The transdiagnostic approach has potentials to address the problems of comorbidity of diagnostic entities and heterogeneity in psychopathology. This approach may unveil the underlying mechanisms across different diagnostic entities. It is also important to study the potential risk factors for aggravating trajectories to develop specific psychiatric conditions. By extending the current theoretical models, we propose the repetitive-intrusive-thinking process (RITP) as a transdiagnostic framework to link rumination, obsession and delusion together as a continuum. Attention-control-deficit, cognitive-inflexibility, and impaired-reality-monitoring are core features of the self-referential RITP framework, associated with hyperactivation of the default-mode-network, and dysregulation of the salience network and the fronto-parietal network. Clarifying the shared mechanisms between rumination, obsession and delusion using the transdiagnostic perspective will benefit clinical care and facilitate personalized, domain-specific assessments and interventions across symptoms in psychiatric patients.
Brain connectivity disruption is a hallmark of neurodegenerative disorders, including Alzheimer's disease (AD), yet how network breakdown gives rise to cognitive deficits remains unclear. Here, we review the evidence bearing on three interconnected processes that have been proposed to link molecular pathology to cognitive decline. First, we summarize evidence that misfolded proteins propagate along brain connectivity pathways, making the connectome the biological substrate for disease progression. Second, we discuss the divergent trajectory reported across the AD continuum, an initial compensatory hyperconnectivity followed by progressive hypoconnectivity and network collapse, together with the accompanying oscillatory changes (intrusion of slow-wave activity and suppression of fast oscillatory rhythms). Third, we examine the proposal that these oscillatory alterations compromise neural replay mechanisms, critical for memory consolidation, representing the potential link between network dysfunction and cognitive decline. By integrating evidence from human neuroimaging, electrophysiology, and animal models in the AD field, this framework offers new perspectives for therapeutic interventions targeting brain connectivity and replay mechanisms in neurodegenerative diseases.
Post-traumatic stress disorder (PTSD) is a multifactorial psychiatric condition characterized by re-experiencing, avoidance, hyperarousal, negative alterations in cognition and mood, and disturbances in social and emotional functioning. Within this broader clinical syndrome, persistent traumatic memories and excessive fear generalization represent important mechanistic and therapeutic domains. Despite substantial advances in understanding its neurobiological basis, current treatments remain suboptimal, with limited efficacy and high dropout rates. The neuropeptide oxytocin (OXT), a key modulator of social behavior, stress regulation, and memory, has been investigated as a potential therapeutic target. Accumulating evidence indicates that severe trauma profoundly disrupts endogenous OXTergic signaling, whereas pharmacological studies suggest that exogenous OXT can modulate fear-memory processing through region-, dose-, route-, and context-dependent mechanisms. Evidence from fear-conditioning indicates that across acquisition, consolidation, retrieval, reconsolidation, and extinction, the direction of OXT’s effects is heterogeneous rather than uniformly anxiolytic and pro-extinction. OXT may influence threat discrimination, fear expression, memory updating, and extinction by modulating specific neural circuits and neurochemical pathways. However, most preclinical models capture selected dimensions of PTSD rather than the full clinical disorder. Human studies further indicate that intranasal OXT can modulate neural, physiological, and social-cognitive processes relevant to PTSD, although evidence for consistent clinical efficacy remains limited and heterogeneous. This review synthesizes current findings on OXT and its synthetic analogs within a stage- and context-dependent framework to better investigate their heterogeneous effects and assess their potential relevance and translational limitations in PTSD.
Chronic stress or acute severe stressors have been extensively used as putative animal models of psychiatric diseases, particularly depression and post-traumatic stress disorder (PTSD), respectively. The hypothalamus-pituitary-adrenal (HPA) axis not only represents a prototypical stress response system, but also mediates or modulates a wide range of the behavioral and physiological consequences of stress exposure. Therefore, particular attention has been paid to the parallelisms between stress-induced alterations of the HPA axis in animal models and the alterations observed in PTSD and depression. The canonical views suggest that PTSD patients are characterized by hypocortisolemia and an enhanced negative glucocorticoid feedback (nGF), whereas major depression patients typically show hypercortisolemia and impaired nGF. Here, we critically review studies on the effects of different stress models on nGF, distinguishing between nGF under resting and stress conditions. The evidence that chronic stress exposure is associated with impaired nGF is weak, except for HPA activity under resting conditions. The evidence that a single exposure to severe stressors leads to enhanced nGF under stress conditions is controversial, and the studies supporting this present important limitations. In general, the major limitations of nGF studies are the lack of plasma ACTH data, the assessment of nGF using exposure to a stressor with which animals have prior experience, and the predominant use of dexamethasone instead of natural glucocorticoids. At the dexamethasone doses typically used, this drug acts mainly at the anterior pituitary rather than at the brain level, making it difficult to relate altered nGF with changes in brain corticosteroid receptors.
