High altitude exposes the brain to heterogeneous hypoxic, hemodynamic, rheological, inflammatory, and healthcare-access conditions. This heterogeneity makes altitude biologically informative for stroke research, but it does not justify treating natural altitude exposure as a single protective or harmful state. In this structured narrative review, we searched and organized the literature to ask which altitude-associated hypoxic cues resemble or reveal mechanisms compatible with cerebral ischemic tolerance, and what level of evidence supports that claim. We separate long-term adaptation, short-term acclimatization, chronic or excessive environmental hypoxia, and experimental hypoxic conditioning; define direct, supportive, and indirect evidence tiers; and integrate neurovascular-unit biology with multi-omics and stroke pathophysiology. Experimental hypoxic preconditioning remains the clearest direct evidence that a defined sublethal hypoxic stimulus can induce a time-limited tolerant state. In contrast, human high-altitude epidemiology, physiology, and genetics mainly constrain the clinical context and nominate candidate pathways rather than prove stroke-specific protection. We also emphasize that chronic hypoxia can be maladaptive through endothelial dysfunction, oxidative stress, erythrocytosis, thrombogenicity, blood–brain barrier impairment, and microvascular injury. Across neurovascular-unit cell types, a transparent evidence-weighting framework prioritizes endothelial biology because of its direct connection to BBB stability, effective reperfusion, hemorrhagic transformation risk, and no-reflow, while neurons, astrocytes, microglia, oligodendrocyte-lineage cells, and pericytes require different degrees of causal and human validation. We argue that the most productive path forward is not to label altitude as protective, but to use altitude-related biology to prioritize testable, stroke-facing hypotheses regarding BBB stability, microvascular patency, metabolic support, inflammatory thresholds, white-matter resilience, and biomarker-defined conditioning windows.
Oscillatory dynamics as the coordination layer of the organism: waves, Markov blankets, and the virtual space of cognition
Neural oscillations are not a mechanism that implements cognition. We present a new theoretical framework through a synthesis of relevant literature that has emerged in recent years: metabolic activity in the body, including but not limited to neural tissue, gives rise to an oscillatory pattern that contains information accessible to individual cells. The resulting dynamical structure allows cognitive activity to map the body in fine detail, to perceive its surroundings, or to extend into representations of objects and possibilities never encountered in the world. This array of possibilities is enabled by the coordination of the body’s components, which imposes invariant structural regularities among them, in turn creating a moment-to-moment series of states shared across a distributed network of cells. Metabolic success involves ensuring adequate access to nutrition and waste removal for every cell and, when achieved, can give rise to a series of leaps manifested as increased access to complex higher-order affordances. The body’s metabolic activity yields observable coordination; however, the mental actions themselves are inscrutable, existing only within a virtual space that unfolds in the interplay of the constituents of a particular body. Access to advanced functions is categorical; this virtual space expands during development and contracts in response to reduced metabolic sufficiency. Markov blankets formalize this asymmetry: brain-scanning technology clarifies the substrate, but no amount of information about the substrate provides direct access to cognitive activity. Frequency bands of oscillation correspond to spatial scales of inter-blanket communication, with cross-frequency coupling carrying information up and down the nested hierarchy. Several clinical conditions—ME/CFS, Long Coronavirus Disease (COVID), cancer-related cognitive impairment, Alzheimer’s disease, and age-related decline—share a common upstream mechanism within this framework: cellular damage degrades the substrate, which contracts the space of accessible cognitive operations and produces the categorical incapacity patients report. The framework generates a testable prediction: aperiodic spectral flattening should temporally precede the loss of specific oscillatory peaks as the substrate degrades.
Focal volume, steering, and aberration correction in transcranial focused ultrasound: reconsidering the tradeoffs between single-element transducers, phased arrays, and acoustic holograms
Transducer architecture is an increasingly important design consideration in transcranial focused ultrasound, where focal precision, electronic steering, skull-aberration correction, workflow complexity, and cost must be balanced. Under matched aperture, transmit frequency, focal depth, effective source geometry, and equivalent aberration correction, subdividing an aperture into multiple independently driven elements does not by itself reduce the diffraction-limited focal volume. Phased arrays provide important capabilities that single-element transducers generally lack, including electronic steering, dynamic phase correction, and flexible control of energy deposition. These capabilities can improve the realized intracranial field, particularly when skull-induced aberrations would otherwise broaden, shift, or split the focus. Single-element systems may also be extended through patient-specific acoustic holograms or lenses, which impose spatially varying phase delays to compensate for aberrations, steer the focus, or shape the pressure field. These approaches may reduce system complexity but are typically static and less adaptable than phased arrays. We therefore frame transducer selection as an application-driven design-matching problem: the relevant question is not which architecture is inherently “more focused” under matched conditions, but which best meets a study’s requirements for steering, skull-aberration correction, temporal reconfigurability, spatial degrees of freedom, workflow burden, cost, positioning robustness, and safety.
