Do I care for you or for me? Processing of protected and non-protected moral values in subjects with extreme scores on the Dark Triad.

Protected moral values facilitate empathic concern for others, who are exposed to an existential threat, so that one spontaneously helps without taking into account utilitarian cost-benefit considerations. Subjects scoring high on the "Dark Triad" machiavellism, psychopathy, and narcissism are prone to ignore such appeals for selfless help. Until now, data on moral processing and moral decision-making following requests for altruistic help, which directly contrast appeals to protected and non-protected values in subjects with high and low scores on Dark Triad traits, have been missing. In this pilot study 25 healthy subjects with high and 27 with low Dark Triad scores participated in this functional magnetic resonance imaging study. We used a script-driven imagery paradigm to directly contrast requests for selfless help appealing to protected versus non-protected, negotiable moral values. Appeals to protected versus non-protected moral values elicited stronger activations in a large network including insula, amygdala, supramarginal gyrus, and dorsolateral prefrontal cortex. Non-protected values evoked stronger activation in superior frontal sulcus, occipito-temporal junction, and posterior cingulate cortex. During decision-making, high-scorers on the Dark Triad showed increased activations in the superior parietal lobule, precuneus, and intraparietal sulcus. Behaviorally, protected versus non-protected values strongly reduced the reliance on personal cost-benefit calculations in low-scorers, while high-scorers continued to rely on utilitarian deliberations. Data suggest that appeals to protected versus non-protected values activate distinct brain regions associated with strong moral emotions, other-directed cognition, and rule-based decision-making processes. High-scorers display an increased reliance on cost-benefit calculations, which persists even when protected values are threatened.

Pain-modulating effects of oxytocin in patients with chronic low back pain.

The neuropeptide oxytocin (OT) has been shown to play a modulatory role in nociception. However, analgesic effects of OT in chronic pain conditions remain elusive and the neural underpinnings have not yet been investigated in humans. Here, we conducted an exploratory, randomized, placebo-controlled, cross-over study to examine effects of intranasal OT in male patients suffering from chronic low back pain (CBP) versus healthy controls (HC). N = 22 participants with CBP and 22 HCs were scanned using functional magnetic resonance imaging (fMRI) while they continuously rated either spontaneously occurring back pain or acute thermal pain stimuli applied to the lower back. During heat pain processing we found that OT versus PL attenuated pain intensity ratings and increased BOLD responses in the caudate nucleus of the striatum in CBP versus HCs. Spontaneously experienced pain in contrast to heat pain was associated with activation changes in the medial frontal cortex (MFC) and the anterior cingulate cortex (ACC) as reported in previous studies. However, we did not observe OT effects on spontaneously experienced pain in CBP patients. Overall, our preliminary data may suggest that the striatum is a key structure underlying the pain-modulating effects of OT in patients with chronic pain and adds to the growing evidence linking the neuropeptide to pain modulation in humans. Further studies on neuronal OT effects in larger samples of chronic back pain patients are needed to understand probable mechanisms of OT effects in chronic pain. This article is part of the special issue on Neuropeptides.

Oxytocin modulates intrinsic neural activity in patients with chronic low back pain.

BACKGROUND: Modulation of pain perception by oxytocin (OXT) has attracted increased scientific and clinical interest. Neural mechanisms underlying these effects are poorly understood. In this study, we aimed to investigate the effects of intranasally applied OXT on intrinsic neural activity in patients with chronic low back pain (cLBP). METHODS: Twenty-four male patients with cLBP and 23 healthy males were examined using resting-state functional magnetic resonance imaging. Participants were scanned twice and received either intranasally applied OXT (24 international units) or placebo 40 min before scanning. The fractional amplitude of low-frequency fluctuations (fALFF) was computed to investigate regionally specific effects of OXT on intrinsic neural activity. In addition a multivariate statistical data analysis strategy was employed to explore OXT-effects on functional network strength. RESULTS: Differential effects of OXT were observed in cLBP and healthy controls. FALFF decreased in left nucleus accumbens and right thalamus in cLBP and increased in right thalamus in healthy controls after OXT application compared to placebo. OXT also induced activity changes in bilateral thalamus, left caudate nucleus and right amygdala in cLBP. OXT was associated with increased medial frontal, parietal and occipital functional network strength, though this effect was not group-specific. Regression analyses revealed significant associations between left nucleus accumbens, left caudate nucleus and right amygdala with pain-specific psychometric scores in cLBP. CONCLUSIONS: These data suggest OXT-related modulation of regional activity and neural network strength in patients with cLBP and healthy controls. In patients, distinct regions of the pain matrix may be responsive to modulation by OXT. SIGNIFICANCE: Our data suggest significant oxytocin-related modulation of intrinsic regional activity and neural network strength in patients with chronic low back pain and healthy controls. In patients, distinct regions of the pain matrix may be responsive to modulation by oxytocin. Therapeutic effects of oxytocin for improved pain treatment need to be further investigated.

