Acute TMS/fMRI response explains offline TMS network effects - An interleaved TMS-fMRI study.

BACKGROUND: Transcranial magnetic stimulation (TMS) is an FDA-approved therapeutic option for treatment resistant depression. However, exact mechanisms-of-action are not fully understood and individual responses are variable. Moreover, although previously suggested, the exact network effects underlying TMS' efficacy are poorly understood as of today. Although, it is supposed that DLPFC stimulation indirectly modulates the sgACC, recent evidence is sparse. METHODS: Here, we used concurrent interleaved TMS/fMRI and state-of-the-science purpose-designed MRI head coils to delineate networks and downstream regions activated by DLPFC-TMS. RESULTS: We show that regions of increased acute BOLD signal activation during TMS resemble a resting-state brain network previously shown to be modulated by offline TMS. There was a topographical overlap in wide spread cortical and sub-cortical areas within this specific RSN#17 derived from the 1000 functional connectomes project. CONCLUSION: These data imply a causal relation between DLPFC-TMS and activation of the ACC and a broader network that has been implicated in MDD. In the broader context of our recent work, these data imply a direct relation between initial changes in BOLD activity mediated by connectivity to the DLPFC target site, and later consolidation of connectivity between these regions. These insights advance our understanding of the mechanistic targets of DLPFC-TMS and may provide novel opportunities to characterize and optimize TMS therapy in other neurological and psychiatric disorders.

Impact of emotionally-charged images and trial order on downstream cognitive processing: An ERP study.

Theories of emotion-cognition interactions suggest that emotional valence can both facilitate or limit cognitive performance. One cause for the mixed findings may be the order (random versus non-random presentation) in which emotional stimuli are presented. To investigate the impact of stimuli order on cognitive control processing, EEG data were recorded as 130 undergraduate students (M age = 22.2, SD = 5.4; 79 female) completed a modified version of the AX-Continuous Performance Task in which the cue was followed by an emotionally-valenced image (positive, negative, and neutral). Specifically, the task was designed so that valenced images were presented in either a block or random order, prior to probe presentation. We examined two event-related potentials (ERPs), the N2, which reflects aspects of cognitive control, and the late positive potential (LPP), which reflects attention allocation to emotional stimuli. We assessed the impact of emotionally oriented attention (LPP) on downstream cognitive control (N2) and how this relationship might differ for a block versus random (order of emotional image) task design. Consistent with the LPP literature, we found a main effect of image valence with the negative trials showing larger LPPs than the positive and neutral trials. For N2s, we found that the negative trials were associated with smaller N2s than both the positive and neutral trials. We observed that as LPP amplitude increased, subsequent N2 amplitude was reduced, specifically for negative trials in the random design. These results suggest an emotion-related depletion of neural cognitive resources. Lastly, we found larger N2s for the block design versus the random design. Together, these results indicate the importance of paying attention to both trial order (block versus random) and within trial stimulus sequence when designing emotion induction tasks.

The administration of the opioid buprenorphine decreases motivational error signals.

While opioid addiction has reached pandemic proportions, we still lack a good understanding of how the administration of opioids interacts with cognitive functions. Error processing - the ability to detect erroneous actions and correct one's behaviour afterwards - is one such cognitive function that might be susceptible to opioidergic influences. Errors are hypothesised to induce aversive negative arousal, while opioids have been suggested to reduce aversive arousal induced by unpleasant and stressful stimuli. Thus, this study investigated whether the acute administration of an opioid would affect error processing. In a double-blind between-subject study, 42 male volunteers were recruited and received either 0.2 mg buprenorphine (a partial µ-opioid receptor agonist and κ-opioid receptor antagonist) or a placebo pill before they performed a stimulus-response task provoking errors. Electroencephalograms (EEG) were recorded while participants performed the task. We observed no group differences in terms of reaction times, error rates, and affective state ratings during the task between buprenorphine and control participants. Additional measures of adaptive control, however, showed interfering effects of buprenorphine administration. On the neural level, decreased Pe (Error Positivity) amplitudes were found in buprenorphine compared to control participants following error commission. Further, frontal delta oscillations were decreased in the buprenorphine group after all responses. Our neural results jointly demonstrate a general reduction in error processing in those participants who received an opioid before task completion, thereby suggesting that opioids might have indeed the potential to dampen motivational error signals. Importantly, the effects of the opioid were evident in more elaborate error processing stages, thereby impacting on processes of conscious error appraisal and evidence accumulation.

