Cognitive symptoms are common in functional neurological disorder (FND), yet evidence of impaired neurocognitive test performance is variable. We aimed to assess self-reported cognitive symptoms, neurocognitive test performance, and metacognitive confidence in patients with functional seizures (FS) and functional motor symptoms (FMS).

Participants with FS (n = 50) and FMS (n = 50) were compared to age- and gender-matched healthy controls (HC, n = 50), and clinical controls with depression and/or anxiety disorders (CC, n = 50). The Cambridge Neuropsychological Test Automated Battery was used to examine response speed, working memory, executive functions, and social–emotional processing, with subjective confidence rated for each test. Intellectual functioning, performance validity, and self-reported cognitive symptoms were also assessed.

The FND groups reported elevated cognitive symptoms compared to HC and CC (p-values<0.001). Impaired performance was demonstrated in both FND groups on tests of sustained attention (p-values = 0.03- < 0.001) and set-shifting (p-values = 0.01–0.001). Performance validity was comparable between groups (p = 0.64). The FND groups reported reduced post-diction confidence for sustained attention (p < 0.001). Executive performance deficits correlated with reduced test-specific confidence in FS/FMS (p-values = 0.02- < 0.001). In FMS, post-diction confidence for sustained attention performance correlated negatively with cognitive symptoms (p = 0.002). Cognitive symptoms were associated with psychological/physical symptom load, quality-of-life, and/or general functioning in FND and CC groups (p-values = 0.04- < 0.001).

Patients with FS and FMS displayed localized deficits on tests of executive functioning, with reduced domain-specific metacognitive confidence, alongside significant cognitive symptoms. These neurocognitive features were associated with poorer clinical status, warranting interventions targeting cognitive control and/or cognitive symptoms in everyday life.

Anhedonia is defined as a reduced interest in or inability to experience pleasure from reward-related activities. Recent studies have demonstrated deficient effort-based motivation in anhedonia, but the neural dynamics underlying the interface between effort and reward remain unclear.

To address this issue, we recruited an anhedonia (ANH) group (N = 40) and a control (CNT) group (N = 40) to complete two tasks: (1) an effort–reward task where participants earned varying rewards by exerting different levels of physical effort and (2) an effort-based decision-making task where they chose between a no-effort option for a smaller reward and a high-effort option for a larger reward. We recorded EEG during both tasks and analyzed the resulting neural responses.

As expected, the ANH group showed reduced reward responses in both self-reported ratings and event-related potential (ERP) data in response to cue stimuli (indexed by the cue-P3) and reward feedback (indexed by the reward positivity). Importantly, the ANH group exhibited inefficient integration between effort and reward, showing an absent effort-discounting effect on the feedback-P3 during reward evaluation and a lack of reward-related theta modulation during effort-based decision-making.

Our findings suggest a neurodynamic motivation model in anhedonia that informs precise interventions for relevant neuropsychiatric disorders.

Schizophrenia (SZ) is a debilitating psychiatric disorder where patients experience cognitive decline. Antipsychotic drugs alleviate positive symptoms but do not improve cognitive performance. We previously demonstrated that Toll-like receptors (TLRs), involved in cytokine production, can predict cognitive deficits in SZ patients. In this study, we aim to investigate the potential moderating effects of antipsychotic drugs on the associations between cytokines, TLRs, and cognition.

In total, 280 participants (201 controls and 79 cases of SZ) were recruited in Ireland. Venous blood from the participants was stimulated with TLR ligands. Levels of cytokines were measured from plasma and post-blood stimulation. The participants were administered a battery of cognitive tasks using the Cambridge Neuropsychological Test Automated Battery and Wechsler Adult Intelligence Scale-IIIR. Olanzapine equivalents were calculated using the defined daily dose method.

The results indicate that antipsychotic drug dose does not predict TLR activity or cognition, indicating that antipsychotic drug dose does not have a direct effect on cognition or TLR activity. However, the relationship between TLR4 activity and visual learning and memory is moderated by the antipsychotic drug dose (B = −0.065; p < 0.001), where increasing doses have a decreasing impact on their relationship.

Our data indicate that the dose of antipsychotic drugs alone cannot predict changes in cognitive performance and TLR4-activity. It also suggests that antipsychotic drug doses significantly affect TLR activity and its relationship with cognition. These effects are more pronounced on some domains than others. These findings open up new avenues for understanding the complex interplay between antipsychotic drugs, TLRs, and cognitive deficits in SZ.