Synaptic output from suprachiasmatic nucleus cholecystokinin neurons regulates locomotor rhythmicity
BackgroundThe mammalian suprachiasmatic nucleus (SCN) serves as the master circadian pacemaker, which coordinates daily behavioral and physiological rhythms through functionally diverse neuronal subtypes. Cholecystokinin (CCK) is expressed in a subset of SCN neurons; however, its role in locomotor activity rhythms remains poorly understood.MethodsTo study the functional contribution of SCN CCK-expressing (SCNCCK) neurons, we selectively blocked synaptic transmission by injecting a Cre-dependent tetanus toxin (TeNT) viral vector into the SCN of CCK-IRES-Cre mice. Before and after the virus injection, spontaneous locomotor activity was continuously recorded under a 12:12 h light–dark (LD) cycle. Subsequently, we used Cre-dependent fluorescent reporter (mYongHong) to label SCNCCK neurons and performed whole-brain projection mapping to characterize their downstream connectivity.ResultsSynaptic inhibition of SCNCCK neurons significantly attenuated the strength of locomotor rhythmicity, resulting in reduced rhythm organization and a more uniform distribution of activity. This disruption was mainly driven by a significant decrease in dark-phase locomotor activity, while light-phase activity remained unchanged. Anatomically, SCNCCK neurons are widely projected along the anterior and posterior axes to multiple hypothalamic, thalamic, and limbic regions, including the medial preoptic area (MPA), paraventricular thalamic nucleus (PVT), paraventricular hypothalamic nucleus (PVH), anterior hypothalamic area (AHC), dorsomedial hypothalamic nucleus (DMH), ventromedial hypothalamic nucleus (VMH), and medial amygdala nucleus (MeA). Quantitative analysis revealed projections to these downstream regions, with moderate variation in projection density across targets.ConclusionTogether, these findings identify SCNCCK neurons as an important neuronal subpopulation, which contributes to the robustness and consolidation of spontaneous locomotor rhythms, likely through a wide range of downstream circuits.
From sympathetic storm to systemic inflammation: spatiotemporal dynamics of the brain-lung axis in neurogenic pulmonary edema
Neurogenic pulmonary edema (NPE) is a life-threatening complication of acute central nervous system (CNS) injury, characterized by the rapid onset of hypoxemia and pulmonary fluid accumulation in the absence of underlying cardiopulmonary disease. In recent years, emerging integrative frameworks such as the “neuroimmunoaxis” and “brain-lung axis” have provided new perspectives on how CNS injury leads to systemic immune dysregulation and pulmonary dysfunction. However, critical questions remain regarding the interplay between excessive sympathetic activation, immune homeostasis disruption, and lung tissue injury. This narrative review proposes a neurotransmitter-immune-inflammatory model that integrates mechanical, adrenergic, and inflammatory pathways across the spatiotemporal evolution of NPE. We identify four progressive stages involving sympathetic storm initiation due to central autonomic network disinhibition, pulmonary vascular barrier disruption through Piezo channel activation and angiotensin II-norepinephrine synergy, inflammatory amplification from loss of the cholinergic anti-inflammatory reflex, and systemic progression involving gut-lung axis dysregulation. The model generates three testable predictions. Lesions disrupting the nucleus tractus solitarius-ventromedial hypothalamus-intermediolateral column projection should produce more severe NPE. And selective activation of TRPA1+ dorsal root ganglion neurons should attenuate sympathetic outflow and pulmonary edema. Enhancing α7 nicotinic acetylcholine receptor signaling should mitigate systemic inflammation. These predictions offer experimental avenues for validating the hijacking hypothesis. Translational implications include stage-specific interventions, early sympathetic blockade, mid-phase anti-inflammatory and neuro-modulatory strategies, and late-stage lung-protective ventilation. This study aims to offer a comprehensive analysis of NPE by exploring its pathological mechanisms—from central sympathetic signaling to peripheral lung damage. Emphasis is placed on examining the interactions between neural signals, neurotransmitters, and immune responses to uncover the spatiotemporal dynamics of NPE. By identifying potential pathways for early diagnosis and targeted therapies, the research seeks to improve disease management and contribute to better clinical outcomes for affected patients.