Durable memories and efficient neural coding through mnemonic training using the method of loci.

Mnemonic techniques, such as the method of loci, can powerfully boost memory. We compared memory athletes ranked among the world's top 50 in memory sports to mnemonics-naïve controls. In a second study, participants completed a 6-week memory training, working memory training, or no intervention. Behaviorally, memory training enhanced durable, longer-lasting memories. Functional magnetic resonance imaging during encoding and recognition revealed task-based activation decreases in lateral prefrontal, as well as in parahippocampal and retrosplenial cortices in both memory athletes and participants after memory training, partly associated with better performance after 4 months. This was complemented by hippocampal-neocortical coupling during consolidation, which was stronger the more durable memories participants formed. Our findings advance knowledge on how mnemonic training boosts durable memory formation through decreased task-based activation and increased consolidation thereafter. This is in line with conceptual accounts of neural efficiency and highlights a complex interplay of neural processes critical for extraordinary memory.

Interplay of self-other distinction and cognitive control mechanisms in a social automatic imitation task: An ERP study.

The regulation of motor resonance processes in daily life is indispensable. The automatic imitation task is an experimental model of those daily-life motor resonance processes. Recent research suggests that both self-other distinction and cognitive control processes may be involved in interference control during automatic imitation. Yet, we lack a clear understanding of the chronological sequence of interacting processes. To this end, this study used event-related potentials (ERPs) to investigate the time course underlying interference control during automatic imitation. We moreover aimed to extend previous results by investigating its modulation by social context. Cognitive conflict/action monitoring was assessed with the N2, in an exploratory manner the N450, and the CRN components. The Pre-Motor Positivity (PMP), associated with movement initiation, was suggested as a possible correlate of the successful resolution of self-other distinction. The cognitive control/action monitoring ERP components were influenced by the social context manipulation and partly by congruency, while PMP amplitudes were only sensitive to congruency. In addition, the exploratorily investigated N450 component predicted response times on incongruent relative to congruent trials in the different social contexts. This suggested that cognitive control/action monitoring processes, reflected in the N450, are guiding behavioral outcomes. Overall, interference control may primarily be guided by processes of cognitive control/action monitoring, whilst being modulated by social context demands.

Watching others in a positive state does not induce optimism bias in common marmosets (Callithrix jacchus), but leads to behaviour indicative of competition.

Emotional contagion is suggested to facilitate group life by enhancing synchronized responses to the environment. Cooperative breeders are an example of a social system that requires such intricate coordination between individuals. Therefore, we studied emotional contagion in common marmosets by means of a judgement bias test. Demonstrators were exposed to an emotion manipulation (i.e., positive, negative, control), and observers perceived only the demonstrator's behaviour. We predicted that the positive or negative states of the demonstrator would induce matching states in the observer, indicating emotional contagion. All subjects' emotional states were assessed through behaviour and cognition, the latter by means of a judgement bias test. Behavioural results showed a successful emotion manipulation of demonstrators, with manipulation-congruent expressions (i.e., positive calls in the positive condition, and negative calls and pilo-erect tail in the negative condition). Observers showed no manipulation-congruent expressions, but showed more scratching and arousal after the positive manipulation. Concerning the judgement bias test, we predicted that subjects in a positive state should increase their response to ambiguous cues (i.e., optimism bias), and subjects in a negative state should decrease their response (i.e., pessimism bias). This prediction was not supported as neither demonstrators nor observers showed such bias in either manipulation. Yet, demonstrators showed an increased response to the near-positive cue, and additional analyses showed unexpected responses to the reference cues, as well as a researcher identity effect. We discuss all results combined, including recently raised validation concerns of the judgement bias test, and inherent challenges to empirically studying emotional contagion.

When differences matter: rTMS/fMRI reveals how differences in dispositional empathy translate to distinct neural underpinnings of self-other distinction in empathy.

