How side effects can improve treatment efficacy: a randomized trial.

While treatment side effects may adversely impact patients, they could also potentially function as indicators for effective treatment. In this study, we investigated whether and how side effects can trigger positive treatment expectations and enhance treatment outcomes. In this preregistered trial (DRKS00026648), 77 healthy participants were made to believe that they will receive fentanyl nasal sprays before receiving thermal pain in a controlled experimental setting. However, nasal sprays did not contain fentanyl, rather they either contained capsaicin to induce a side effect (mild burning sensation) or saline (inert). After the first session, participants were randomized to two groups and underwent functional magnetic resonance imaging (fMRI). One group continued to believe that the nasal sprays could contain fentanyl while the other group was explicitly informed that no fentanyl was included. This allowed for the independent manipulation of the side effects and the expectation of pain relief. Our results revealed that nasal sprays with a side effect lead to lower pain than inert nasal sprays without side effects. The influence of side effects on pain was dependent on individual beliefs about how side effects are related to treatment outcome, as well as on expectations about received treatment. FMRI data indicated an involvement of the descending pain modulatory system including the anterior cingulate cortex and the periaqueductal gray during pain after experiencing a nasal spray with side effects. In summary, our data show that mild side effects can serve as a signal for effective treatment thereby influencing treatment expectations and outcomes, which is mediated by the descending pain modulatory system. Using these mechanisms in clinical practice could provide an efficient way to optimize treatment outcome. In addition, our results indicate an important confound in clinical trials, where a treatment (with potential side effects) is compared to placebo.

The relationship between negative life events and cortical structural connectivity in adolescents.

Adolescence is a crucial period for physical and psychological development. The impact of negative life events represents a risk factor for the onset of neuropsychiatric disorders. This study aims to investigate the relationship between negative life events and structural brain connectivity, considering both graph theory and connectivity strength. A group (n = 487) of adolescents from the IMAGEN Consortium was divided into Low and High Stress groups. Brain networks were extracted at an individual level, based on morphological similarity between grey matter regions with regions defined using an atlas-based region of interest (ROI) approach. Between-group comparisons were performed with global and local graph theory measures in a range of sparsity levels. The analysis was also performed in a larger sample of adolescents (n = 976) to examine linear correlations between stress level and network measures. Connectivity strength differences were investigated with network-based statistics. Negative life events were not found to be a factor influencing global network measures at any sparsity level. At local network level, between-group differences were found in centrality measures of the left somato-motor network (a decrease of betweenness centrality was seen at sparsity 5%), of the bilateral central visual and the left dorsal attention network (increase of degree at sparsity 10% at sparsity 30% respectively). Network-based statistics analysis showed an increase in connectivity strength in the High stress group in edges connecting the dorsal attention, limbic and salience networks. This study suggests negative life events alone do not alter structural connectivity globally, but they are associated to connectivity properties in areas involved in emotion and attention.

Population clustering of structural brain aging and its association with brain development.

Structural brain aging has demonstrated strong inter-individual heterogeneity and mirroring patterns with brain development. However, due to the lack of large-scale longitudinal neuroimaging studies, most of the existing research focused on the cross-sectional changes of brain aging. In this investigation, we present a data-driven approach that incorporate both cross-sectional changes and longitudinal trajectories of structural brain aging and identified two brain aging patterns among 37,013 healthy participants from UK Biobank. Participants with accelerated brain aging also demonstrated accelerated biological aging, cognitive decline and increased genetic susceptibilities to major neuropsychiatric disorders. Further, by integrating longitudinal neuroimaging studies from a multi-center adolescent cohort, we validated the "last in, first out" mirroring hypothesis and identified brain regions with manifested mirroring patterns between brain aging and brain development. Genomic analyses revealed risk loci and genes contributing to accelerated brain aging and delayed brain development, providing molecular basis for elucidating the biological mechanisms underlying brain aging and related disorders.

Psychological risk factors for Long COVID and their modification: study protocol of a three-arm, randomised controlled trial (SOMA.COV).

