The effects of experimental pain on episodic memory and its top-down modulation: a preregistered pooled analysis.

Introduction: Pain can automatically interfere with ongoing cognitive processes such as attention and memory. The extent of pain's negative effects on cognitive functioning seems to depend on a balance between top-down and bottom-up factors. Objectives: In this large, preregistered, pooled reanalysis of 8 studies, we investigated the robustness of the detrimental effect of acute pain on recognition memory and whether top-down mechanisms such as pain-related expectations or cognitions (pain-related fear, pain catastrophizing) modulate this effect. Methods: Two hundred forty-seven healthy participants underwent similar experimental paradigms, including a visual categorization task with images randomly paired with (or without) concomitant painful stimulation and a subsequent unannounced recognition task. Recognition memory (ie, d', recollection, and familiarity) and categorization performance (ie, reaction time, accuracy) served as proxies for the effect of pain on cognitive performance. Results: Acute painful stimulation significantly impaired recognition performance (d', familiarity). However, recognition performance was not significantly modulated by participants' expectations regarding the effect of pain on task performance or pain-related cognitions in this sample of healthy participants. Conclusion: Our results corroborate the negative effects of pain on (visual) memory encoding reported in previous studies and reports of "memory problems" from patients with chronic pain. To characterize the role of bottom-up and top-down factors for the detrimental effects of pain, large-scale studies with more nuanced study designs are necessary. Future studies in patient cohorts must unravel the interaction of maladaptive pain-related cognitions and the often-reported impaired cognitive performance in chronic pain patients.

An externally validated resting-state brain connectivity signature of pain-related learning.

Pain can be conceptualized as a precision signal for reinforcement learning in the brain and alterations in these processes are a hallmark of chronic pain conditions. Investigating individual differences in pain-related learning therefore holds important clinical and translational relevance. Here, we developed and externally validated a novel resting-state brain connectivity-based predictive model of pain-related learning. The pre-registered external validation indicates that the proposed model explains 8-12% of the inter-individual variance in pain-related learning. Model predictions are driven by connections of the amygdala, posterior insula, sensorimotor, frontoparietal, and cerebellar regions, outlining a network commonly described in aversive learning and pain. We propose the resulting model as a robust and highly accessible biomarker candidate for clinical and translational pain research, with promising implications for personalized treatment approaches and with a high potential to advance our understanding of the neural mechanisms of pain-related learning.

Hydrocortisone Differentially Affects Reinstatement of Pain-related Responses in Patients With Chronic Back Pain and Healthy Volunteers.

Despite the crucial role of effective and sustained extinction of conditioned pain-related fear in cognitive-behavioral treatment approaches for chronic pain, experimental research on extinction memory retrieval in chronic pain remains scarce. In healthy populations, extinction efficacy of fear memory is affected by stress. Therefore, we investigated the effects of oral hydrocortisone administration on the reinstatement of pain-related associations in 57 patients with non-specific chronic back pain (CBP) and 59 healthy control (HC) participants in a differential pain-related conditioning paradigm within a placebo-controlled, randomized, and double-blind design. Participants' skin conductance responses indicate hydrocortisone-induced reinstatement effects in HCs but no observable reinstatement in HCs receiving placebo treatment. Interestingly, these effects were reversed in patients with CBP, that is, reinstatement responses were only observed in the placebo and not in the hydrocortisone group. Our findings corroborate previous evidence of stress-induced effects on extinction efficacy and reinstatement of fear memory in HCs, extending them into the pain context, and call for more research to clarify the role of stress in fear extinction and return of fear phenomena possibly contributing to treatment failure in chronic pain treatment. PERSPECTIVE: Opposing effects in HCs and patients with non-specific CBP may be associated with changes in the patients' stress systems. These findings could be of relevance to optimizing psychological, extinction-based treatment approaches.

Open-label placebo treatment does not enhance cognitive abilities in healthy volunteers.

The use of so-called 'smart drugs' such as modafinil to improve cognitive performance has recently attracted considerable attention. However, their side effects have limited user enthusiasm. Open-label placebo (OLP) treatment, i.e., inert treatments that are openly disclosed to individuals as having no active pharmacological ingredient, has been shown to improve various medical symptoms and conditions, including those related to cognitive performance. OLP treatment could therefore be an exciting alternative to pharmacological cognitive enhancers. Here, we used a randomized-controlled design to investigate the effect of a 21-day OLP treatment on several sub-domains of cognitive performance in N = 78 healthy volunteers. Subjective and objective measures of cognitive performance as well as different measures of well-being were obtained before and after the treatment period. Using a combination of classic Frequentist and Bayesian analysis approaches showed no additional benefit from OLP treatment in any of the subjective or objective measures of cognitive performance. Our study thus highlights possible limitations of OLP treatment in boosting cognitive performance in healthy volunteers. These findings are discussed in the light of expectancy-value considerations that may determine OLP efficacy.

