Amplified gut feelings under inflammation and depressed mood: A randomized fMRI trial on interoceptive pain in healthy volunteers.

BACKGROUND: Inflammation and depressed mood constitute clinically relevant vulnerability factors for enhanced interoceptive sensitivity and chronic visceral pain, but their putative interaction remains untested in human mechanistic studies. We tested interaction effects of acute systemic inflammation and sad mood on the expectation and experience of visceral pain by combining experimental endotoxemia with a mood induction paradigm. METHODS: The double-blind, placebo-controlled, balanced crossover fMRI-trial in N = 39 healthy male and female volunteers involved 2 study days with either intravenous administration of low-dose lipopolysaccharide (LPS, 0.4 ng/kg body weight; inflammation condition) or saline (placebo condition). On each study, day two scanning sessions were conducted in an experimentally induced negative (i.e., sad) and in a neutral mood state, accomplished in balanced order. As a model of visceral pain, rectal distensions were implemented, which were initially calibrated to be moderately painful. In all sessions, an identical series of visceral pain stimuli was accomplished, signaled by predictive visual conditioning cues to assess pain anticipation. We assessed neural activation during the expectation and experience of visceral pain, along with unpleasantness ratings in a condition combining an inflammatory state with sad mood and in control conditions. All statistical analyses were accomplished using sex as covariate. RESULTS: LPS administration led to an acute systemic inflammatory response (inflammation X time interaction effects for TNF-α, IL-6, and sickness symptoms, all p <.001). The mood paradigm effectively induced distinct mood states (mood X time interaction, p <.001), with greater sadness in the negative mood conditions (both p <.001) but no difference between LPS and saline conditions. Significant main and interaction effects of inflammation and negative mood were observed for pain unpleasantness (all p <.05). During cued pain anticipation, a significant inflammation X mood interaction emerged for activation of the bilateral caudate nucleus and right hippocampus (all pFWE < 0.05). Main effects of both inflammation and mood were observed in multiple regions, including insula, midcingulate cortex, prefrontal gyri, and hippocampus for inflammation, and midcingulate, caudate, and thalamus for mood (all pFWE < 0.05). CONCLUSIONS: Results support an interplay of inflammation and sad mood on striatal and hippocampal circuitry engaged during visceral pain anticipation as well as on pain experience. This may reflect a nocebo mechanism, which may contribute to altered perception and interpretation of bodily signals. At the interface of affective neuroscience and the gut-brain axis, concurrent inflammation and negative mood may be vulnerability factors for chronic visceral pain.

The impact of age and gender on the ICF-based assessment of chronic low back pain.

PURPOSE: To evaluate the impact of age and gender on the international classification of functioning, disability and health (ICF)-based assessment for chronic low back pain. METHODS: Two hundred forty-four chronic low back pain patients (52% female) with a mean age of 49 years (SD =17.64) were interviewed with the comprehensive ICF core set for activities and participation, and environmental factors. After conducting explorative factor analysis, the impact of age and gender on the different factors was analyzed using analyzes of variances. RESULTS: Results revealed that older patients experienced more limitations within "self-care and mobility" and "walking" but less problems with "transportation" compared to younger patients. Older or middle-aged low back pain patients further perceived more facilitation through "architecture and products for communication", "health services", and "social services and products for mobility" than younger patients. Regarding gender differences, women reported more restriction in "housework" than men. An interaction effect between age and gender was found for "social activities and recreation" with young male patients reporting the highest impairment. CONCLUSIONS: The study demonstrated that the comprehensive ICF core set classification for chronic low back pain is influenced by age and gender. This impact is relevant for ICF-based assessments in clinical practice, and should be considered in intervention planning for rehabilitative programs. Implications for rehabilitation It is important to consider age and gender differences when classifying with the ICF. The intervention planning based on the ICF should focus on improvement of bodily functioning and mobility in older patients, facilitation of household activities in women, consideration of work-life balance and recreation (e.g., through mindfulness based stress reduction), and reduction of dissatisfaction with rehabilitation in younger patients. It is important to offer patients the opportunity to participate in intervention planning based on the ICF. For intervention planning professionals should bear in mind the resource-oriented approach of the ICF (e.g., facilitation through environmental factors), and a collaboration with other professionals.