BACKGROUND: Growing evidence suggests that in addition to pathophysiological, there are psychological risk factors involved in the development of Long COVID. Illness-related anxiety and dysfunctional symptom expectations seem to contribute to symptom persistence. AIMS: With regard to the development of effective therapies, our primary aim is to investigate whether symptoms of Long COVID can be improved by a targeted modification of illness-related anxiety and dysfunctional symptom expectations. Second, we aim to identify additional psychosocial risk factors that contribute to the persistence of Long COVID, and compare them with risk factors for symptom persistence in other clinical conditions. METHOD: We will conduct an observer-blinded, three-arm, randomised controlled trial. A total of 258 patients with Long COVID will be randomised into three groups of equal size: targeted expectation management in addition to treatment as usual (TAU), non-specific supportive treatment plus TAU, or TAU only. Both active intervention groups will comprise three individual online video consultation sessions and a booster session after 3 months. The primary outcome is baseline to post-interventional change in overall somatic symptom severity. CONCLUSIONS: The study will shed light onto the action mechanisms of a targeted expectation management intervention for Long COVID, which, if proven effective, can be used stand-alone or in the context of broader therapeutic approaches. Further, the study will enable a better understanding of symptom persistence in Long COVID by identifying additional psychological risk factors.

Temporal Summation of the Thermal Grill Illusion is Comparable to That Observed Following Noxious Heat.

The thermal grill illusion (TGI) describes a peculiar or even painful percept caused by non-noxious, interlaced warm and cold stimuli. It involves the glutamatergic system and is affected in putatively nociplastic syndromes such as fibromyalgia. The glutamatergic system is also involved in wind-up, that is, the increased activation of spinal neurons following repeated noxious stimulation leading to a temporal summation of perceived stimulus intensity. Here we combined both stimulation methods to further investigate whether non-noxious stimuli as employed in the TGI can lead to a similar summation of perceived stimulus intensity. In an experiment using a full crossover within-subjects design, 35 healthy volunteers received repeated stimuli, either in a thermal grill configuration or simply noxious heat. Both modalities were presented as sequences of 1 lead-in contact, followed by 11 consecutive contacts (each between 1.5 and 3 seconds), with either fast repetition ("wind-up" condition), or 2 slow-repeating control conditions. The main analyses concerned the relative pre-to-post sequence changes to quantify putatively wind-up-related effects. Pain ratings and skin conductance level (SCL) increased more strongly in "wind-up" than in control conditions. Interestingly, wind-up-related effects were of the same magnitude in TGI as compared to the pain control modality. Further, contact-by-contact SCL tracked how the effect emerged over time. These results indicate that although TGI does not involve noxious stimuli it is amenable to temporal summation and wind-up-like processes. Since both phenomena involve the glutamatergic system, the combination of wind-up with the TGI could yield a promising tool for the investigation of chronic pain conditions. PERSPECTIVE: Using thermal stimuli in an experimental protocol to combine 1) the TGI (painful or peculiar percept from simultaneous cold/warm stimulation) and 2) wind-up (increase in stimulus intensity after repeated exposure) holds promise to investigate pain and thermoceptive mechanisms, and chronic pain conditions.

Association between activity in the ventral premotor cortex and spinal cord activation during force generation-A combined cortico-spinal fMRI study.

Force generation is a crucial element of dexterity and a highly relevant skill of the human motor system. How cerebral and spinal components interact and how spinal activation is associated with the activity in the cerebral primary motor and premotor areas is poorly understood. Here, we conducted combined cortico-spinal functional magnetic resonance imaging during a simple visually guided isometric force generation task in 20 healthy young subjects. Activation was localized in the right cervical spinal cord and left primary motor and premotor areas. The main finding is that spinal activation was negatively correlated with ventral premotor cortex activation. Spinal activation was furthermore significantly correlated with primary motor cortex activation, while increasing target forces led to an increase in the amount of activation. These data indicate that human premotor areas such as the ventral premotor cortex might be functionally connected to the lower cervical spinal cord contributing to distal upper limb functions, a finding that extends our understanding of human motor function beyond the animal literature.

The influence of psychological traits and prior experience on treatment expectations.

BACKGROUND: Placebo and nocebo responses are modulated by the treatment expectations of participants and patients. However, interindividual differences predicting treatment expectations and placebo responses are unclear. In this large-scale pooled analysis, we aim to investigate the influence of psychological traits and prior experiences on treatment expectations. METHODS: This paper analyses data from six different placebo studies (total n = 748). In all studies, participants' sociodemographic information, treatment expectations and prior treatment experiences and traits relating to stress, somatization, depression and anxiety, the Big Five and behavioral inhibition and approach tendencies were assessed using the same established questionnaires. Correlation coefficients and structural equation models were calculated to investigate the relationship between trait variables and expectations. RESULTS: We found small positive correlations between side effect expectations and improvement expectations (r = 0.187), perceived stress (r = 0.154), somatization (r = 0.115), agitation (r = 0.108), anhedonia (r = 0.118), and dysthymia (r = 0.118). In the structural equation model previous experiences emerged as the strongest predictors of improvement (ß = 0.32, p = .005), worsening (ß = -0.24, p = .005) and side effect expectations (ß = 0.47, p = .005). Traits related to positive affect (ß = - 0.09; p = .007) and negative affect (ß = 0.04; p = .014) were associated with side effect expectations. DISCUSSION: This study is the first large analysis to investigate the relationship between traits, prior experiences and treatment expectations. Exploratory analyses indicate that experiences of symptom improvement are associated with improvement and worsening expectations, while previous negative experiences are only related to side effect expectations. Additionally, a proneness to experience negative affect may be a predictor for side effect expectation and thus mediate the occurrence of nocebo responses.