Neural underpinnings of preferential pain learning and the modulatory role of fear.

Due to its unique biological relevance, pain-related learning might differ from learning from other aversive experiences. This functional magnetic resonance imaging study compared neural mechanisms underlying the acquisition and extinction of different threats in healthy humans. We investigated whether cue-pain associations are acquired faster and extinguished slower than cue associations with an equally unpleasant tone. Additionally, we studied the modulatory role of stimulus-related fear. Therefore, we used a differential conditioning paradigm, in which somatic heat pain stimuli and unpleasantness-matched auditory stimuli served as US. Our results show stronger acquisition learning for pain- than tone-predicting cues, which was augmented in participants with relatively higher levels of fear of pain. These behavioral findings were paralleled by activation of brain regions implicated in threat processing (insula, amygdala) and personal significance (ventromedial prefrontal cortex). By contrast, extinction learning seemed to be less dependent on the threat value of the US, both on the behavioral and neural levels. Amygdala activity, however, scaled with pain-related fear during extinction learning. Our findings on faster and stronger (i.e. "preferential") pain learning and the role of fear of pain are consistent with the biological relevance of pain and may be relevant to the development or maintenance of chronic pain.

A randomized-controlled trial to evaluate the app-based multimodal weight loss program zanadio for patients with obesity.

OBJECTIVE: This study aimed to evaluate the effectiveness of the app-based, multimodal weight loss program zanadio. METHODS: A randomized-controlled trial was conducted from January 2021 to March 2022. A total of 150 adults with obesity were randomized into an intervention group and used zanadio for 1 year or into a wait list control group. The primary end point, weight change, and the secondary end points, quality of life, well-being, and waist to height ratio, were assessed every 3 months for up to 1 year via telephone interviews and online questionnaires. RESULTS: After 12 months, participants of the intervention group lost, on average, -7.75% (95% CI: -9.66% to -5.84%) of their initial weight, achieving a clinically relevant and statistically stronger weight reduction than the control group (mean = 0.00% [95% CI: -1.98% to 1.99%]). All secondary end points improved significantly in the intervention group, with significantly greater improvements in well-being and waist to height ratio than in the control group. CONCLUSIONS: This study showed that adults with obesity who have used zanadio achieved a significant and clinically relevant weight loss within 12 months and improved further obesity-related health variables compared with a control group. Because of its effectiveness and flexible applicability, the app-based multimodal treatment zanadio might alleviate the present care gap for patients with obesity in Germany.

Introducing zanadio-A Digitalized, Multimodal Program to Treat Obesity.

While the prevalence of overweight and obesity has been increasing annually, the accessibility of on-site treatment programs is not rising correspondingly. Digital, evidence-based obesity treatment programs could potentially alleviate this situation. The application zanadio has been developed to enable patients with obesity (BMI 30-45 kg/m2) to participate in a digital, multimodal weight reduction program based on current treatment guidelines. This article is divided into two parts: (I) it introduces zanadio, its aims and therapeutic concept, and (II) provides a first impression and demographic data on more than 11,000 patients from across the country who have used zanadio within the last 16 months, which demonstrates the demand for a digital obesity treatment. zanadio has the potential to partially close the current gap in obesity care. Future work should focus on identifying predictors of successful weight loss to further individualize digital obesity treatment, and an important next step would be to prevent obesity, i.e., to start the treatment at lower BMI levels, and to invent digital treatment programs for children and adolescents.

Greater interruption of visual processing and memory encoding by visceral than somatic pain in healthy volunteers - An fMRI study.

Visceral pain is regarded as more salient than somatic pain. It has greater affective and emotional components, i.e., it elicits higher levels of pain-related fear and is perceived as more unpleasant than somatic pain. In this fMRI study, we examined the neural effects of painful visceral as compared to painful somatic stimulation on visual processing and memory encoding in a visual categorization and surprise recognition task in healthy volunteers. During the categorization task, participants received either rectal distensions or heat stimuli applied to the forearm, with stimuli being individually matched for unpleasantness. Behaviorally, visceral pain reduced memory encoding as compared to somatic pain (Kleine-Borgmann et al., 2021). Imaging analyses now revealed that visceral pain was associated with reduced activity (i.e., greater pain-related interruption) in neural areas typically involved in visual processing and memory encoding. These include the parahippocampal gyrus, fusiform gyrus, striatum, occipital cortex, insula, and the amygdala. Moreover, reduced engagement of the lateral occipital complex during visual categorization under visceral pain was associated with higher visceral pain-related fear. These findings obtained in healthy volunteers shed light on the neural circuitry underlying the interruptive effect of visceral pain and pave the way for future studies in patient samples.

