Background: Apathy is present in about 50% of patients suffering from schizophrenia (SZ) and mood disorders (MD). Even though these two disorders are different, in psychiatry, apathy refers typically to the same unidimensional clinical entity, sharing the same pathophysiological processes and symptoms regardless of the underlying diagnosis. Neurology proposes another perspective: three forms of apathy —emotional, executive, and initiative— are related to a disturbance in motivation, cognitive control, and effort-based decision-making, respectively. We explored whether this latter model can be applied in psychiatry by identifying differences between SZ and MD through a PRISMA meta-analysis of imaging studies on reward processing, cognitive control, and effort-based decision-making networks. Methods: We searched the Sleuth BrainMap and PubMed databases for studies on SZ, MD, and/or healthy controls using tasks probing reward processing, cognitive control, and effort-based decision-making. Twenty-three functional MRI studies were identified and included for a coordinate-based activation likelihood estimation analysis. Results: In SZ, hypoactivity in reward-processing structures, a specific hyperactivity in the right cerebellar vermis that has previously been linked to emotional blunting and apathy, and a lack of activation during effort-based decision-making that could imply an impaired reward processing, suggest a dominant form of emotional apathy. In MD, hypoactivity in both cognitive control and reward-processing structures, which has previously been linked to the co-occurrence of executive difficulty and amotivation, suggests a mixed emotional/executive apathy profile. Limitations: The main limitations include the use of two databases, a small number of existing studies, a lack of control over treatment, age, and disorder severity, as well as the inherent heterogeneity of each diagnosis. Conclusion: By highlighting different dominant forms of apathy in SZ and MD, these results could help target new individualized treatment strategies in precision psychiatry based on a multidimensional conceptualization of apathy. Registration: This review was not prospectively registered.
Bio-psycho-social models of psychopathology have been long proposed. Despite this, few details have been identified in part due to the poor match between clinical phenomenology and diagnostic categories (e.g., overlapping symptoms and comorbidity). In the present paper, the author reviews the evidence for three factors thought to affect vulnerability across diagnoses: mesocorticolimbic function, early life adversity, and early propensities to high emotional and behavioral reactivity. All three factors now have compelling support but their effects on clinical outcomes are small to moderate in isolation. In comparison, our preliminary studies suggest that combining these factors yields a powerful model that predicts liability to all common psychiatric disorders. Narrower mental health problems are identified when the model incorporates high brain reactivity to disorder-specific stimuli. Since the combination of these factors accounts for more variance than the sum of their parts, this novel, hierarchical model might explain how the structure of psychopathology arises.
BACKGROUND:Cognitive impairment is a frequent feature of bipolar disorder (BD), often persisting during euthymic phases and affecting multiple cognitive domains. These deficits impair functional recovery and quality of life. Pharmacological treatments have shown limited efficacy in ameliorating cognitive dysfunction in BD. Cognitive remediation (CR) has emerged as a promising nonpharmacological alternative. However, reviews of its efficacy in BD have reported inconsistent findings. One major limitation highlighted in past reviews is the heterogeneity of study samples, due to the inclusion of participants without cognitive impairment, potentially introducing a ceiling effect that may obscure treatment benefits. This review addresses this gap by examining only studies that selected participants through objective or structured subjective cognitive screening. METHODS:A systematic search of PubMed and Web of Science (finalized 27 January 2026) identified interventional studies of CR in adults with BD requiring objective or subjective cognitive impairment for inclusion. Of 2662 records retrieved, 128 full texts were reviewed, and 6 studies met eligibility criteria; 2 secondary analyses derived from 2 of these studies were also retained for synthesis. Four studies were randomized controlled trials, one was non-randomized with a control group, and one was uncontrolled. Two reviewers independently screened studies, extracted data, and assessed risk of bias. Given methodological variability, results were synthesized narratively. RESULTS:Six studies met inclusion criteria. Findings were inconsistent: three reported significant cognitive improvements following CR or related interventions, whereas three randomized trials found no significant cognitive effects. Variability in screening methods, intervention formats, and outcome selection precluded meta-analysis. LIMITATIONS:Evidence is constrained by the small number of eligible studies, methodological heterogeneity, and variable risk of bias. CONCLUSIONS:Current evidence from enriched samples suggests that CR may improve specific cognitive domains in BD, but overall results remain inconclusive. Future trials should employ rigorous cognitive screening, harmonized outcome measures, and more individualized interventions to clarify efficacy. PROSPERO registration ID: CRD42025642423.