Self-other distinction is crucial for empathy, since it prevents the confusion of self-experienced emotions with those of others. We aimed to extend our understanding of the neurocognitive mechanisms of self-other distinction. Thirty-one female participants underwent continuous theta burst transcranial magnetic stimulation (cTBS) targeting the right supramarginal gyrus (rSMG), a sub-region of the temporoparietal junction previously shown to be involved in self-other distinction, and the vertex, a cortical control site. Right after stimulation they completed a visuo-tactile empathy task in an MRI scanner. Self-other distinction was assessed by differences in emotion judgments, and brain activity between conditions differing in the requirement for self-other distinction. Effects of brain stimulation on self-other distinction depended on individual differences in dispositional empathic understanding: cTBS of rSMG, compared to vertex, enhanced self-other distinction in participants with lower dispositional empathic understanding, but diminished it in participants with higher empathic understanding. On the neural level, this inverse relationship between empathic disposition and self-other distinction performance was linked to a reduction of cTBS-induced rSMG activity in persons with lower dispositional empathy, and an increase in those with higher dispositional empathy. These two opposite impacts of cTBS were associated with two anatomically and functionally distinct networks. These findings open up novel perspectives on the causal role of rSMG in self-other distinction and empathy. They also suggest that considering individual differences may yield novel insights into how brain stimulation affects higher-level affect and cognition, and its neural correlates.

Challenges in the comparative study of empathy and related phenomena in animals.

The aim of this review is to discuss recent arguments and findings in the comparative study of empathy. Based on a multidisciplinary approach including psychology and ethology, we review the non-human animal literature concerning theoretical frameworks, methodology, and research outcomes. One specific objective is to highlight discrepancies between theory and empirical findings, and to discuss ambiguities present in current data and their interpretation. In particular, we focus on emotional contagion and its experimental investigation, and on consolation and targeted helping as measures for sympathy. Additionally, we address the feasibility of comparing across species with behavioural data alone. One main conclusion of our review is that animal research on empathy still faces the challenge of closing the gap between theoretical concepts and empirical evidence. To advance our knowledge, we propose to focus more on the emotional basis of empathy, rather than on possibly ambiguous behavioural indicators, and we provide suggestions to overcome the limitations of previous research .

Acute stress alters neural patterns of value representation for others.

Acute stress is often evoked during social interactions, by feelings of threat or negative evaluation by other people. We also constantly interact with others while under stress - in the workplace or in private alike. However, it is not clear how stress affects social interactions. For one, individuals could become more selfish and focused on their own goals. On the other hand, individuals might also become more focused on affiliating with potential social partners, in order to secure their support. There is, indeed, accumulating behavioral evidence that prosocial behaviors increase rather than decrease under stress. Here, we tested the underlying brain processes of such findings, by assessing the effects of stress on the neural representations of (monetary) value for self and other. Participants (N â€‹= â€‹30; male, 18-40 years) played a gambling task for themselves and for another participant while undergoing functional magnetic resonance imaging (fMRI). Each participant played the gambling task twice: once immediately following acute stress induction, and once in a control session. We compared neural patterns of value representation in the dorsomedial prefrontal cortex (dmPFC), ventromedial prefrontal cortex (vmPFC) and striatum using representational similarity analysis (RSA). We found that under stress, dmPFC and striatum showed higher dissimilarity between neural patterns underlying high and low value for the other. Dissimilarity of neural patterns underlying high and low value for the self was unaffected by stress. These findings suggest that participants track the magnitude of possible rewards for others more under stress, suggesting increased prosocial orientation.

Exogenous testosterone increases status-seeking motivation in men with unstable low social status.