Acquisition learning is stronger for aversive than appetitive events.

Appetitive and aversive learning are both key building blocks of adaptive behavior, yet knowledge regarding their differences is sparse. Using a capsaicin heat pain model in 36 healthy participants, this study directly compared the acquisition and extinction of conditioned stimuli (CS) predicting pain exacerbation and relief. Valence ratings show stronger acquisition during aversive compared to appetitive learning, but no differences in extinction. Skin conductance responses and contingency ratings confirmed these results. Findings were unrelated to individual differences in pain sensitivity or psychological factors. Our results support the notion of an evolutionarily hardwired preponderance to acquire aversive rather than appetitive cues as is protective for acute aversive states such as pain but may contribute to the development and maintenance of clinical conditions such as chronic pain, depression or anxiety disorders.

Impaired pain-related threat and safety learning in patients with chronic back pain.

ABSTRACT: Pain-related learning mechanisms likely play a key role in the development and maintenance of chronic pain. Previous smaller-scale studies have suggested impaired pain-related learning in patients with chronic pain, but results are mixed, and chronic back pain (CBP) particularly has been poorly studied. In a differential conditioning paradigm with painful heat as unconditioned stimuli, we examined pain-related acquisition and extinction learning in 62 patients with CBP and 61 pain-free healthy male and female volunteers using valence and contingency ratings and skin conductance responses. Valence ratings indicate significantly reduced threat and safety learning in patients with CBP, whereas no significant differences were observed in contingency awareness and physiological responding. Moreover, threat learning in this group was more impaired the longer patients had been in pain. State anxiety was linked to increased safety learning in healthy volunteers but enhanced threat learning in the patient group. Our findings corroborate previous evidence of altered pain-related threat and safety learning in patients with chronic pain. Longitudinal studies exploring pain-related learning in (sub)acute and chronic pain are needed to further unravel the role of aberrant pain-related learning in the development and maintenance of chronic pain.

Does pain modality play a role in the interruptive function of acute visceral compared with somatic pain?

ABSTRACT: Acute pain captures attentional resources and interferes with ongoing cognitive processes, including memory encoding. Despite broad clinical implications of this interruptive function of pain for the pathophysiology and treatment of chronic pain conditions, existing knowledge exclusively relies on studies using somatic pain models. Visceral pain is highly prevalent and seems to be more salient and threatening, suggesting that the interruptive function of pain may be higher in acute visceral compared with somatic pain. Implementing rectal distensions as a clinically relevant experimental model of visceral pain along with thermal cutaneous pain for the somatic modality, we herein examined the impact of pain modality on visual processing and memory performance in a visual encoding and recognition task and explored the modulatory role of pain-related fear and expectation in 30 healthy participants. Despite careful and dynamically adjusted matching of stimulus intensities to perceived pain unpleasantness over the course of trials, we observed greater impairment of cognition performance for the visceral modality with a medium effect size. Task performance was not modulated by expectations or by pain-related fear. Hence, even at matched unpleasantness levels, acute visceral pain is capable of interfering with memory encoding, and this impact seems to be relatively independent of pain-related cognitions or emotions, at least in healthy individuals. These results likely underestimate the detrimental effect of chronic pain on cognitive performance, which may be particularly pronounced in acute and chronic visceral pain.

Associative learning and extinction of conditioned threat predictors across sensory modalities.

The formation and persistence of negative pain-related expectations by classical conditioning remain incompletely understood. We elucidated behavioural and neural correlates involved in the acquisition and extinction of negative expectations towards different threats across sensory modalities. In two complementary functional magnetic resonance imaging studies in healthy humans, differential conditioning paradigms combined interoceptive visceral pain with somatic pain (study 1) and aversive tone (study 2) as exteroceptive threats. Conditioned responses to interoceptive threat predictors were enhanced in both studies, consistently involving the insula and cingulate cortex. Interoceptive threats had a greater impact on extinction efficacy, resulting in disruption of ongoing extinction (study 1), and selective resurgence of interoceptive CS-US associations after complete extinction (study 2). In the face of multiple threats, we preferentially learn, store, and remember interoceptive danger signals. As key mediators of nocebo effects, conditioned responses may be particularly relevant to clinical conditions involving disturbed interoception and chronic visceral pain.