Adolescent mental health has worsened, and prevention efforts have become increasingly important. The purpose of this study was to examine longitudinal symptom trajectories of depression and anxiety throughout adolescence, in a contemporary sample. The stress–diathesis model was used to inform potential vulnerability factors and stressors associated with these trajectories.

Symptoms of depression and generalized anxiety were assessed in a school-based population sample of N = 6102 adolescents (aged 13–14 at baseline). Growth mixture models across four time points were used to model longitudinal trajectories of symptoms. Multinomial regression was used to examine factors associated with each trajectory class.

Of the full sample, 49.5% were female, 45.9% were male, and 4.6% were gender diverse. Four discrete classes for both depression and anxiety trajectories were identified, which comprised consistently low symptoms (‘low’; 72.5% depression; 66.9% anxiety), consistently high symptoms (‘high’; 11.5% depression; 18.4% anxiety), elevated symptoms that reduced over time (‘decreasing’; 8.3% depression; 6.9% anxiety), and low-moderate symptoms that increased over time (‘increasing’; 7.7% depression; 7.8% anxiety). Factors associated with poorer trajectories were being female or gender diverse, lower socioeconomic status, higher levels of neuroticism and lower levels of conscientiousness, greater adverse childhood experiences, higher levels of peer problems, bullying victimization, and negative family interactions.

A range of background vulnerabilities and specific stressors were associated with poorer depression and anxiety trajectories over a 3-year period. Prevention approaches may require policy and practice changes that promote more supportive family, school, and societal environments from childhood to adolescence.

Oxytocin (OT) exerts widely modulatory effects on socio-emotional functions in humans, which can be achieved via enhancing the salience of social cues by interacting with the dopaminergic attention system. However, there is a lack of direct evidence for OT modulating attentional processing, with its underlying neural mechanisms remaining to be elucidated.

In a double-blind, placebo-controlled, between-subject design, 60 healthy male participants were recruited. We combined pharmaco-electroencephalography with two modified tasks (a cue-target visual search [CTVS] task and a face distractor interference [FDI] task) to investigate whether intranasal OT can modulate attentional processing of social cues in top-down versus bottom-up task sets.

In the CTVS task, OT accelerated participants’ response time to target faces, which was paralleled by a larger N170 and stronger theta power, suggesting that OT promoted early top-down attentional processing of social cues. In the FDI task, OT inhibited the distractive effect of task-irrelevant emotional faces in the first half of the task via facilitating top-down attentional control to targets as reflected by enhanced attentional selection (increased N2pc) and more efficient attentional processing (decreased P300). However, in the second half, OT switched from facilitating top-down attentional control to potentiating bottom-up attentional capture by emotional face distractors, as evidenced by OT reducing response accuracy but having no effects on the N2pc and P300.

Our findings not only provide evidence for the role of OT in modulating attentional processing of social cues but also lend support to its therapeutic potential in normalizing such attentional deficits.

DNA methylation influences gene–environment interactions and brain development in bipolar disorder (BD). We aimed to identify BD-associated epigenetic loci and examine their associations with brain structural variation.

We conducted an epigenome-wide association study (BD group, n = 90; healthy controls group, n = 161) to identify BD-associated DNA methylation loci, and we additionally performed copy number alteration and functional enrichment analyses. The correlations between epigenetic loci and cortical thickness (CT) were assessed using Pearson’s partial correlation analysis, and the co-methylation effect of the epigenetic loci identified in the neuroimaging–epigenetic analysis was investigated.

A total of 156 differentially methylated positions (DMPs) and 7 differentially methylated regions were identified, and the genes associated with them were observed to be enriched in biological processes related to muscle hypertrophy and neuronal activity. Significant correlations between the methylation levels of 13 DMPs associated with three genes (miR886, PLEC1, and ICAM5) and the CT of the right postcentral gyrus and inferior frontal gyrus were identified. Specifically, 10 DMPs associated with the CpG island in the upstream region of the miR886 gene showed negative correlations with the right postcentral gyrus CT, implicating miR886-associated CpG-island methylation in regional cortical thinning.

Epigenetic changes might play an important role in brain structural changes in BD. These multimodal findings nominate miR886-related methylation as a candidate molecular correlate of cortical thinning and warrant replication and mechanistic follow-up in larger, state-diverse cohorts.

Repetitive negative thinking (RNT) and neuroticism are risk factors for internalizing psychopathology. However, their interaction has only been investigated at the self-report level, and studies elucidating their interrelationship at the neural level are lacking. We therefore investigated the interaction of trait RNT and neuroticism with respect to the dynamics of neural networks during negative self-referential processing.