Association between vmPFC gray matter volume and smoking initiation in adolescents.

Smoking of cigarettes among young adolescents is a pressing public health issue. However, the neural mechanisms underlying smoking initiation and sustenance during adolescence, especially the potential causal interactions between altered brain development and smoking behaviour, remain elusive. Here, using large longitudinal adolescence imaging genetic cohorts, we identify associations between left ventromedial prefrontal cortex (vmPFC) gray matter volume (GMV) and subsequent self-reported smoking initiation, and between right vmPFC GMV and the maintenance of smoking behaviour. Rule-breaking behaviour mediates the association between smaller left vmPFC GMV and smoking behaviour based on longitudinal cross-lagged analysis and Mendelian randomisation. In contrast, smoking behaviour associated longitudinal covariation of right vmPFC GMV and sensation seeking (especially hedonic experience) highlights a potential reward-based mechanism for sustaining addictive behaviour. Taken together, our findings reveal vmPFC GMV as a possible biomarker for the early stages of nicotine addiction, with implications for its prevention and treatment.

A shared neural basis underlying psychiatric comorbidity.

Recent studies proposed a general psychopathology factor underlying common comorbidities among psychiatric disorders. However, its neurobiological mechanisms and generalizability remain elusive. In this study, we used a large longitudinal neuroimaging cohort from adolescence to young adulthood (IMAGEN) to define a neuropsychopathological (NP) factor across externalizing and internalizing symptoms using multitask connectomes. We demonstrate that this NP factor might represent a unified, genetically determined, delayed development of the prefrontal cortex that further leads to poor executive function. We also show this NP factor to be reproducible in multiple developmental periods, from preadolescence to early adulthood, and generalizable to the resting-state connectome and clinical samples (the ADHD-200 Sample and the Stratify Project). In conclusion, we identify a reproducible and general neural basis underlying symptoms of multiple mental health disorders, bridging multidimensional evidence from behavioral, neuroimaging and genetic substrates. These findings may help to develop new therapeutic interventions for psychiatric comorbidities.

Expectations and Prior Experiences Associated With Adverse Effects of COVID-19 Vaccination.

Importance: Uptake of vaccination against COVID-19 is strongly affected by concerns about adverse effects. Research on nocebo effects suggests that these concerns can amplify symptom burden. Objective: To investigate whether positive and negative expectations prior to COVID-19 vaccination are associated with systemic adverse effects. Design, Setting, and Participants: This prospective cohort study analyzed the association of expected benefits and risks of vaccination, adverse effects at first vaccination, and observed adverse effects in close contacts with severity of systemic adverse effects among adults receiving a second dose of messenger RNA (mRNA)-based vaccines between August 16 and 28, 2021. A total of 7771 individuals receiving the second dose at a state vaccination center in Hamburg, Germany, were invited to participate; of these, 5370 did not respond, 535 provided incomplete information, and 188 were excluded retrospectively. The mobile application m-Path was used for data collection. Main Outcomes and Measures: Primary outcome was a composite severity index of systemic adverse effects in 12 symptom areas measured once daily with an electronic symptom diary over 7 consecutive days. Data were analyzed by mixed-effects multivariable ordered logistic regression adjusted for prevaccine symptom levels and observation times. Results: A total of 10 447 observations from 1678 individuals receiving vaccinations (BNT162b2 [Pfizer BioNTech] in 1297 [77.3%] and mRNA-1273 [Moderna] in 381 [22.7%]) were collected. The participants' median age was 34 (IQR, 27-44) years, and 862 (51.4%) were women. The risk for more severe adverse effects was higher for persons expecting a lower benefit of vaccination (odds ratio [OR] for higher expectations, 0.72 [95% CI, 0.63-0.83]; P < .001), expecting higher adverse effects of vaccination (OR, 1.39 [95% CI, 1.23-1.58]; P < .001), having experienced higher symptom burden at the first vaccination (OR, 1.60 [95% CI, 1.42-1.82]; P < .001), scoring higher on the Somatosensory Amplification Scale (OR, 1.21 [95% CI, 1.06-1.38]; P = .004), and if the vaccine mRNA-1273 was given rather than BNT162b2 (OR, 2.45 [95% CI, 2.01-2.99]; P < .001). No associations were seen for observed experiences. Conclusions and Relevance: In this cohort study, several nocebo effects occurred in the first week after COVID-19 vaccination. The severity of systemic adverse effects was associated not only with vaccine-specific reactogenicity but also more negative prior experiences with adverse effects from the first COVID-19 vaccination, more negative expectations regarding vaccination, and tendency to catastrophize instead of normalize benign bodily sensations. Clinician-patient interactions and public vaccine campaigns may both benefit from these insights by optimizing and contextualizing information provided about COVID-19 vaccines.