BACKGROUND:While analyzing distance-dependent functional connectivity strength (FCS) yields valuable information about brain activity, whether the FCS alterations found in obsessive-compulsive disorder (OCD) are linked to inter-regional anatomical distance is still unknown. This study investigated distance-associated functional reorganization in OCD and its associations with clinical assessment data and neurotransmitter receptor/transporter densities. METHODS:To quantify FCS across global, long-range, and short-range scales, we analyzed resting-state functional MRI data from 99 OCD patients and 104 matched healthy controls (HCs), followed by a post hoc exploratory seed-based functional connectivity (FC) analysis to further characterize the key brain regions that may contribute to the observed FCS abnormalities. Group differences and correlations with clinical measures (symptom severity, illness duration, and age of onset) and positron emission tomography-derived neurotransmitter receptor/transporter densities were examined. RESULTS:Compared to HCs, OCD patients exhibited reduced long-range FCS in the bilateral fusiform and parahippocampal gyri, primarily driven by weakened connections with frontal, superior/middle temporal, precuneus, and cingulate regions. Short-range FCS was increased in the right dorsolateral prefrontal cortex but decreased in the precentral gyrus and middle cingulate cortex, mainly due to altered local connections involving the middle frontal gyrus, precentral gyrus, precuneus, and cerebellum. These alterations were robust in cross-validation. No significant correlations were found with clinical measures. However, both long- and short-range FCS changes correlated significantly with neurotransmitter receptors/transporter densities, particularly the excitatory-inhibitory ratio profile. LIMITATIONS:Neurotransmitter receptor/transporter maps were derived from publicly available datasets, which may not capture individual variation in receptor density. CONCLUSION:This study highlights distance-dependent functional connectivity reorganization in OCD and its neurochemical underpinnings, providing new insights into the disorder's pathophysiology.
Background: Depression is a common psychological and behavioural symptom experienced by people with migraines. However, the underlying neural mechanisms of depressive symptoms in this population are unclear. Methods: In this study, we investigated the neural mechanisms underlying excitation-inhibition imbalance in patients with migraine accompanied by depressive symptoms (MD) using the Hurst exponent. We used Analysis of covariance to compare differences in the Hurst exponent between patients with MD, patients with migraine accompanied by non-depressive symptoms (MnD), and healthy controls (HC). Spearman's correlation analysis was used to calculate the correlation between the Hurst exponent of different brain regions and clinical variables. Results: Compared with patients with migraine accompanied by MnD, patients with MD showed an increased Hurst exponent in the left lingual gyrus and medial superior frontal cortex. Compared with HC, MD showed an increased Hurst exponent in the right cerebellum crus 1 and right lingual gyrus. Compared with HC, MnD showed an increased Hurst exponent in the left cerebellum crus 2 and medial superior frontal cortex. The Hurst exponent of the medial superior frontal cortex in patients with migraine was significantly positively correlated with depression scores (r = 0.3501, p = 0.0001). Conclusions: Our study has identified imaging features of excitatory-inhibitory imbalance in MD. Imbalances in excitation and inhibition in the medial superior frontal cortex may serve as a promising candidate imaging marker for diagnosing and intervening in depressive symptoms in migraine.
Thoughts are traditionally classified by their cognitive contents, such as task-related versus task-unrelated or internally versus externally oriented. However, content-based distinctions often lack diagnostic specificity in psychiatric disorders, where similar thought contents may manifest across conditions such as schizophrenia and major depressive disorder. Here, we propose a complementary framework that characterizes thoughts by their dynamics, the pattern of changes in the thought contents over time--that is, their duration, speed, and temporal precision. Converging evidence in healthy individuals shows that distinct thought dimensions map onto specific neural timescales, ranging from fine-grained oscillatory phase dynamics to coarse-grained temporal windows. Extending this framework to psychopathology, schizophrenia is characterized by temporal imprecision of thought contents across shorter and longer timescales, yielding fragmented and poorly differentiated thoughts. In contrast, major depressive disorder is marked by abnormally prolonged timescales with abnormal slowness leading to rarely changing thought contents, e.g., ruminations. We propose that the timescales of thought contents and, more generally, thought dynamics may serve as a promising marker for the differential diagnosis of thought disturbances in mental disorders.