A sample of 110 healthy subjects reported trait RNT and neuroticism, followed by an RNT induction paradigm during fMRI. Dynamic coactivation pattern (CAP) analysis was used to identify a set of recurring coactivation patterns and to quantify their persistence and count rates. Next, the effects of trait RNT, neuroticism, and their interaction on brain dynamics were tested using regression models.

Negative interactions between RNT and neuroticism were found for persistence and counts of the canonical default mode network (DMN) as well as salience network (SAL) CAP. Simple slope analysis revealed that subjects scoring high on neuroticism exhibited a negative association between trait RNT and DMN as well as canonical SAL dynamics. Furthermore, trait RNT was positively associated with persistence and count rates of a hybrid FPN+DMN coactivation state.

Our results suggest that individuals with high neuroticism who spend more time in SAL and DMN CAPs may be less vulnerable to RNT, potentially reflecting more adaptive network configurations. Furthermore, less segregated CAPs, evident by the concurrent activation of functionally antagonistic networks (FPN+DMN), emerge more often in individuals prone to RNT, likely reflecting disrupted network interactions.

Unpredictability in the child’s environment has recently emerged as a significant and unique form of early life adversity (ELA). Cross-sectional studies have linked childhood unpredictability with increased post-traumatic stress disorder (PTSD) symptoms in adults; however, no prospective studies have tested the link between childhood unpredictability and PTSD risk in later life, nor what processes, such as increased anhedonia symptoms, might mediate such risk. Here, we leveraged three distinct prospective, longitudinal cohorts to test the hypothesis that unpredictability during childhood contributes to adult PTSD via worsening anhedonia symptoms.

Participants were male service members (n=314), adult females (n=170), and adolescents (n=137) recruited for separate longitudinal investigations. All completed dimensional assessments of anhedonia symptoms and PTSD; childhood trauma and childhood unpredictability were measured by the Questionnaire for Unpredictability in Childhood (QUIC). Pearson correlations tested relations between QUIC, anhedonia symptoms, and PTSD symptoms. Mediational models tested whether the link between childhood unpredictability and PTSD is mediated by increased anhedonia symptoms by estimating indirect effects via bootstrapped path analysis.

Childhood unpredictability was associated with increased adult PTSD symptoms in all three cohorts (rs>.19, ps<.016). Further, in all three cohorts, the relationship was partially mediated by higher anhedonia symptoms (bs>0.046, 95% confidence intervals = 0.01–0.12). All effects remained significant when controlling for levels of childhood trauma and removing anhedonia-related PTSD items.

Unpredictability during childhood may confer risk for adult PTSD, and this increased risk may occur via alterations in anhedonia symptoms. Efforts to increase predictability during childhood could enhance resilience to later traumatic events.

Subthreshold depression (StD) is considered a prodromal stage of major depressive disorder (MDD). This study aims to investigate the neurobiological mechanisms of StD by analyzing functional connectivity (FC) and cognitive function in comparison to MDD.

A total of 153 StD individuals, 188 MDD patients, and 110 healthy controls (HCs) were studied using resting-state functional magnetic resonance imaging (fMRI). Whole-brain FC was calculated using seeds from the default mode network (DMN), salience network (SN), executive control network, and affective network (AN). Cognitive function was assessed across seven domains.

StD showed only a deficit in social cognition, while MDD exhibited multidomain cognitive impairments compared to HCs. Both MDD and StD exhibited reduced FC between the right anterior insula (AI) and the left inferior frontal gyrus (IFG), and increased FC between the right subcallosal cingulate cortex and the left posterior cingulate cortex (PCC), key areas of the SN and AN, compared to HCs. MDD particularly showed decreased connectivity between the left PCC and the left middle temporal gyrus, and within the left PCC, while no abnormal FC of the DMN was found in StD. Altered AI-IFG FC was positively correlated with social cognition in StD.

Abnormal connectivity patterns of the SN and AN may contribute to the development of depressive symptoms in StD and MDD, while altered FC of the DMN may be involved in the onset of the disease. A social cognition deficit appeared first in StD, relating to the abnormal connectivity of the SN.

Individuals with severe mental illnesses (SMIs) experience anxiety that impairs functioning and quality of life. This cluster randomized trial evaluated exposure-based cognitive behavioral therapy (ebCBT) integrated into assertive community treatment (ACT) teams to reduce anxiety.