“Mirror, mirror, on the wall, without you, I will fall”: investigation into body dysmorphic disorder from an attachment perspective
ObjectiveBody dysmorphic disorder (BDD) is a prevalent concern among young adults. However, the underlying mechanisms of BDD development remain elusive. This study aims to investigate the intricate relationship between attachment styles and BDD symptoms, with appearance-based rejection sensitivity (ARS) as a mediating factor and gender as a moderator.MethodsA total of 815 young adults participated, completing a battery of questionnaires including the Revised Adult Attachment Scale (RAAS), Appearance-Based Rejection Sensitivity Scale (ARSS), and Scale of Body Image (SBI).ResultsData indicated a positive association between attachment anxiety and BDD symptoms, with ARS found to mediate this link. Furthermore, gender differences were observed to moderate the relationship between ARS and BDD symptoms.ConclusionThis study sheds light on the foundational mechanisms of BDD, tracing its origins to early caregiver-infant bonds and highlighting the enduring impact of ambivalent care on body image perceptions. Additionally, the identification of ARS as a specific contributing factor to BDD onset underscores its significance in understanding and addressing this disorder. By considering the influence of social norms and cultural context, gender differences in the association between ARS and BDD symptoms are elucidated.
Intranasal esketamine plus oral antidepressant for treatment-resistant depression: acute induction and maintenance relapse-prevention outcomes in a systematic review and meta-analysis
Treatment-resistant depression (TRD) remains a major clinical challenge. Intranasal esketamine, used adjunctively with an oral antidepressant, has been evaluated in randomized trials, but uncertainty persists regarding the magnitude and consistency of benefit, durability, and key harms. This systematic review and meta-analysis included randomized controlled trials comparing intranasal esketamine plus an oral antidepressant versus placebo nasal spray plus the same oral antidepressant in TRD. Acute induction (≈4 weeks) and maintenance randomized-withdrawal phases were analyzed separately. Depression outcomes were assessed primarily using the Montgomery–Åsberg Depression Rating Scale (MADRS), and functional outcomes using the Sheehan Disability Scale (SDS). Two reviewers independently screened studies, extracted data, and assessed risk of bias using RoB 2.0. Random-effects models pooled mean differences (MD) for continuous outcomes, risk ratios (RR) for binary outcomes, and hazard ratios (HR) for relapse prevention. Certainty of evidence was rated using GRADE. From 1,518 records, nine reports representing six unique RCTs (1,836 participants) were included. Four acute induction RCTs (n=937) showed greater symptom reduction at day 28 with esketamine (MADRS MD −2.99, 95% CI −5.10 to −0.89; I²=48.5%). Rapid improvement was evident by day 2 (MD −3.25, 95% CI −4.65 to −1.85). Esketamine increased day-28 response (RR 1.44, 95% CI 1.20–1.74) and remission (RR 1.52, 95% CI 1.20–1.92), corresponding to approximately +154 responders and +106 remitters per 1,000 patients, respectively, based on pooled control risks. Functioning improved (SDS MD −1.70, 95% CI −2.61 to −0.79). Two maintenance randomized-withdrawal RCTs (n=899) demonstrated reduced relapse risk with continued esketamine (HR 0.51, 95% CI 0.42–0.62; I²=0%). In acute induction, esketamine increased any treatment-emergent adverse event (TEAE) (RR 1.37, 95% CI 1.25–1.50) and discontinuation due to adverse events (RR 2.68, 95% CI 1.35–5.29), with notable increases in dissociation (RR 7.33, 95% CI 4.49–11.98) and blood pressure increased events (RR 3.96, 95% CI 2.24–7.01). Maintenance TEAE rates were similar between groups (RR 1.07, 95% CI 0.99–1.17). Intranasal esketamine plus an oral antidepressant provides rapid, modest acute improvement and reduces relapse risk during maintenance among stabilized responders/remitters, but increases acute adverse events, supporting use within supervised care and individualized benefit–risk assessment.
