Growing evidence points to a close neurophysiological link between brain and body. Recent rodent studies have shown that the dopaminergic mesolimbic pathway, which underlies expectations of positive outcomes, also modulates immune function. However, it remains unknown whether a similar brain-immune link exists in humans and whether it involves conscious positive expectations. In a preregistered, double-blind randomized controlled trial, we used fMRI neurofeedback (NF) to train healthy participants to increase reward mesolimbic activity through self-chosen mental strategies, followed by an immune challenge with the hepatitis B virus (HBV) vaccine and assessments of HBV antibody (HBVab) levels. Eighty-five participants were randomized to (1) reward mesolimbic upregulation (n = 34), (2) non-mesolimbic control upregulation (n = 34) or (3) no-NF control (n = 17). Prespecified primary outcomes were (1) differences in reward mesolimbic activation between NF groups, (2) correlation between reward mesolimbic upregulation and post-vaccination HBVab changes across both NF groups and (3) group differences in post-vaccination HBVab changes. Both NF groups showed significant increases in reward mesolimbic activation. Notably, greater ventral tegmental area (VTA) upregulation—but not nucleus accumbens or control region activation—was associated with larger post-vaccination increases in HBVab levels (r = 0.31, P = 0.018). Sustained VTA upregulation was further linked to mental strategies involving positive expectations. Post-vaccination antibody levels did not differ between groups, and no adverse effects occurred. Together, these findings suggest that consciously generated positive expectations can engage reward circuitry to influence immune function, a process that may be leveraged for non-invasive immune modulation. ClinicalTrials.gov identifier: NCT03951870 . Upregulation of the ventral tegmental area via neurofeedback is associated with a stronger immune response to hepatitis B virus vaccination, and VTA upregulation is achieved through conscious positive expectations.

Introduction:Motivation drives goal-directed behavior, often requiring individuals to approach rewards while facing potential punishment (i.e., goal-conflict). Premenstrual dysphoric disorder (PMDD) is marked by emotional and cognitive impairments that may affect motivational functioning. While emotional deficits in PMDD are well-known, their impact on motivation under goal-conflict remains unclear. This study examined neurobehavioral indications for motivational deficits in PMDD during naturalistic goal-conflict and their relation to symptom severity. Methods:Fifty-one women with regular menstrual cycles (28 with PMDD, 23 healthy controls) completed a computer-based approach-avoidance task during fMRI scanning in the luteal phase. The task included high and low goal-conflict (HiGC or LoGC) conditions, where rewards were threatened by punishment. Neural activity in mesostriatal reward-related regions - the ventral striatum (VS) and ventral tegmental area (VTA) - was analyzed using general linear models. Symptom severity was assessed using the Premenstrual Tension Syndrome Observer Rating Scale (PMTS-OR). Results:Compared with healthy controls, participants with PMDD were less able to increase approach behavior as conflict decreased, resulting in fewer approach events under LoGC condition, while no group differences were observed under HiGC. Additionally, within the PMDD group, greater symptom severity (depression and anxiety) was associated with lower approach behavior under HiGC conditions. fMRI analyses revealed diminished activation in the VS and VTA under HiGC in the PMDD group, suggesting reduced conflict-related engagement of reward-related circuitry. Conclusion:PMDD is associated with impaired motivational adaptation across conflict levels, reflected in a blunted increase in approach behavior under conditions of lower risk. Diminished conflict-related activity in reward-related mesostriatal regions (VS, VTA) may underlie this deficit. These findings highlight the potential role of mesolimbic circuitry dysfunction in PMDD and point toward reward processing pathways as candidate therapeutic targets. Trial registration number:NCT02448836, ClinicalTrials.gov.

Emotional experiences are never static but continuously evolve in response to internal and external contexts. Little is known about how neural patterns change as a function of these experiences, particularly in response to complex, real-world stimuli. This study aimed to identify generalizable neural patterns as individuals collectively engage and disengage from emotions dynamically. To do so, we analyzed functional magnetic resonance imaging along with subjective emotional annotations from two independent studies as individuals watched negative and neutral movie clips. We used predictive modeling to test if a model trained to predict a group emotional signature response in one study generalizes to the other study and vice versa. Disengagement patterns generalized specifically across intense clips. They were supported by connections within and between the sensorimotor and salience networks, maybe reflecting the processing of feeling states as individuals regulate their emotions. Prediction success for the engagement signature was mixed, but primarily linked to connections within the visual and between the visual and dorsal attention networks, maybe supporting visual attention orienting as emotions intensify. This work offers potential pathways for identifying generalizable neural patterns contributing to future affective research and clinical applications aiming to better understand dynamic emotional responses to naturalistic stimuli.