Background: Obsessive-compulsive disorder (OCD) is heterogeneous, and differences in age at onset may be associated with important feature of distinct subtype. However, no studies have investigated the differences between early-and late-onset OCD using structural and functional multimodal neuroimaging methods that reflect different neurobiological backgrounds. Methods: Structural and resting-state functional magnetic resonance imaging data were obtained from 130 participants (76 medication-free patients with OCD and 54 healthy controls (HCs)). We investigated group differences among early-and late-onset OCD and HCs in the fractional amplitude of low-frequency fluctuation (fALFF) and local gyrification index (LGI). Results: In the fALFF analysis, group differences were detected in the left lateral occipital cortex and bilateral thalamus (a voxel-height threshold of p < 0.001 and a cluster-level threshold of p < 0.05, with a false discovery rate correction). Both patients with early-and late-onset OCD had significantly lower fALFF in the thalamus compared to HCs (Bonferroni corrected p < 0.01). Patients with early-onset OCD exhibited significantly lower fALFF in the lateral occipital cortex than those with late-onset OCD and HCs (Bonferroni corrected p < 0.01). No significant differences were observed in the LGI analysis (a nonparametric permutation approach (10 000 iterations)), a cluster-wise threshold of p < 0.05, and a cluster-defining threshold of p < 0.001). Limitations: Our cross-sectional data could limit the interpretation of our results. Conclusions: Our results emphasize the importance of the thalamus in the pathophysiology regardless of the age-of-onset subtype of OCD. In addition, altered fALFF in the lateral occipital cortex, not accompanied by deficits of LGI, could represent a disruption of normal functional developmental processes resulting from the OCD onset at a young age. Future study should examine the relationship between the alteration of fALFF in lateral occipital cortex and clinical and treatment-refractory features of early-onset OCD, potentially improving therapeutic strategies.
Background: The bed nucleus of the stria terminalis (BNST) plays a critical role in the neural processing of negative emotions. To date, no studies have investigated whether intrinsic connectivity of the BNST is associated with major depressive disorder (MDD) or with the severity of clinical symptoms in individuals with depression. Methods: Resting-state functional magnetic resonance imaging (7 Tesla (7T)) with seed-to-voxel-analysis was used to compare the intrinsic connectivity of the BNST between individuals with MDD (N = 17) and healthy volunteers (N = 29). Exploratory analyses were also conducted to determine whether intrinsic connectivity of the BNST was associated with the severity of clinical mood or anxiety symptoms in individuals with MDD, as assessed via scores on the clinician-administered Hamilton Anxiety Rating Scale and the Montgomery-Asberg Depression Rating Scale. Results: Compared to healthy volunteers, individuals with MDD exhibited reduced intrinsic connectivity between the BNST and regions of the right ventral striatum. No significant associations were noted between intrinsic connectivity and the severity of anxious or depressive symptoms in MDD participants. Limitations: The small sample size makes it difficult to assess whether clinical heterogeneity impacted these findings. Future studies that combine experimental paradigms with neuroimaging are needed to shed light on the functional implications of these results. Conclusions: Reduced intrinsic connectivity between the BNST and striatum may reflect altered activity in the neural circuits responsible for stress and reward processing. These findings can be used to guide future work investigating risk factors for MDD and provide potential targets for clinical intervention. Clinicaltrials.gov Identifier: NCT02543983, NCT02484456, NCT02122562
BACKGROUND:Inhibitory control deficits are a core feature of schizophrenia, yet their spectral and temporal characteristics remain poorly defined. This study investigates fast-response inhibition in first-episode schizophrenia (FES) by focusing on low gamma-band (30-50 Hz) oscillations within the right inferior frontal gyrus (rIFG)-pre-supplementary motor area (preSMA) circuit. METHODS:We conducted a magnetoencephalography (MEG) study involving FES, their first-degree relatives (FDR), and healthy controls (HCs), examining post-stimulus low gamma (30-50 Hz) and beta-band activity across rIFG-preSMA and preSMA-lM1 circuits. Power spectral density (PSD) and functional connectivity (FC) were segmented into middle (150-250 ms) and later (250-400 ms) stages. Behavioral data (BIS-11, DSST) were integrated with MEG features in two canonical discriminant models (Model 1: multimodal; Model 2: behavior-only), with independent temporal validation. RESULTS:FES patients showed early low gamma power reductions in rIFG and preSMA, followed by increased rIFG-preSMA connectivity during later stages-suggesting phase-specific disruption and compensatory adaptation. Model 1 achieved 95.2% classification accuracy (80.6% cross-validated), identifying rIFG-preSMA low gamma connectivity as the strongest neural discriminator. Model 2 retained 88.5% accuracy on temporally independent samples using only BIS and DSST measures. FDR occupied an intermediate position in both models, supporting a dimensional liability continuum. LIMITATIONS:The modest sample size, especially for the MEG recordings, may limit generalizability. Medication effects in the FES group and the cross-sectional design may also confound causal interpretation. CONCLUSION:This study delineates a frequency- and phase-specific disruption in fast-response inhibition in schizophrenia, centered on rIFG-preSMA low gamma desynchronization. The identified neural and behavioral signatures support a dimensional risk framework and may inform early detection strategies in clinical and familial populations.
Erythropoietin-producing hepatocellular (Eph) receptors are tyrosine kinase receptors that are canonically activated by their membrane tethered ligands, the ephrins. The Eph-ephrin system is critical in neurodevelopment, involved in processes such as neuronal growth and proliferation, axonal growth cone guidance, and cell survival. However, there is a significant knowledge gap in our understanding of the functional role of the Eph-ephrin system in later development, in both the adolescent and the adult brain. As various Eph receptor subtypes, and their associated ephrin ligands, are involved in the regulation of processes implicated in brain disorder pathogenesis, the Eph-ephrin system may represent an unexplored avenue for therapeutic target identification. Here, we will consolidate what is known about the Eph-ephrin system in synaptic plasticity, inflammation, and vascular permeability, linking the effects of specific ephrins and Eph receptors to depression and anxiety, autism, and schizophrenia. Novel insights into those Eph receptors with the most therapeutic promise will be provided and potential challenges of targeting these widely expressed receptor kinases discussed.
Background: Addiction is a multifaceted disorder driven by complex neurobiological and psychological mechanisms. The Addictions Neuroclinical Assessment (ANA) framework offers a dimensional mechanistic approach, focusing on three core domains: incentive salience, negative emotionality, and executive function. This study aimed to validate the ANA framework in relation to hazardous drinking using a machine learning approach, with the hypothesis that incentive salience and negative emotionality would be most strongly associated with drinking severity. Methods: We analysed two independent datasets: a cohort of 1260 nonclinical community-based adults ascertained in 2016-2018 and a cohort of 655 young adults reporting regular binge drinking ascertained in 2017-2018. The three ANA domains were operationalized using behavioural and self-report measures. Four machine learning models (elastic net, support vector machines, random forest, and gradient boosting machines) with nested five-fold cross-validation were used to assess relations between ANA domains and hazardous drinking as measured via the Alcohol Use Disorder Identification Test (AUDIT), a validated screening instrument. Results: Across both datasets, elastic net consistently outperformed other models. Incentive salience, largely reflecting alcohol's reinforcing value, was most robustly related to AUDIT score (R2 = 0.389-0.419), followed by negative emotionality (R2 = 0.293-0.317), largely reflecting drinking to cope. Executive function, reflecting impulsivity and inhibitory control, accounted for less variance (R2 = 0.098-0.109). Optimizing elastic net models via meta-learner further improved performance, explaining more than half of the variance (R2 = 0.539-0.549). Limitations: These findings may not generalize to individuals who are older or have severe AUD. Cross-sectional data limits longitudinal causal inferences. Conclusion: These results provide robust computational validation for the ANA framework, emphasizing incentive salience and negative emotionality as key domains linked to AUDIT score. Future research should explore diagnostic and longitudinal applications.