Opinion: On the reasons for underutilization of ECT in individuals with intellectual and developmental disability
Exercise interventions are most consistently supported for depressive disorders: an umbrella review of diagnosed depressive and anxiety disorders
BackgroundExercise is increasingly discussed as part of lifestyle-based and multimodal care for mood and anxiety disorders, but review-level evidence often mixes formally diagnosed clinical populations with symptom-defined or medically mixed samples.MethodsWe conducted an umbrella review of systematic reviews, meta-analyses, and network meta-analyses of structured exercise interventions for adults with depressive or anxiety disorders. Six databases were searched from inception to 1 March 2026. Primary outcomes were depressive and anxiety symptom severity, remission, and response; secondary outcomes were acceptability and tolerability. Review quality was appraised with AMSTAR 2, and primary-study overlap was quantified with corrected covered area (CCA), including overall and symptom-cluster analyses. The synthesis was designed to summarize review-level credibility and clinical interpretability rather than to generate a second-order pooled efficacy estimate.ResultsNine reviews met eligibility criteria; four supplied directly extractable primary overall review-level estimates for core psychiatric symptom outcomes. AMSTAR 2 appraisal rated one review as high, three as low, and five as critically low. Recalculated overall overlap was slight (112 primary-study occurrences, 89 unique primary studies; CCA = 3.23%), although cluster-level analyses identified localized redundancy, particularly within anxiety-disorder-specific reviews. In major depressive disorder, one clinically focused review reported a large reduction in depressive symptoms for aerobic exercise versus non-exercise comparators (Hedges’ g = -0.79, 95% CI -1.00 to -0.57; I² = 21%). Across diagnosed depressive and/or anxiety disorders, broader review-level estimates also favored exercise for depressive symptoms (SMD = -0.97, 95% CI -1.28 to -0.66) and anxiety symptoms (SMD = -0.66, 95% CI -1.09 to -0.23), but heterogeneity was high. Anxiety-disorder-specific evidence was less secure: the primary DSM-IV anxiety-disorder pooled estimate showed no clear benefit over selected controls (SMD = 0.02, 95% CI -0.20 to 0.24). Acceptability estimates were close to null, and adverse-event reporting was too sparse to support confident safety conclusions.ConclusionExercise is best supported as an adjunctive, patient-centered component of care for depressive disorders. Anxiety-disorder-specific efficacy remains uncertain when comparator rigor, diagnostic heterogeneity, and localized overlap are considered, and safety reporting needs substantial improvement.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD420261364264.
Health outcomes across socioeconomic strata B, C, and DE among Brazilian adults living in moderate social vulnerability
ObjectivesThis study examined whether socioeconomic status was associated with anxiety symptoms, depressive symptoms, BMI, waist-to-hip ratio, and quality of life among Brazilian adults living in areas of moderate social vulnerability. In addition, we described anxiety and depressive symptoms, BMI and waist-to-hip ratio, and quality of life in individuals living in moderate social vulnerability.MethodsThis is a cross-sectional study. In a socially vulnerable cohort, interviews captured demographics, comorbidities, medications, anxiety and depressive symptoms, and quality of life, followed by measurement of anthropometric characteristics.ResultsAmong 299 socially vulnerable adults, 8% had moderate–severe depressive symptoms and 7% had moderate–severe anxiety symptoms; ~50% showed increased risk of cardiometabolic diseases (i.e., waist-to-hip ratio greater or equal to 0.90 for men and 0.85 for women, respectively). Poor quality of life affected 4–12% across domains. Mental health, anthropometrics (waist-to-hip ratio, BMI), increased risk of cardiometabolic diseases and quality of life in physical, social and environmental domains did not differ by socioeconomic status (B, C, DE; all P>0.05). Poor psychological quality of life was more frequent among participants in higher socioeconomic status (B: 8%; C: 6%; DE: 4%, P = 0.0157). Linear regression analyses showed no statistically significant differences across socioeconomic status in depressive symptoms, anxiety symptoms, BMI, waist-to-hip ratio, or quality of life scores in any domain (all P>0.05).ConclusionsOur findings suggest that, among Brazilian adults living in moderate social vulnerability and classified within socioeconomic status B, C, and DE, mental health, BMI, waist-to-hip ratio, and quality-of-life indicators were similar across socioeconomic strata. However, these results should be interpreted as reflecting intra-group socioeconomic differences within a moderately vulnerable population and should not be generalized to individuals from the highest socioeconomic status.