Effects of open-label placebos on test performance and psychological well-being in healthy medical students: a randomized controlled trial.

Psychological distress is prevalent in students and can predispose to psychiatric disorders. Recent findings indicate that distress might be linked to impaired cognitive performance in students. Experimental findings in healthy participants suggest that placebo interventions can improve cognition. However, whether non-deceptive (i.e., open-label, OLP) placebos can enhance cognitive function and emotional well-being is unclear. Using a randomized-controlled design we demonstrate a positive impact of OLP on subjective well-being (i.e., stress, fatigue, and confusion) after a 21-day OLP application in healthy students during midterm exams. OLP did not improve test performance, but, within the OLP group, test performance was positively correlated with measures of general belief in the benefit of medication. These results show that OLP can counteract negative effects of acute stress on psychological well-being and might improve cognitive performance if supported by positive treatment expectations. Additionally, our findings in healthy volunteers warrant further investigation in exploring the potential of OLP in reducing stress-related psychological effects in patients. The trial was preregistered at the German Clinical Trials Register on December 20, 2017 (DRKS00013557).

Enhanced pain-related conditioning for face compared to hand pain.

Pain is evolutionarily hardwired to signal potential danger and threat. It has been proposed that altered pain-related associative learning processes, i.e., emotional or fear conditioning, might contribute to the development and maintenance of chronic pain. Pain in or near the face plays a special role in pain perception and processing, especially with regard to increased pain-related fear and unpleasantness. However, differences in pain-related learning mechanisms between the face and other body parts have not yet been investigated. Here, we examined body-site specific differences in associative emotional conditioning using electrical stimuli applied to the face and the hand. Acquisition, extinction, and reinstatement of cue-pain associations were assessed in a 2-day emotional conditioning paradigm using a within-subject design. Data of 34 healthy subjects revealed higher fear of face pain as compared to hand pain. During acquisition, face pain (as compared to hand pain) led to a steeper increase in pain-related negative emotions in response to conditioned stimuli (CS) as assessed using valence ratings. While no significant differences between both conditions were observed during the extinction phase, a reinstatement effect for face but not for hand pain was revealed on the descriptive level and contingency awareness was higher for face pain compared to hand pain. Our results indicate a stronger propensity to acquire cue-pain-associations for face compared to hand pain, which might also be reinstated more easily. These differences in learning and resultant pain-related emotions might play an important role in the chronification and high prevalence of chronic facial pain and stress the evolutionary significance of pain in the head and face.

Quantitative Sensory Testing (QST) in Drug-Naïve Patients with Parkinson's Disease.

BACKGROUND: Pain is highly prevalent in patients with Parkinson's disease (PD), but underlying pathophysiological mechanisms are largely unclear. Alterations in somatosensory processing might contribute to sensory abnormalities in PD. OBJECTIVE: This study investigated sensory processing in PD patients. METHODS: We used the standardized "Quantitative Sensory Testing" (QST) protocol (German Research Network on Neuropathic Pain) to investigate 13 somatosensory parameters in 19 PD patients naïve to dopaminergic medication and 19 healthy controls matched for age, gender, and handedness. We tested for differences in sensory parameters between i) drug-naïve PD patients and healthy controls, ii) patients' more and less affected body side, and iii) for an association of somatosensory parameters with disease-specific factors. RESULTS: We did not observe any significant group differences in somatosensory parameters between PD patients and healthy subjects. In PD patients, QST mean z-scores did not differ between the predominantly and the less affected body side, PD patients with and without PD-specific chronic pain or between different PD subtypes. Age, but not PD disease severity, was associated with a greater loss of function in thermal and mechanical detection thresholds. CONCLUSIONS: Somatosensory processing, as assessed with the well-established QST protocol, was normal in drug-naïve PD patients. Thus, somatosensory abnormalities previously reported in medicated PD patients might rather be a result of dopaminergic medication, or may occur later in the course of the disease or with increasing age.

Enhanced Neural Reinstatement for Evoked Facial Pain Compared With Evoked Hand Pain.