Background: Obsessive-compulsive disorder (OCD) remains refractory to conventional pharmacological and psychotherapeutic treatments in a substantial proportion of patients. Neuromodulation has emerged as a promising intervention, but optimal neural circuit targets remain unclear. This systematic review and meta-analysis aimed to evaluate the efficacy of invasive and non-invasive neuromodulation for OCD using a circuit-based framework and to translate these findings into clinical practice. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials investigating neuromodulation for OCD. PubMed/MEDLINE, Web of Science, and the Cochrane Library were searched from database inception to December 2023. Eligible studies included adult patients with a primary diagnosis of OCD receiving invasive or non-invasive neuromodulation, with symptom outcomes assessed using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool. Random-or fixed-effects meta-analyses were performed using mean differences or standardized mean differences, depending on heterogeneity. The review was registered in PROSPERO (CRD42024518326). Results: Twenty-seven randomized controlled trials involving 868 patients met inclusion criteria. Overall, neuromodulation significantly reduced OCD symptoms compared with control conditions. Circuit-based subgroup analyses indicated that modulation of the fronto-limbic circuit--primarily via invasive deep brain stimulation--was associated with the largest and most consistent Y-BOCS improvements, while sensorimotor, dorsal cognitive, and ventral affective circuits also demonstrated significant but more heterogeneous effects. Invasive neuromodulation showed greater efficacy than non-invasive approaches. These findings informed a translational multi-target deep brain stimulation case, demonstrating clinically meaningful symptom improvement (Y-BOCS decreased from 25 to 16 after 6 months). Limitations: Heterogeneity across non-invasive studies, short follow-up durations, and limited circuit-specific data constrain interpretation of long-term and symptom-domain-specific effects. Conclusions: This systematic review, meta-analysis, and case study suggest that circuit-based neuromodulation--particularly targeting the fronto-limbic circuit--may offer the most consistent benefit for treatment-refractory OCD. Larger, longer-term, and circuit-informed trials are needed to optimize individualized neuromodulation strategies.
BACKGROUND:Late-life depression (LLD) is the major risk factor for elderly suicide, and suicidal ideation (SI) is a crucial stage for prevention. However, LLD are less likely openly express SI. Gamma oscillations, closely linked to cognition and mental processes, may contribute to the pathophysiology of LLD and suicidal behavior through their dysregulation within large-scale brain networks. The aim of our research was to investigate the cortical functional networks in the gamma band to better understand the neurobiological mechanisms underlying SI in LLD. METHODS:Electroencephalography (EEG) was recorded from 30 LLD with SI (LLD-SI), 32 LLD without SI (LLD-NSI), and 34 normal controls. We applied source-level graph theory based on functional connectivity in gamma band and utilized machine learning to differentiate between LLD-SI and LLD-NSI groups using network features. RESULTS:Significant diminished gamma functional connectivity, particularly involving the orbitofrontal cortex, was observed in both subtypes of the LLD group. In graph theory analysis, LLD-SI showed decreased average clustering coefficient (p < 0.001) and characteristic path length (p = 0.021), along with increased global efficiency (p = 0.015) compared to LLD-NSI. Compared to NC, LLD-SI also demonstrated reduced average clustering coefficient (p = 0.004), characteristic path length (p = 0.004), and higher global efficiency (p = 0.004). We also found several nodal metrics, which suggested potential hubs related to SI. The graph theorical method effectively distinguished SI in LLD, with an accuracy of 69.35%, sensitivity of 73.33%, and specificity of 65.63% based on gamma-band network features. LIMITATIONS:The sample sizes are relatively small. Higher-density EEG systems and interventional study designs should be included in future research. Future studies should incorporate external validation datasets to confirm the clinical utility of the proposed classification framework. CONCLUSION:Our research provides valuable insights into the brain connectome in gamma band of SI in LLD. Gamma-band network indices may serve as potential biomarkers for detecting SI and offer frequency-specific targets for neuromodulation in suicide prevention and treatment strategies for LLD patients.