Identifying brain regions that exhibit altered functional connectivity across cognitive or emotional states is a key problem in neuroscience. Existing methods, such as edge-wise testing, seed-based psychophysiological interaction (PPI) analysis, or correlation network comparison, typically suffer from low statistical power, arbitrary thresholding, and limited ability to capture distributed or nonlinear dependence patterns. We propose SpARCD (Spectral Analysis of Revealing Connectivity Differences), a novel statistical framework for detecting differences in brain connectivity between two experimental conditions. SpARCD leverages distance correlation, a dependence measure sensitive to both linear and nonlinear associations, to construct a weighted graph for each condition. It then constructs a differential operator via spectral filtering and uncovers connectivity changes by computing its leading eigenvectors. Inference is achieved via a permutation-based testing scheme that yields interpretable, region-level significance maps. Extensive simulation studies demonstrate that SpARCD achieves superior power relative to conventional edge-wise or univariate approaches, particularly in the presence of complex dependency structures. Application to fMRI data from 113 early PTSD patients performing an emotional face-matching task reveals distinct networks associated with emotional reactivity and regulatory processes. Overall, SpARCD provides a statistically rigorous and computationally efficient framework for comparing high-dimensional connectivity structures, with broad applicability to neuroimaging and other network-based scientific domains.

This fMRI study examined the neural mechanisms underlying cognitive performance under stress, with a focus on individual differences in this capacity. Using an Ecological Multitasking under Stress (EMTS) paradigm, 50 healthy males performed a dual task combining executive function and flight navigation across five levels of task demand. The task was performed twice - with or without an additional stressor unrelated to task demand, consisting of social evaluation and aversive sirens. Subjective distress and autonomic measures were recorded throughout the task, confirming the effectiveness of the stress manipulation. Behavioral results showed that both stress and task demand significantly hampered performance accuracy and speed and increased subjective distress. Neural activation increased with task demand in the executive control network (ECN) and default mode network (DMN), whereas additional stress selectively increased activation in the salience network. Higher task demand across runs was also associated with enhanced ECN-DMN anticorrelation, indicating reduced functional integration between these networks. Notably, at the highest task-demand level under stress, perceived stress predicted performance decline and mediated the association between greater ECN activation and poorer executive performance. These findings further highlight a potential mechanism through which subjective distress may impair performance, whereby increased ECN engagement under conditions of high demand and stress may reflect inefficient cognitive control. This work may inform the development of brain-guided interventions to improve coping with high cognitive demands under stress.

Ketamine produces both analgesic and dissociative effects, but whether analgesia depends on dissociation remains debated. This question is part of a broader discussion on whether the subjective experiences elicited by psychoactive drugs are necessary for their therapeutic benefits. Here, we tested whether ketamine-induced analgesia and dissociation show separable behavioral and neural signatures. In a within-subject, placebo-controlled fMRI study, 37 healthy volunteers (21 female) underwent two sessions: intravenous ketamine (0.4 mg/kg bolus over 10 min followed by 0.4 mg/kg/h continuous infusion) or saline placebo. Individually calibrated thermal pain stimuli were applied to the right leg during scanning. Dissociative states were measured repeatedly using the Clinician-Administered Dissociative States Scale. Whole-brain univariate and multivariate analyses, as well as network-based functional connectivity analyses, were performed. Ketamine induced both analgesia (session × pain intensity interaction: F(1,54) = 11.22, p = 0.001) and dissociation (main effect of session: F(1,32) = 57.44, p < 0.001), and the two corresponded to distinct neural indices. Greater pain was associated with increased univariate activity in regions such as the anterior insula, as well as with stronger expression of a pain-predictive multivoxel pattern (ρ = 0.6, p < 0.001), whereas higher dissociation intensity was selectively associated with reduced default mode network connectivity (ρ = .49, p < 0.01). Neurobehavioral markers of pain and dissociation did not covary (ρ = -0.24 to 0.32, all p > 0.09), consistent with distinct neural correlates of ketamine's analgesic and dissociative effects.