The role of expectations, control and reward in the development of pain persistence based on a unified model.

Chronic, or persistent pain affects more than 10% of adults in the general population. This makes it one of the major physical and mental health care problems. Although pain is an important acute warning signal that allows the organism to take action before tissue damage occurs, it can become persistent and its role as a warning signal thereby inadequate. Although per definition, pain can only be labeled as persistent after 3 months, the trajectory from acute to persistent pain is likely to be determined very early and might even start at the time of injury. The biopsychosocial model has revolutionized our understanding of chronic pain and paved the way for psychological treatments for persistent pain, which routinely outperform other forms of treatment. This suggests that psychological processes could also be important in shaping the very early trajectory from acute to persistent pain and that targeting these processes could prevent the development of persistent pain. In this review, we develop an integrative model and suggest novel interventions during early pain trajectories, based on predictions from this model.

Multivariate functional neuroimaging analyses reveal that strength-dependent face expectations are represented in higher-level face-identity areas.

Perception is an active inference in which prior expectations are combined with sensory input. It is still unclear how the strength of prior expectations is represented in the human brain. The strength, or precision, of a prior could be represented with its content, potentially in higher-level sensory areas. We used multivariate analyses of functional resonance imaging data to test whether expectation strength is represented together with the expected face in high-level face-sensitive regions. Participants were trained to associate images of scenes with subsequently presented images of different faces. Each scene predicted three faces, each with either low, intermediate, or high probability. We found that anticipation enhances the similarity of response patterns in the face-sensitive anterior temporal lobe to response patterns specifically associated with the image of the expected face. In contrast, during face presentation, activity increased for unexpected faces in a typical prediction error network, containing areas such as the caudate and the insula. Our findings show that strength-dependent face expectations are represented in higher-level face-identity areas, supporting hierarchical theories of predictive processing according to which higher-level sensory regions represent weighted priors.

Agency affects pain inference through prior shift as opposed to likelihood precision modulation in a Bayesian pain model.

Agency and expectations play a crucial role in pain perception and treatment. In the Bayesian pain model, somatosensation (likelihood) and expectations (prior) are weighted by their precision and integrated to form a pain percept (posterior). Combining pain treatment with stimulus-related expectations allows the mechanistic assessment of whether agency enters this model as a shift of the prior or a relaxation of the likelihood precision. In two experiments, heat pain was sham treated either externally or by the subject, while a predictive cue was utilized to create high or low treatment expectations. Both experiments revealed additive effects and greater pain relief under self-treatment and high treatment expectations. Formal model comparisons favored a prior shift rather than a modulation of likelihood precision. Electroencephalography revealed a theta-to-alpha effect, temporally associated with expectations, which was correlated with trial-by-trial pain ratings, further supporting a prior shift through which agency exerts its influence in the Bayesian pain model.

Longitudinal associations between adolescent catch-up sleep, white-matter maturation and internalizing problems.

Sleep is an important contributor for neural maturation and emotion regulation during adolescence, with long-term effects on a range of white matter tracts implicated in affective processing in at-risk populations. We investigated the effects of adolescent sleep patterns on longitudinal changes in white matter development and whether this is related to the emergence of emotional (internalizing) problems. Sleep patterns and internalizing problems were assessed using self-report questionnaires in adolescents recruited in the general population followed up from age 14-19 years (N = 111 White matter structure was measured using diffusion tensor imaging (DTI) and estimated using fractional anisotropy (FA). We found that longitudinal increases in time in bed (TIB) on weekends and increases in TIB-variability between weekdays to weekend, were associated with an increase in FA in various interhemispheric and cortico-striatal tracts. Extracted FA values from left superior longitudinal fasciculus mediated the relationship between increases in TIB on weekends and a decrease in internalizing problems. These results imply that while insufficient sleep might have potentially harmful effects on long-term white matter development and internalizing problems, longer sleep duration on weekends (catch-up sleep) might be a natural counteractive and protective strategy.