Testosterone is associated with status-seeking behaviors such as competition, which may depend on whether one wins or loses status, but also on the stability of one's status. We examined (1) to what extent testosterone administration affects competition behavior in repeated social contests in men with high or low rank, and (2), whether this relationship is moderated by hierarchy stability, as predicted by the status instability hypothesis. Using a real effort-based design in healthy male participants (N = 173 males), we first found that testosterone (vs. placebo) increased motivation to compete for status, but only in individuals with an unstable low status. A second part of the experiment, tailored to directly compare stable with unstable hierarchies, indicated that exogenous testosterone again increased competitive motivation in individuals with a low unstable status, but decreased competition behavior in men with low stable status. Additionally, exogenous testosterone increased motivation in those with a stable high status. Further analysis suggested that these effects were moderated by individuals' trait dominance, and genetic differences assessed by the androgen receptor (CAG-repeat) and dopamine transporter (DAT1) polymorphisms. Our study provides evidence that testosterone specifically boosts status-related motivation when there is an opportunity to improve one's social status. The findings contribute to our understanding of testosterone's causal role in status-seeking motivation in competition behavior, and indicate that testosterone adaptively increases our drive for high status in a context-dependent manner. We discuss potential neurobiological pathways through which testosterone may attain these effects on behavior.

The Other and Me: Effects of oxytocin on self-other distinction.

Distinguishing self- from other-related representations plays an important role in social interactions. The neuropeptide oxytocin has been shown to modulate social behavior as well as underlying social cognitions and emotions. However, how exactly oxytocin modulates representations of self and other is still unclear. The present study therefore aimed to assess effects of oxytocin on self-other distinction on two different processing levels (i.e., lower-level imitation-inhibition and higher-level perspective taking) in a male sample (n = 56) by performing a double-blind, placebo-controlled oxytocin administration study. Oxytocin improved visual perspective-taking and thus affected self-other distinction on the cognitive level, but had no effects on self-other distinction on the perceptual-motor level nor on a control task measuring attention reorientation. Thus, our findings suggest that oxytocin reduces ambiguity during perspective-taking in social interactions, which in turn may encourage social approach motivation and affiliative behavior.

Psychopharmacological modulation of event-related potentials suggests that first-hand pain and empathy for pain rely on similar opioidergic processes.

Accumulating evidence suggests that empathy for pain recruits similar neural processes as the first-hand experience of pain. The pain-related P2, an event-related potential component, has been suggested as a reliable indicator of neural processes associated with first-hand pain. Recent evidence indicates that placebo analgesia modulates this component for both first-hand pain and empathy for pain. Moreover, a psychopharmacological study showed that administration of an opioid antagonist blocked the effects of placebo analgesia on self-report of both first-hand pain and empathy for pain. Together, these findings suggest that the opioid system plays a similar role during first-hand pain and empathy for pain. However, such a conclusion requires evidence showing that neural activity during both experiences is similarly affected by psychopharmacological blockage of opioid receptors. Here, we measured pain-related P2 amplitudes and self-report in a group of participants who first underwent a placebo analgesia induction procedure. Then, they received an opioid receptor antagonist known to block the previously induced analgesic effects. Self-report showed that blocking opioid receptors after the induction of placebo analgesia increased both first-hand pain and empathy for pain, replicating previous findings. Importantly, P2 amplitudes were also increased during both experiences. Thus, the present findings extend models proposing that empathy for pain is partially grounded in first-hand pain by suggesting that this also applies to the underlying opioidergic neurochemical processes.

Default mode network deactivation during emotion processing predicts early antidepressant response.

Several previous functional magnetic resonance imaging (fMRI) studies have demonstrated the predictive value of brain activity during emotion processing for antidepressant response, with a focus on clinical outcome after 6-8 weeks. However, longitudinal studies emphasize the paramount importance of early symptom improvement for the course of disease in major depressive disorder (MDD). We therefore aimed to assess whether neural activity during the emotion discrimination task (EDT) predicts early antidepressant effects, and how these predictive measures relate to more sustained response. Twenty-three MDD patients were investigated once with ultrahigh-field 7T fMRI and the EDT. Following fMRI, patients received Escitalopram in a flexible dose schema and were assessed with the Hamilton Depression Rating Scale (HAMD) before, and after 2 and 4 weeks of treatment. Deactivation of the precuneus and posterior cingulate cortex (PCC) during the EDT predicted change in HAMD scores after 2 weeks of treatment. Baseline EDT activity was not predictive of HAMD change after 4 weeks of treatment. The precuneus and PCC are integral components of the default mode network (DMN). We show that patients who exhibit stronger DMN suppression during emotion processing are more likely to show antidepressant response after 2 weeks. This is, to our knowledge, the first study to show that DMN activity predicts early antidepressant effects. However, DMN deactivation did not predict response at 4 weeks, suggesting that our finding is representative of early, likely treatment-related, yet unspecific symptom improvement. Regardless, early effects may be harnessed for optimization of treatment regimens and patient care.

