of attention.