Current dimensional approaches to psychiatric disorders have largely focused on explaining differences between individuals, whereas it remains unknown whether symptom dynamics within individuals are organized by the same underlying dimensions. In PTSD, temporal symptom variability may represent a clinically meaningful source of heterogeneity relevant to spontaneous recovery, chronicity, and treatment response. Our reciprocal inhibition model of PTSD proposed that both between-individual heterogeneity and within-individual dynamics may be organized along a dimension reflecting the relative balance between re-experiencing and avoidance symptoms (symptom imbalance), potentially corresponding to shifts between states of emotional under- and overmodulation. Here, using seven longitudinal and two cross-sectional PTSD cohorts spanning disorder development, chronicity, and recovery, we examined whether symptom heterogeneity between individuals and within individuals over time is organized along shared latent symptom dimensions. Principal component analysis (PCA) performed separately on between-individual variability (individual differences) and within-individual variation (temporal variability) consistently recovered the same two axes: the first indexing overall symptom severity and the second reflecting the proposed symptom imbalance. To enable direct comparison across cohorts and between-individual and temporal scales, we integrated cohort-specific covariance structures using hierarchical multi-group PCA yielding universal axes (uPC1/uPC2). Mapping treatment trajectories onto this shared symptom space revealed that two first-line psychotherapies: cognitive processing therapy (CPT) and eye movement desensitization and reprocessing (EMDR): produced comparable reductions in overall symptom severity (uPC1), but opposite shifts along symptom imbalance (uPC2). These findings suggest treatment-related symptom trajectories that are not captured by severity alone and provide a quantitative basis for treatment stratification grounded in symptom imbalance dynamics, motivating prospective tests of state-dependent intervention in PTSD and related psychiatric disorders.

Ketamine, a psychoactive medication, exerts both analgesic and dissociative effects. However, whether its analgesic effect stems from its dissociative properties is a topic of debate. Our study aimed to determine whether ketamine’s analgesic and dissociative effects are supported by distinct neural mechanisms. In a within-subject, placebo-controlled study, 37 healthy volunteers were administered ketamine (0.4 mg/kg bolus followed by a continuous drip of 0.4 mg/kg/h) or saline during fMRI sessions where thermal pain was induced. Our results indicate that while ketamine significantly reduced thermal pain ratings and produced robust dissociative effects, these outcomes were not correlated. Neurally, ketamine reduced pain-related brain activations across a network of regions, including the insula and anterior cingulate cortex. Additionally, ketamine significantly diminished functional connectivity between default mode network regions, and this reduction was correlated with the intensity of dissociation. These findings suggest that ketamine’s analgesic and dissociative effects are independent and mediated by distinct neural pathways. ### Competing Interest Statement The authors have declared no competing interest.

BACKGROUND:Posttraumatic stress disorder (PTSD) is a heterogeneous condition with diverse symptom presentations and emotional experiences. While fear is traditionally viewed as central, growing evidence highlights the role of non-fear-based emotions, such as sadness, guilt, and shame-collectively termed emotional pain. This study aimed to identify fear- and emotional pain-based PTSD symptom profiles and their neural correlates across 2 independent samples. METHODS:In study 1 (N = 838), trauma-exposed individuals with probable PTSD completed the PTSD Checklist for DSM-5 and subjective ratings of fear and emotional pain. Item-level network analysis was conducted to identify central symptoms and relationships. In study 2 (N = 162), recent trauma survivors with high PTSD symptoms underwent resting-state and task-based functional magnetic resonance imaging scans 1 month after trauma and completed follow-up clinical assessment at 14 months after trauma. Connectome-based predictive modeling (CPM) was used to predict chronic symptom severity for fear- and emotional pain-based profiles, identified in study 1. RESULTS:Emotional pain was rated as more impairing than fear by most participants (69%). Symptom networks showed distinct patterns: Fear was associated with flashbacks, nightmares, distressing memories, exaggerated startle, and external avoidance; emotional pain was linked to anhedonia, negative beliefs, negative emotions, sleep disturbance, and emotional reactivity. CPM predicted chronic fear-based symptom severity (ρ = 0.228, p < .001), but not emotional pain (ρ = 0.167, p = .055). Predictive features included connections across anterior default mode, central executive, salience, motor-sensory, and subcortical networks. CONCLUSIONS:Emotional pain and fear may represent distinct PTSD dimensions. Disentangling their neural signatures may improve diagnostic precision and guide personalized, mechanism-based interventions for trauma-related psychopathology.