Increased neural responses to empathy for pain might explain how acute stress increases prosociality.

Recent behavioral investigations suggest that acute stress can increase prosocial behavior. Here, we investigated whether increased empathy represents a potential mechanism for this finding. Using functional magnetic resonance imaging, we assessed the effects of acute stress on neural responses related to automatic and regulatory components of empathy for pain as well as subsequent prosocial behavior. Stress increased activation in brain areas associated with the automatic sharing of others' pain, such as the anterior insula, the anterior midcingulate cortex, and the primary somatosensory cortex. In addition, we found increased prosocial behavior under stress. Furthermore, activation in the anterior midcingulate cortex mediated the effects of stress on prosocial behavior. However, stressed participants also displayed stronger and inappropriate other-related responses in situations which required them to take the perspective of another person, and to regulate their automatic affective responses. Thus, while acute stress may increase prosocial behavior by intensifying the sharing of others' emotions, this comes at the cost of reduced cognitive appraisal abilities. Depending on the contextual constraints, stress may therefore affect empathy in ways that are either beneficial or detrimental.

Retrospective characterisation of solitary cutaneous histiocytoma with lymph node metastasis in eight dogs.

OBJECTIVES: To describe a small subset of canine solitary cutaneous histiocytoma in which lymph node metastasis has been documented. METHODS: Cases of dogs with solitary cutaneous histiocytoma lesions and regional lymph node metastasis diagnosed via histopathology were found through a retrospective search of the databases of IDEXX Laboratories and the University of California, Davis Veterinary Medical Teaching Hospital Clinical Diagnostic Laboratories. Information on signalment, history and clinical follow-up was obtained from the submittal form and/or via a questionnaire to the submitting veterinarian. Slides were available for review in seven cases and when possible immunohistochemistry was reviewed or performed by a single pathologist. RESULTS: Eight cases met the inclusion criteria. The neoplasms had the typical appearance of histiocytomas. All tested samples were immunoreactive for CD18 and lacked immunoreactivity for other lymphocyte markers and CD11d. Immunoreactivity for E-cadherin varied among the neoplasms tested. Outcome was known for five dogs and at the time of manuscript preparation three of those dogs were alive 1682 days, 570 days and 318 days post-diagnosis. Of the other two dogs with known outcome, one was euthanased shortly after diagnosis and another was hit by a car. Of the dogs that were eventually lost to follow-up, one was reported to be disease-free 1003 days after diagnosis. CLINICAL SIGNIFICANCE: Metastatic histiocytoma is rarely reported and distinction from aggressive disease processes such as histiocytic sarcoma may be difficult. Based upon a small number of cases with known outcomes, some dogs with solitary metastatic histiocytoma may experience favourable outcomes.

The role of the right temporoparietal junction in the elicitation of vicarious experiences and detection accuracy while observing pain and touch.

This study investigated the effects of observing pain and touch in others upon vicarious somatosensory experiences and the detection of subtle somatosensory stimuli. Furthermore, transcranial direct current stimulation (tDCS) was used to assess the role of the right temporoparietal junction (rTPJ), as this brain region has been suggested to be involved in perspective taking and self-other distinction. Undergraduates (N = 22) viewed videos depicting hands being touched, hands being pricked, and control scenes (same approaching movement as in the other video categories but without the painful/touching object), while experiencing vibrotactile stimuli themselves on the left, right, or both hands. Participants reported the location at which they felt a somatosensory stimulus. Vibrotactile stimuli and visual scenes were applied in a congruent or incongruent way. During three separate testing sessions, excitability of the rTPJ was modulated with tDCS (cathodal, anodal, or sham). We calculated the proportion of correct responses and false alarms (i.e., number of trials in which a vicarious somatosensory experience was reported congruent to the site of the visual information). Pain-related scenes facilitated the correct detection of tactile stimuli and augmented the number of vicarious somatosensory experiences compared with observing touch or control videos. Stimulation of the rTPJ had no reliable influence upon detection accuracy or the number of vicarious errors. This study indicates that the observation of pain-related scenes compared to the observation of touch or control videos increases the likelihood that a somatosensory stimulus is detected. Contrary to our expectations, the rTPJ did not modulate detection accuracy.