Does Human Experimental Endotoxemia Impact Negative Cognitions Related to the Self?

A role of inflammatory processes in the pathophysiology of depression is increasingly recognized. Experimental endotoxemia offers an established model to induce transient systemic inflammation in healthy humans, and has been proposed as an experimental paradigm of depression. Indeed, different symptoms of depression can be observed during experimental endotoxemia, including negative mood or dysthymia as key symptoms of depression. Hopelessness and low self-esteem constitute common cognitive symptoms in depression, but have not been specifically assessed during endotoxemia. Thus, we pooled data from healthy volunteers who received low-dose endotoxin (i.e., 0.4 or 0.8 ng/kg lipopolysaccharide, LPS) or placebo in three randomized, controlled studies to investigate the effects of LPS on cognitive schemata related to depression. Validated questionnaires were used to assess self-esteem, hopelessness and the vulnerability factor intolerance of uncertainty after intravenous injection of LPS or placebo. Plasma tumor necrosis factor (TNF)-α and interleukin (IL)-6 were repeatedly assessed, along with self-reported mood. Because not all questionnaires were available from primary studies, data were analyzed in two separate data sets: In data set 1, self-esteem and intolerance of uncertainty were assessed in N = 87 healthy volunteers, who randomly received either 0.4 or 0.8 ng/kg LPS or placebo. In data set 2, hopelessness was measured in N = 59 volunteers who randomly received either LPS (0.8 ng/kg) or placebo. In both data sets, LPS-application led to significant increases in TNF-α and IL-6, reflecting systemic inflammation. Positive mood was significantly decreased in response to LPS, in line with inflammation-induced mood impairment. General self-esteem, intolerance of uncertainty and hopelessness did not differ between LPS- and placebo groups, suggesting that these negative cognitive schemata are not responsive to acute LPS-induced systemic inflammation. Interestingly, LPS-treated volunteers reported significantly lower body-related self-esteem, which was associated with increased TNF-α concentration. Thus, certain aspects of self-esteem related to physical attractiveness and sportiness were reduced. It is conceivable that this effect is primarily related to physical sickness symptoms and reduced physical ability during experimental endotoxemia. With respect to cognitive symptoms of depression, it is conceivable that LPS affects cognitive processes, but not negative cognitive schemata, which are rather based on learning and repeated experiences.

Cognitive Correlates of Different Mentalizing Abilities in Individuals with High and Low Trait Schizotypy: Findings from an Extreme-Group Design.

Mentalizing or Theory of Mind (ToM) deficits in schizophrenia have been studied to great extent, but studies involving samples of trait schizotypy yield ambiguous results. Executive functions like cognitive inhibition, cognitive flexibility, and agency are all prerequisites of mentalizing, and it is assumed that the impairment of these functions contributes to ToM deficits in schizophrenia. Whether these impairments influence the ToM performance of people with high trait schizotypy remains unclear. Although impaired self-agency has repeatedly been identified in people with schizotypy, its role in mentalizing is yet to be investigated. The main aim of this study was to explore whether deficits in cognitive and affective ToM can be found in high trait schizotypy, and to identify in what way these deficits are related to the positive and negative dimensions of schizotypy. The secondary aim was to examine whether these deficits correlate with executive functions. Based on the dimensional view of the schizophrenia spectrum, an extreme-group design was applied to non-clinical volunteers demonstrating high (N = 39) and low (N = 47) trait schizotypy. Affective and cognitive ToM were investigated using the Movie for Assessment of Social Cognition, a sensitive and video-based measurement. Cognitive inhibition was assessed using the Stroop Test, and cognitive flexibility was analyzed using the Trail-Making Test. Agency was measured using a computerized self-agency paradigm. Participants in the high-schizotypy group performed significantly worse in the affective ToM task (d = 0.79), and their overall ToM performance was significantly impaired (d = 0.60). No between-group differences were found with regards to cognitive ToM, executive functions, and self-agency. Cognitive flexibility correlated negatively with positive schizotypy, and contributed to a worse overall and affective ToM. Impaired cognitive inhibition contributed to undermentalizing-type errors. It was found that non-clinical participants with high trait (positive) schizotypy - especially those with slight executive-function deficits - may have difficulties in understanding the emotional state of others and consequently in functioning in social situations.