Fifteen ACT teams were allocated to ebCBT + ACT (k = 8, n = 50) or ACT-only (k = 7, n = 43). The intervention followed four steps: situation identification, four-component analysis (behavior, cognition, emotion, physical symptoms), psychoeducation, and graded exposure. Staff received 50 h training and bimonthly supervision over 12 months. Co-primary outcomes were trait and social anxiety; secondary outcomes were psychiatric symptoms, functioning, quality of life, and recovery.

The ebCBT + ACT group showed significant improvements in State–Trait Anxiety Inventory–Trait scores at 12 months (AMD = −5.30, 95% CI = −8.71 to −1.90, p = 0.002, d = −0.64) and 18 months (AMD = −7.22, 95% CI = −12.1 to −2.34, p = 0.004, d = −0.60). Brief Fear of Negative Evaluation scores showed near-significant improvement at 18 months (AMD = −3.70, 95% CI = −7.44 to 0.04, p = 0.052, d = −0.40). Secondary outcomes, including global functioning, recovery, and quality of life, also improved. Cost-effectiveness analyses indicated favorable cost-effectiveness for anxiety outcomes.

Embedding ebCBT within ACT services may reduce anxiety-related fear and avoidance and enhance recovery-related outcomes in individuals with SMI. These findings support the feasibility and clinical value of integrating structured psychological interventions into intensive community-based outreach services.

Romantic relationships are important contexts for substance use and emotional well-being. We tested the hypotheses that (i) genetic predispositions for alcohol consumption would be positively associated with partner substance use, (ii) partner substance use would moderate genetic influences on one’s own alcohol outcomes, and (iii) partner discordance in substance use would be associated with lower emotional well-being and relationship quality.

Analyses included 2,357 participants (Mage = 51.4, 58.2% female) from the Collaborative Studies on the Genetics of Alcoholism. Focal measures included participants’ reports of their own and their current partner’s past-year substance use (frequencies of alcohol use, heavy drinking, drunkenness, cannabis use, and nicotine use), emotional well-being, and relationship quality. Participants’ genetic predispositions were indexed with genome-wide polygenic scores for alcohol consumption (PGSAlc). Participant–partner substance use discordance was calculated as the difference between the participant’s and their partner’s use for each substance use measure, separately.

Participant PGSAlc was not significantly associated with partners’ perceived substance use. Frequent perceived partner alcohol use and heavy drinking significantly amplified the association between PGSAlc and alcohol use or drunkenness. Frequent perceived partner drunkenness and cannabis use significantly attenuated the association between PGSAlc and heavy drinking or frequency of alcohol use. Participant–partner discordance for several substance use measures was significantly associated with lower emotional well-being and relationship quality, controlling for participant and partner substance use main effects.

The results highlight the importance of partner substance use in etiological models of alcohol use, emotional health outcomes, and relationship quality.

Empathy involves communicating and understanding others’ emotion in multisensory contexts, including visual and auditory modalities. Schizophrenia (SCZ) patients have impaired empathy, but whether the impact of visual/auditory context would be altered in SCZ patients and people with high social anhedonia (HSoA) remained unclear.

We administered the modified Chinese version of the Empathic Accuracy Task (EAT) to clinical (50 SCZ patients and 50 healthy controls) and subclinical samples (59 HSoA and 60 low social anhedonia [LSoA] participants). The EAT employed audio-only, audiovisual, and audioavatar visual conditions to assess the impact of multimodal information on empathy during positive and negative emotional events.

In positive-valenced context, SCZ patients performed worse than controls in cognitive and affective empathy. The Modality-by-Group interaction on empathic accuracy was significant, that is, SCZ patients performed worse than controls in both audiovisual and audioavatar visual conditions, but comparable to controls in audio-only condition. In negative-valenced context, SCZ patients performed worse than controls in cognitive empathy. The Modality-by-Group interaction on empathic accuracy was significant, that is, SCZ patients performed worse than controls in audio-only and audiovisual conditions. Moreover, HSoA participants exhibited lower cognitive empathy than controls in positive-valenced context; and lower cognitive empathy and empathic motivation in negative-valenced context. No significant Modality-by-Group interaction was found in the HSoA–LSoA sample.

SCZ patients have generalized impairments of cognitive and affective empathy across positive and negative contexts, particularly in multimodal conditions. HSoA individuals are primarily impaired in cognitive empathy and empathic motivation.