From shared to distinct self-other representations in empathy: evidence from neurotypical function and socio-cognitive disorders.

Neuroscientific research has identified two fundamental components of empathy: shared emotional representations between self and other, and self-other distinction. The concept of shared representations suggests that during empathy, we co-represent another person's affect by engaging brain and bodily functions underpinning the first-hand experience of the emotion we are empathizing with. This possible grounding of empathy in our own emotional experiences explains the necessity for self-other distinction, which is the capacity to correctly distinguish between our own affective representations and those related to the other. In spite of the importance of these two components in empathy, several aspects still remain controversial. This paper addresses some of them and focuses on (i) the distinction between shared activations versus representations, raising the question what shared representations entail in terms of the underlying neural mechanisms, (ii) the possible mechanisms behind self-other distinction in the cognitive and the affective domains, and whether they have distinct neural underpinnings and (iii) the consequences associated with a selective impairment of one of the two components, thereby addressing their importance in mental disorders such as autism spectrum disorders, psychopathy and alexithymia.

Micro-CT analyses of historical bone samples presenting with osteomyelitis.

OBJECTIVE: Osteomyelitis is an inflammation of the bone marrow mainly caused by bacteria such as Staphylococcus aureus. It typically affects long bones, e.g. femora, tibiae and humeri. Recently micro-computed tomography (µCT) techniques offer the opportunity to investigate bone micro-architecture in great detail. Since there is no information on long bone microstructure in osteomyelitis, we studied historic bone samples with osteomyelitis by µCT. MATERIALS AND METHODS: We investigated 23 femora of 22 individuals suffering from osteomyelitis provided by the Collection of Anatomical Pathology, Museum of Natural History, Vienna (average age 44 ±19 years); 9 femora from body donors made available by the Department of Applied Anatomy, Medical University of Vienna (age range, 56-102 years) were studied as controls. Bone microstructure was assessed by µCT VISCOM X 8060 II with a minimal resolution of 18 µm. RESULTS: In the osteomyelitic femora, most prominent alterations were seen in the cortical compartment. In 71.4% of the individuals with osteomyelitis, cortical porosity occurred. 57.1% of the individuals showed cortical thinning. In 42.9% trabecularisation of cortical bone was observed. CONCLUSION: Osteomyelitis is associated with severe alterations of cortical bone structure otherwise typically observed at old age such as cortical porosity and cortical thinning.

p62/Sequestosome-1: Mapping Sites of Protein-Handling Stress in Canine Cutaneous Mast Cell Tumors.

Canine cutaneous mast cell tumors (MCT) are common, frequently malignant neoplasms that are currently graded histologically for provision of prognostic information. Continuing evidence of subsets of MCT within certain grades (with differing survival times) indicate the need for biomarkers that will facilitate better patient stratification and also provide further information on the biological processes involved in progression. We decided to investigate the expression of p62/sequestosome-1 (p62/SQSTM1), a stress-inducible "hub protein" found in all cell types that shuttles rapidly between the nucleus and cytoplasm and is known to play important roles in protein handling and tumorigenesis. The identity of canine p62/SQSTM1 was confirmed in silico and by validation of a commercial antibody using both Western blotting and functional (pharmaceutical-based) analyses in cell culture. Using immunohistochemistry, 3 patterns of p62 expression were identified based on the predominant intracellular localization, that is, nuclear, mixed (nuclear and cytoplasmic), and cytoplasmic. There was a highly significant association with the 2-tier (Kiupel) grade (P < .0001), with all p62-nuclear immunoreactivity being associated with low grade and most p62-cytoplasmic immunoreactivity (93%) with high grade. Most but not all mixed nuclear-cytoplasmic labeling occurred in low-grade MCT; in other (human) tumor types, this pattern has been interpreted as borderline malignant. These data indicate that there is a shift in protein-handling stress from the nucleus to the cytoplasm in association with increasing malignancy in MCT. Studies to identify the processes and drug-able targets involved in this progression are ongoing.