Flexible sensory-motor mapping rules manifest in correlated variability of stimulus and action codes across the brain.

Humans and non-human primates can flexibly switch between different arbitrary mappings from sensation to action to solve a cognitive task. It has remained unknown how the brain implements such flexible sensory-motor mapping rules. Here, we uncovered a dynamic reconfiguration of task-specific correlated variability between sensory and motor brain regions. Human participants switched between two rules for reporting visual orientation judgments during fMRI recordings. Rule switches were either signaled explicitly or inferred by the participants from ambiguous cues. We used behavioral modeling to reconstruct the time course of their belief about the active rule. In both contexts, the patterns of correlations between ongoing fluctuations in stimulus- and action-selective activity across visual- and action-related brain regions tracked participants' belief about the active rule. The rule-specific correlation patterns broke down around the time of behavioral errors. We conclude that internal beliefs about task state are instantiated in brain-wide, selective patterns of correlated variability.

Insulin sensitivity in mesolimbic pathways predicts and improves with weight loss in older dieters.

Central insulin is critically involved in the regulation of hedonic feeding. Insulin resistance in overweight has recently been shown to reduce the inhibitory function of insulin in the human brain. How this relates to effective weight management is unclear, especially in older people, who are highly vulnerable to hyperinsulinemia and in whom neural target systems of insulin action undergo age-related changes. Here, 50 overweight, non-diabetic older adults participated in a double-blind, placebo-controlled, pharmacological functional magnetic resonance imaging study before and after randomization to a 3-month caloric restriction or active waiting group. Our data show that treatment outcome in dieters can be predicted by baseline measures of individual intranasal insulin (INI) inhibition of value signals in the ventral tegmental area related to sweet food liking as well as, independently, by peripheral insulin sensitivity. At follow-up, both INI inhibition of hedonic value signals in the nucleus accumbens and peripheral insulin sensitivity improved with weight loss. These data highlight the critical role of central insulin function in mesolimbic systems for weight management in humans and directly demonstrate that neural insulin function can be improved by weight loss even in older age, which may be essential for preventing metabolic disorders in later life.

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.

The human insula processes both modality-independent and pain-selective learning signals.

Prediction errors (PEs) are generated when there are differences between an expected and an actual event or sensory input. The insula is a key brain region involved in pain processing, and studies have shown that the insula encodes the magnitude of an unexpected outcome (unsigned PEs). In addition to signaling this general magnitude information, PEs can give specific information on the direction of this deviation-i.e., whether an event is better or worse than expected. It is unclear whether the unsigned PE responses in the insula are selective for pain or reflective of a more general processing of aversive events irrespective of modality. It is also unknown whether the insula can process signed PEs at all. Understanding these specific mechanisms has implications for understanding how pain is processed in the brain in both health and in chronic pain conditions. In this study, 47 participants learned associations between 2 conditioned stimuli (CS) with 4 unconditioned stimuli (US; painful heat or loud sound, of one low and one high intensity each) while undergoing functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) measurements. We demonstrate that activation in the anterior insula correlated with unsigned intensity PEs, irrespective of modality, indicating an unspecific aversive surprise signal. Conversely, signed intensity PE signals were modality specific, with signed PEs following pain but not sound located in the dorsal posterior insula, an area implicated in pain intensity processing. Previous studies have identified abnormal insula function and abnormal learning as potential causes of pain chronification. Our findings link these results and suggest that a misrepresentation of learning relevant PEs in the insular cortex may serve as an underlying factor in chronic pain.

Opioid analgesia alters corticospinal coupling along the descending pain system in healthy participants.

Opioids are potent analgesic drugs with widespread cortical, subcortical, and spinal targets. In particular, the central pain system comprising ascending and descending pain pathways has high opioid receptor densities and is thus crucial for opioid analgesia. Here, we investigated the effects of the opioid remifentanil in a large sample (n = 78) of healthy male participants using combined corticospinal functional MRI. This approach offers the possibility to measure BOLD responses simultaneously in the brain and spinal cord, allowing us to investigate the role of corticospinal coupling in opioid analgesia. Our data show that opioids altered activity in regions involved in pain processing such as somatosensory regions, including the spinal cord and pain modulation such as prefrontal regions. Moreover, coupling strength along the descending pain system, that is, between the anterior cingulate cortex, periaqueductal gray, and spinal cord, was stronger in participants who reported stronger analgesia during opioid treatment while participants that received saline showed reduced coupling when experiencing less pain. These results indicate that coupling along the descending pain pathway is a potential mechanism of opioid analgesia and can differentiate between opioid analgesia and unspecific reductions in pain such as habituation.