Oxytocin Effects on Pain Perception and Pain Anticipation.

There is an ongoing debate whether the neuropeptide oxytocin (OT) modulates pain processing in humans. This study differentiates behavioral and neuronal OT effects on pain perception and pain anticipation by using a Pavlovian conditioning paradigm. Forty-six males received intranasally administered OT in a randomized, double-blind, placebo-controlled group design. Although OT exerted no direct effect on perceived pain, OT was found to modulate the blood oxygen level-dependent response in the ventral striatum for painful versus warm unconditioned stimuli and to decrease activity in the anterior insula (IS) with repeated thermal pain stimuli. Regarding pain anticipation, OT increased responses to CSpain versus CSminus in the nucleus accumbens. Furthermore, in the OT condition increased correct expectations, particularly for the most certain conditioned stimuli (CS)-unconditioned stimuli associations (CSminus and CSpain) were found, as well as greatest deactivations in the right posterior IS in response to the least certain condition (CSwarm) with posterior IS activity and correct expectancies being positively correlated. In conclusion, OT seems to have both a direct effect on pain processing via the ventral striatum and by inducing habituation in the anterior IS as well as on pain anticipation by boostering associative learning in general and the neuronal conditioned fear of pain response in particular. PERSPECTIVE: The neuropeptide OT has recently raised the hope to offer a novel avenue for modulating pain experience. This study found OT to modulate pain processing and to facilitate the anticipation of pain, inspiring further research on OT effects on the affective dimension of the pain experience.

Cognitive Impairment Along the Course of Depression: Non-Pharmacological Treatment Options.

Major Depressive Disorder (MDD) is one of the most common psychiatric disorders, with a large global impact on both the individual and the society. In this narrative review, we summarize neurocognitive deficits during acute and (partially) remitted states of depression. Furthermore, we outline the potential negative effect of cognitive impairment (CI) on functional recovery, and discuss the role of several variables in the development of CI for MDD patients. Though there is cumulating evidence regarding persistent CI in unipolar depression, research on treatment options specific for this patient group is still scarce. Hence the central aim of our review is to present non-pharmacological interventions, which are thought to reduce CI in affected MDD patients. We discuss cognitive remediation therapy (CRT), physical exercise, yoga, mindfulness-based therapy, and modern neuromodulation approaches like neurostimulation and neurofeedback training. In conclusion, we propose future directions for research on CI in depression. Looking further ahead, we suggest creative interventional designs that include a direct comparison of different non-pharmacological treatment approaches on neurocognition and functional outcome of MDD. Furthermore, additive and synergistic effects of CRT with other treatment approaches should be examined and compared to create multimodal and even personalized intervention programs.

Short- and long-term A3 adenosine receptor activation inhibits the Na+/H+ exchanger NHE3 activity and expression in opossum kidney cells.

The renal function of the A(3) adenosine receptor (A3AR) is poorly characterized. In this study, we report that the A3AR-selective agonist, 1-[2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purine-9-yl]-1-deoxy-N-methyl-b-D-ribofuranuronamide (2-Cl-IBMECA) regulates the Na+/H+ exchanger-3 (NHE3) in a dose- and time-dependent fashion. In opossum kidney (OK) cells, 2-Cl-IBMECA at high (10(-6) M) and low (10(-8) M) dose inhibits NHE3 by a multiphasic time course with an acute phase of NHE3 inhibition from 15 min to 1 h, followed by a chronic phase of NHE3 inhibition from 24 to 48 h. Pre-incubation with either the selective A3AR-antagonist MRS1523 (10(-7) M) or the protein kinase C inhibitor, Calphostin C (10(-8) M) completely blocked 10(-6) M 2-Cl-IBMECA-induced acute (15 min) and chronic (24 h) phases of NHE3 inhibition. In contrast, the acute inhibitory phase (15 min) of 10(-8) M 2-Cl-IBMECA was completely prevented only when Calphostin C (10(-8) M) was added in conjunction with the protein kinase A inhibitor, H89 (10(-7) M). Acute (15 or 30 min depending on the A3AR-agonist concentration) A3AR-dependent inhibition of NHE3 activity was accompanied by decrease in cell surface NHE3 protein with no change in total NHE3 antigen. Chronic (24 h) A3AR-mediated down-regulation of NHE3 was associated with reduction of surface NHE3, decreased total NHE3 protein (70%) and a paradoxical rise of NHE3 RNA (40%). In summary, these results indicate that A3AR directly regulates NHE3 at multiple levels in a complex pattern. A3AR-dependent short- and long-term inhibition of NHE3 may be a fundamental mechanism of net sodium and fluid balance.