Understanding the mechanisms behind (mal)adaptive stress responses is crucial for addressing stress-related mental disorders, which remain leading contributors to global disability and mortality. However, individual differences in stress responses present a challenge for single studies due to limited sample sizes. Multi-site studies can overcome this by increasing statistical power and generalizability, but it remains unclear whether even optimally harmonized procedures can ensure cross-site comparability. To investigate the impact of study site on the multimodal response to an acute social stressor, we analyzed data from the Dynamic Modeling of Resilience Observational (DynaM-OBS) Study, encompassing five study sites across Europe and Israel. By employing harmonized procedures for stress induction through the adapted ScanSTRESS-C MRI paradigm, along with consistent protocols for data acquisition and processing, we assessed the following markers: subjective stress ratings, heart rate, salivary cortisol, salivary alpha-amylase levels, and fMRI BOLD response. Bayesian inference allowed us to evaluate the evidence for and against the presence of site effects on stress markers. Results indicate successful stress induction, as evidenced by subjective, cardiac, and neural measures, though the salivary stress markers did, on average, not show a typical increase. Comparable stress responses were observed across most sites, highlighting the potential of rigorous procedural harmonization. However, the notable differences at the geographically most distant site may partially reflect variations in stressor exposure, as well as potential cultural differences. These findings highlight the importance of considering demographic and geo-cultural factors in multi-site stress research. Additionally, we emphasize the value of employing Bayesian approaches to integrate and evaluate data from diverse sources. Overall, while such studies enhance statistical power and generalizability, careful interpretation of site-specific effects is essential for advancing our understanding of stress-related mental health.

BACKGROUND:Stress leads to neurobiological changes, and failure to regulate these can contribute to chronic psychiatric issues. Despite considerable research, the relationship between neural alterations in acute stress and coping with chronic stress is unclear. This longitudinal study examined whole-brain network dynamics following induced acute stress and their role in predicting chronic stress vulnerability. METHODS:Sixty military pre-deployment soldiers underwent a lab-induced stress task where subjective stress and resting-state functional magnetic resonance imaging were acquired repeatedly (before stress, after stress, and at recovery, 90 min later). Baseline depression and post-traumatic stress symptoms were assessed, and again a year later during military deployment. We used the Leading Eigenvector Dynamic Analysis framework to characterize changes in whole-brain dynamics over time. Time spent in each state was compared across acute stress conditions and correlated with psychological outcomes. RESULTS:Findings reveal significant changes at the network level from acute stress to recovery, where the frontoparietal and subcortical states decreased in dominance in favor of the default mode network, sensorimotor, and visual states. A significant normalization of the frontoparietal state activity was related to successful psychological recovery. Immediately after induced stress, a significant increase in the lifetimes of the frontoparietal state was associated with higher depression symptoms (r = 0.49, p < .02) and this association was also observed a year later following combat exposure (r = 0.49, p < .009). CONCLUSIONS:This study revealed how acute stress-related neural alterations predict chronic stress vulnerability. Successful recovery from acute stress involves reducing cognitive-emotional states and enhancing self-awareness and sensory-perceptual states. Elevated frontoparietal activity is suggested as a neural marker of vulnerability to chronic stress.

Psilocybin therapy (PT) is emerging as an effective intervention for Major Depressive Disorder (MDD), offering comparable efficacy to conventional treatments like selective serotonin reuptake inhibitors (SSRIs). Music, an emotionally evocative stimulus, provides a valuable tool to explore changes in hedonic and predictive processing mechanisms via expectancy violations, or ‘surprises’. This study sought to compare behavioural and functional magnetic resonance imaging (fMRI) responses to musical surprises in MDD patients treated with either PT or the SSRI, escitalopram. In this secondary analysis of a trial, 41 MDD patients (with usable fMRI data) were randomly assigned to either PT (n = 22) or escitalopram (n = 19) treatment groups. Participants listened to music during fMRI and tracked their emotional experience, both before and after a 6-week intervention. Surprise-related valence and arousal indices were calculated. Musical surprises were entered as regressors for whole-brain and region of interest fMRI analyses. PT caused a greater decrease in anhedonia scores compared with escitalopram. While escitalopram led to reductions in surprise-related affective responses, PT showed no significant change. Escitalopram was associated with increased activation in memory and emotional processing areas during musical surprises (versus control events) when compared with PT. Following PT, there was greater activation in the ventromedial prefrontal cortex and sensory regions, and reduced activation in the angular gyrus. PT may allow for the subjective response to musical surprises to be maintained through a lasting reduction in the salience of prediction errors, or, alternatively, by increasing hedonic priors. Contrastingly, escitalopram may diminish hedonic priors, highlighting fundamental differences in treatment mechanisms.