Sex and gender can impact cannabis use and related harms, yet the field has historically centered men and male bodies. In our recent systematic review of sex differences in the acute cognitive effects of cannabis, just six of 29 human studies found evidence that female and male participants differed in cognitive responses to cannabis. The goal of this Commentary is to discuss methodological limitations of published studies that complicate interpretation of data and to suggest priorities for future research to move this topic forward. We highlight inadequate statistical power, poor definition and measurement of sex, lack of consideration of sex- or gender-related characteristics, and no inclusion of transgender and gender-diverse individuals in prior studies. Future research should take an intersectional perspective, incorporate hypothesis-driven sex- and gender-informed designs, ensure adequate power for interaction analyses, and consider sex-related variables across the lifespan. This approach is necessary to advance scientific rigor and promote equitable health outcomes related to cannabis use.
For 3000 years, psychedelics have been used in religious contexts to enhance spiritual thinking, well-being, and a sense of community. In the last few years, a renaissance in the use of psychedelic drugs for mental disorders has occurred in Western society; consequently, a pressing scientific need to elucidate the intricate mechanisms underlying their actions has arisen. Psychedelics mainly bind to serotonin (5-HT) receptors, particularly 5-HT2A receptors, but may also bind to other receptors. Unlike conventional psychotropic drugs used in psychiatry, psychedelics introduce a distinctive complexity. They not only engage in receptor activation, but also exert influence over specific neural circuits, thereby facilitating transformative cognitive experiences and fostering what many have identified as a spiritual contemplation or mystical experience. This comprehensive review describes clinical studies that have examined the propensity of psychedelics to enhance spiritual, mystical, and transcendent cognitive states. This multifaceted nature, encompassing diverse components and paradigms, necessitates careful consideration during the investigation of psychedelic mechanisms of action to avoid oversimplification. The present review endeavours to elucidate the mechanisms underlying the actions of 2 principal psychedelic substances, psilocybin and lysergic acid diethylamide (LSD), with a focus on monoamine and glutamate receptor mechanisms; molecular aspects, such as neuroplasticity and epigenetics; as well as the impact of psychedelics on brain circuits, including the default mode network and the cortico-striato-thalamo-cortical network. Given their distinctive and intricate mechanisms of action, psychedelics necessitate a novel conceptual framework in psychiatry, offering insight into the treatment of mental health disorders and facilitating the integration of the realms of brain, mind, and spirituality.
BACKGROUND:Suicide remains a critical public health issue, with self-report-based clinical assessments often failing to detect imminent risk. This study aimed to identify objective electroencephalography (EEG)-based neurobiological markers for differentiating a suicide attempt (SA) from suicidal ideation (SI) using EEG microstate and microstate-based functional connectivity (FC) analyses. METHODS:From 2017 to 2020, this study enrolled 130 medication-naïve major depressive disorder patients (68 SA, evaluated within 7 days of the attempt; 62 SI) at Soonchunhyang University Cheonan Hospital. Resting-state EEG data were analyzed using microstate analysis to explore temporal dynamics of brain topography and microstate-based FC to assess connectivity in theta, alpha, and beta bands. Correlations between EEG features and psychological measures (e.g., suicidal ideation, depression, emotion regulation) were examined. RESULTS:Compared with the SI group, the SA group showed a marginally lower frequency of occurrence for microstates A (auditory/language processing) and B (visual processing) (p = 0.078 for both). The SA group demonstrated significantly higher alpha-band FC during microstate E (linked to the default mode network (DMN)) for several electrode pairs (e.g., F7-C5, p = 0.009; FC5-C5, p = 0.005). The SA group also exhibited marginally higher FC in the alpha band during microstates C (DMN-related) and B, and in the theta band during microstate E. A subsequent within-group analysis revealed that in the SI group, alpha-band FC during microstate E positively correlated with scores for difficulties in emotion regulation (r = 0.433, p = 0.017). LIMITATIONS:Findings are limited by potential physiological confounds in the SA group and by the limited anatomical specificity inherent in sensor-space EEG analysis. CONCLUSION:EEG microstate dynamics and microstate-based FC differ between patients with SA and SI. Specifically, enhanced alpha-band connectivity during microstate E in the SA group potentially reflects condition-specific DMN functions. These EEG-based measures show promise as objective markers that complement clinical suicide risk assessment and inform early intervention strategies.