Memory retrieval is accompanied by a reactivation of cortical and subcortical areas that have been active during encoding. This neural reinstatement is stronger during retrieval of pain-associated material compared with other unpleasant events. In this functional magnetic resonance imaging study, we investigated the differences in neural reinstatement during recognition of visual stimuli that had been paired with face or hand pain during memory encoding. Body site-specific neural reinstatement was tested in 23 healthy young volunteers who performed a visual categorization and a surprise recognition task. Our data shows increased neural reinstatement in task-specific and encoding-related areas, such as the parahippocampus (left: x = -26, y = -30, z = -18, t = 4.11; right: x = 26, y = -38, z = -6, t = 4.36), precuneus (x = 2, y = -56, z = 2, t = 3.77), fusiform gyrus (left: x = -24, y = -26, z = -20, t = 5.41; right: x = 18, y = -58, z = -14, t = 4.52), and amygdala (x = -34, y = -4, z = -20, t = 4.49) for pictures that were previously presented with face compared with hand pain. These results correlated with the individual's recognition confidence, although recognition rates did not differ between the conditions. Functional connectivity was increased between the amygdala and parahippocampus (x = 34, y = -10, z = -28, t = 5.13) for pictures that had previously been paired with face compared with hand pain. Our results were positively correlated with pain-related fear, represented by neural activation in the thalamus (x = -14, y = -35, z = 4, t = 3.54). The reported results can be interpreted as compensatory resource activation and support the notion of a stronger affective component of face compared with hand pain, potentially in line with its greater biological relevance. PERSPECTIVE: This study demonstrates neural reinstatement of face pain-related information, which might be related to the increased biological and affective component of face pain compared with pain on the extremities. Our results might contribute to the understanding of the development and prevalence of head and face pain conditions.

From Anticipation to the Experience of Pain: The Importance of Visceral Versus Somatic Pain Modality in Neural and Behavioral Responses to Pain-Predictive Cues.

OBJECTIVE: The aim of this study was to compare behavioral and neural anticipatory responses to cues predicting either somatic or visceral pain in an associative learning paradigm. METHODS: Healthy women (N = 22) underwent functional magnetic resonance imaging. During an acquisition phase, two different visual cues repeatedly signalled either experimental visceral or somatic pain. In a subsequent extinction phase, identical cues were presented without pain. Before and after each phase, cue valence and contingency awareness were assessed on visual analog scales. RESULTS: Visceral compared to somatic pain-predictive cues were rated as more unpleasant after acquisition (visceral, 32.18 ± 13.03 mm; somatic, -18.36 ± 10.36 mm; p = .021) with similarly accurate cue-pain contingencies. After extinction, cue valence returned to baseline for both modalities (visceral, 1.55 ± 9.81 mm; somatic, -18.45 ± 7.12; p = .41). During acquisition, analyses of cue-induced neural responses revealed joint neural activation engaging areas associated with attention processing and cognitive control. Enhanced deactivation of posterior insula to visceral cues was observed, which correlated with enhanced responses within the salience network (anterior cingulate cortex, anterior insula) during visceral compared to somatic pain stimulation. During extinction, both pain modalities induced anticipatory neural activation in the extinction and salience network (all pFWE values < .05). CONCLUSIONS: Conditioned emotional responses to pain-predictive cues are modality specific and enhanced for the visceral modality, suggesting that pain anticipation is shaped by the salience of painful stimuli. Common but also modality-specific neural mechanisms are involved during cue-pain learning, whereas extinction of cued responses seems unaffected by modality. Future research should examine potential implications for the pathophysiology of chronic pain conditions, especially chronic visceral pain.

Pain Affects Visual Orientation: an Eye-Tracking Study.

Because of its unique evolutionary relevance, it is understood that pain automatically attracts attention. So far, such attentional bias has mainly been shown for pain-related stimuli whereas little is known about shifts in attentional focus after actual painful stimulation. This study investigated attentional shifts by assessing eye movements into the direction of painful stimulation. Healthy participants were presented either a blank screen or a picture showing a natural scene while painful electrical stimuli were applied to the left or right hand. In general, painful stimulation reduced exploratory behavior as reflected by less and slower saccades as well as fewer and longer fixations. Painful stimulation on the right hand induced a rightward bias (ie, increased initial saccades, total number and duration of fixations to the right hemifield of the screen). Pain applied to the left hand as well as no pain induced a leftward bias that was largest for the direction of first saccades. These findings are in line with previous observations of attentional biases toward pain-related information and highlight eye tracking as a valuable tool to assess involuntary attentional consequences of pain. Future studies are needed to investigate how the observed changes in eye movements relate to pain-induced changes in perception and cognition. PERSPECTIVE: The study investigated pain-induced attentional shifts in terms of reflexive eye movements. This attention-capturing quality of pain should be examined in chronic pain conditions because it might contribute to the cognitive impairments often observed in chronic pain patients.