The relationship between musical complexity and enjoyment is often characterized as an inverted U-shaped curve, with maximum hedonic value achieved at intermediate levels of musical complexity. However, the precise psychological processes underpinning this curve remain unclear. In this study, the previously proposed link between rhythmic entrainment and musical hedonia was revisited, to further characterize the processes involved in musical enjoyment related to predictability (inverse of complexity, inherent to entrainment). Building on extensive behavioral literature together with our imaging studies of the neural architecture of rhythmic entrainment and predictive processing, we hypothesized that social bonding and implicit learning may contribute to the relationship between musical complexity and pleasure. Fifty-one healthy participants completed questionnaires and tasks for the assessment of rhythmic entrainment (sensorimotor synchronization task), social bonding (empathy questionnaires), implicit learning (serial reaction time task), and musical pleasure (a, music reward questionnaire and b, pleasure ratings of musical excerpts at varying complexity levels, to asses musical pleasure related to prediction violation). The results showed that the association between rhythmic entrainment (independent variable) and musical pleasure (dependent variable) was significantly mediated by either affective empathy or implicit learning, depending on the musical pleasure metric employed (a or b, respectively). These findings are discussed in view of the active inference thesis and a model is proposed for the psychological forces possibly underlying the inverted U-shaped curve. Beyond supporting the role of music in fostering social bonding and implicit learning, these results speak to a broader adaptive function of music.

Fibromyalgia (FM), involving somatic, cognitive, and affective domains is often regarded as a hallmark central sensitization syndrome. Despite limited current therapeutic options, emerging understanding of its neural underpinnings offers the potential of applying novel neuromodulation strategies. Specifically, limbic dysregulation underlying abnormalities in pain modulation and somatic-affective processing, has been shown to play a key role in FM. Here, we assessed the long-term efficacy of targeted limbic self-neuromodulation for improving clinical disease burden in FM. Forty-seven patients with FM participated in a double-blind, randomized, dual-control study employing a novel specialized neurofeedback probe representing amygdala activity. Patients underwent 10 sessions of either genuine neurofeedback training (NFT = 21), or sham neurofeedback training (NFS = 13), or treatment as usual (TAU = 13). Disease severity and symptom burden were assessed using the Symptom Severity Score (SSS), along with other questionnaires administered before and after treatment. A clinical follow-up was performed 10–12 months post-intervention. NFT led to a significant immediate and long-term reduction in the SSS (F(2,40) = 7.32, p = 0.00, ηp2 = 0.27) and the Fibromyalgia Impact Questionnaire (FIQ) (F(2,40) = 9.85, p = 0.00, ηp2 = 0.33), alongside multidomain short- and long-term clinical benefits. NFS resulted in a long-term reduction in pain but did not affect other disease measures or overall disease burden. The TAU group showed no clinical improvements. Our findings support the intimate involvement of limbic brain areas in the pathophysiology of FM and suggest that targeted neuromodulation offers a novel, mechanism-based approach for managing multidomain symptoms in FM. This study was preregistered with the National Institutes of Health (NIH). Registration number: NCT02146495. Name of trial registry: Targeted Limbic Self-modulation as a Potential Treatment for Patients Suffering From Fibromyalgia https://clinicaltrials.gov/study/NCT02146495 .