Depression as a mental illness is commonly observed to co-occur with various somatic diseases, such as gastrointestinal diseases. However, previous studies have primarily focused on the risk of mental disorders following physical illnesses. Our study took depression as a risk factor, attempting to explore its relationship with gastrointestinal diseases.

A total of 457,940 participants (aged 37–73 years) in the UK Biobank were included. The Cox proportional hazards model was used to assess the relationship between depression and gastrointestinal diseases. Mendelian randomization assessed the causal link between depression and gastrointestinal disorders, and seven machine learning algorithms (including LightGBM, XGBoost, and Random Forest) were trained in the total population to develop predictive models for incident gastrointestinal diseases, with model performance evaluated using the area under the receiver operating characteristic curve (AUC).

During a median follow-up period of 13.7 years, 9563 esophagitis events, 36,420 gastroesophageal reflux disease events, 5469 gastric ulcer events, 3096 duodenal ulcer events, 37,225 gastritis and duodenitis events, and 9153 dyspepsia events were recorded. After adjusting for covariates, depression was associated with increased risk of all six diseases. Two-sample MR analysis supported a causal association. Machine learning models demonstrated good discrimination, with the highest predictive accuracy observed for duodenal ulcer (AUC = 0.76) and gastric ulcer (AUC = 0.75).

Addressing depression as a modifiable risk factor may reduce gastrointestinal disease risk, especially in disadvantaged populations, by integrating mental health care into primary care and using predictive models for early intervention.

Drug use disorder (DUD) clusters in families due partly to shared environment, including sibling influences. Low academic achievement (AA) in adolescence increases DUD risk. This study examined whether low AA in an older sibling causally increases DUD risk in younger siblings.

We studied all Swedish full sibling pairs (n = 309,666) born 1972–1985 and ≤ 5 years apart. Older sibling AA was assessed at age 16. Using Month-of-Birth (MoB) as an instrument, we conducted instrumental variable (IV) analyses and propensity score (PS) models to evaluate the causal impact of older sibling AA on younger sibling DUD risk, assessed by DUD registration in national medical, criminal, or pharmacy registries.

Older sibling AA significantly predicted younger sibling DUD risk across models. Beta coefficients (±95% CI) were 2.04 (1.97–2.12) in raw analysis, 1.88 (0.74–3.02) in IV, and 1.26 (1.17–1.34) in PS models. Together with the strong first-stage association, the IV estimates remain positive under small departures from the ideal identifying assumptions. Effect sizes declined with increasing sibling age differences (p = 0.036 for IV; p < 0.0001 for PS) and were strongest in male–male pairs (IV: 4.01 [1.42–6.61]; PS: 1.74 [1.55–1.93]). Mediation by older sibling DUD was modest.

Findings from two causal inference approaches support a largely causal link between low AA in an older sibling and increased DUD risk in younger siblings. Stronger effects in close-aged and male–male pairs further support this conclusion. Interventions to improve AA in older siblings may yield indirect preventive benefits for younger siblings.

The impact of combat injury on the development of chronic pain and mental health concerns in combat-exposed populations is unknown. This study examined associations of combat injury and injury–related pain with pain-related factors and mental health outcomes, and potential mediation of the relation between combat injury and mental health outcomes by pain-related factors.

Pain interference, pain catastrophizing, pain intensity, post-traumatic stress disorder (PTSD), and major depressive episode (MDE) were assessed in (1) a probability sample of US Army soldiers and veterans cross-sectionally and (2) US Army soldiers before and 1, 3, and 9 months after deployment to Afghanistan. Associations among these variables were modeled using logistic regression and multiple mediation analyses.

Among 5003 service members with cross-sectional data, combat injury–related pain was associated with increased odds of clinically significant pain intensity (OR=2.69), pain interference (OR=3.69), MDE (OR=2.17), and PTSD (OR=3.96) relative to pain from other injuries and conditions. Among 4645 service members assessed pre- and post-deployment, combat injury was associated with increased odds of new-onset pain interference (OR=2.78), pain catastrophizing (OR=2.75), PTSD (OR=4.06), and MDE (OR=2.56) 3 months post-deployment, and PTSD (OR=2.86) and MDE (OR=1.74) 9 months post-deployment. Pain-related factors mediated the relations of combat injury with post-deployment PTSD and MDE.

Combat injury is associated with greater odds of pain interference, pain catastrophizing, PTSD, and MDE compared to other sources of pain in a cohort of US service members. Efforts to address pain-related factors following combat injury may mitigate the risk of subsequent chronic pain and mental health disorders.