Background: Post-traumatic stress disorder (PTSD) manifests through distinct symptom clusters that can respond differently to treatments. Neurofeedback guided by the Amygdala-derived-EEG-fMRI-Pattern (Amyg-EFP-NF) has been utilized to train PTSD patients to regulate amygdala-related activity and decrease symptoms. Methods: We conducted a combined analysis of 128 PTSD patients from three clinical trials of Amyg-EFP-NF to evaluate effects across symptom clusters (as assessed by CAPS-5 subscales) and on emotion regulation processing (evaluated by the ERQ). Results: Amyg-EFP-NF significantly reduced severity across all PTSD symptom clusters immediately post-treatment, with improvements maintained at three-month follow-up. The arousal and reactivity cluster showed continued significant improvement during follow-up. Combined effect sizes were large (η2p = 0.23-0.35) across all symptom clusters. Regression analysis revealed that emotion regulation processes significantly explained 17% of the variance in symptom improvement during the follow-up period. Conclusions: Reduction of PTSD symptoms following Amyg-EFP-NF occurs across all symptom clusters, with emotional regulation processes potentially serving as an underlying mechanism of action. These results support Amyg-EFP-NF as a comprehensive treatment approach for PTSD that continues to show benefits after treatment completion.

Background/Objectives: Up to 75% of patients with major depressive disorder (MDD) exhibit persistent anhedonia symptoms related to abnormalities in the positive valence system. Cumulative evidence points to brain dysfunction in the reward system (RS), including in the ventral striatum, in patients with MDD with anhedonia. This study aims to evaluate the safety and efficacy of a novel neurofeedback (NF) device (termed Prism) which incorporates the EEG–FRI-Pattern biomarker of the reward system (RS-EFP) for use in self-neuromodulation training (RS-EFP-NF) for alleviating depression in patients with MDD with anhedonia. Methods: A total of 49 adults (age range: M = 39.9 ± 11.03) with a DSM-5 diagnosis of MDD with anhedonia (per a SHAPS-C score ≥ 25) were screened for the administration of ten sessions of RS-EFP-NF twice a week on nonconsecutive days. Depression and anhedonia severity was assessed, respectively, by HDRS-17 and SHAPS-C at baseline, midway, and treatment end. Results: A total of 34 patients (77%) completed the protocol and were included in the analyses. No device-related adverse events were serious or required treatment. Depression symptoms were reduced at end of treatment as indicated by the HDRS-17, with a reduction of eight points on average (95% CI: −10.5 to −5.41, p < 0.0001), a clinical improvement rate of 78.47%, and a remission rate of 32.25%. Anhedonia, as indicated by the SHAPS-C score, was diminished, showing an average reduction of 6.3 points (95% CI: −8.51 to −4.14, p < 0.0001). Conclusions: Self-neuromodulation using RS-EFP-NF is a promising and safe treatment for MDD with anhedonia. The intervention demonstrates substantial clinical effects on both depression and anhedonia symptoms, with high patient acceptability and retention. Prism may address a critical mechanism-driven treatment gap for anhedonia that often persists despite conventional therapies. Larger controlled implementation, efficacy, and dosing studies are warranted.

Background: Dissociation, an altered state of consciousness in which individuals feel detached from their body, environment, and sense of self, is a common feature of posttraumatic stress disorder (PTSD). Despite its significance, the neurocognitive processes underlying dissociation remain poorly understood, potentially limiting diagnostic precision and treatment efficacy in PTSD. Methods: To address this gap, we applied network control theory to resting-state functional magnetic resonance imaging to examine neural dynamics during dissociative states in 2 contexts: healthy volunteers (n = 30) undergoing intravenous administration of ketamine, an anesthetic known to induce dissociative states, and patients with PTSD receiving an intervention aimed at alleviating dissociative symptoms (a secondary analysis of data from 78 patients who participated in previously conducted clinical trials). Results: Ketamine administration led to resting-state brain dynamics resembling those observed in patients with PTSD before treatment, characterized by an increased dominance of a default mode network (DMN) meta-state and a decreased dominance of a somatomotor network (SOM) meta-state. Posttreatment reduction in the dominance of the DMN meta-state correlated with a decrease in dissociative symptoms in patients with PTSD. Computational modeling analysis revealed that after treatment, patients with PTSD exhibited a more organized and less entropic brain state. However, contrary to our hypothesis, ketamine administration did not lead to significant changes in these entropy-related indices. Conclusions: Dissociative states, whether induced by pharmacological manipulation or clinical condition, are accompanied by increased dominance of the DMN meta-state and reduced dominance of the SOM meta-state.