Receptor-interacting protein kinase-1 (RIPK1) is a serine-threonine kinase that is activated in the brain early after intracerebral hemorrhage (ICH), but its spatial and temporal course in the subacute period is unknown. We used mice deficient in RIPK1 kinase activity to investigate RIPK1 regulation of clinically relevant outcomes in a collagenase ICH model. At 35 days after ICH in wild-type males, RIPK1 was activated (increased in detergent-insoluble fractions) in striatal neurons, endothelium, and astrocytes. In neurons, RIPK1 activation was associated with loss of its regulators TAK1/TBK1, and RIPK1 regulated post-injury neuronal CaMKII𝛼 expression, pathological tau phosphorylation, and inflammasome activation. RIPK1 regulated post-injury gliosis, blood-brain barrier (BBB) damage and cognitive deficits in males. At 35 days after ICH in females, RIPK1 was activated exclusively in neurons but female neurons lacked the biochemical changes seen in males, and RIPK1 did not regulate increased gliosis, BBB damage, or most cognitive deficits in injured females. The studies are the first to describe cell-specific RIPK1 activation in the subacute period of experimental ICH and highlight important sex differences that should inform clinical trials of RIPK1 inhibitors in patients with ICH. Sex differences should be evaluated for RIPK1 in other brain injury models and neurodegenerative disease paradigms.

BackgroundTargeted temperature management (TTM) is widely used to prevent secondary brain injury in febrile brain-injured patients, and it almost always targets systemic temperature (ST). However, because the therapeutic target is the brain, brain temperature (BT) may represent a more relevant target. We investigated whether BT-targeted TTM improved BT control compared with conventional ST-targeted TTM.MethodsBrain-TTM was a single-center, prospective, randomized controlled pathophysiology study including brain-injured patients monitored with an intracerebral pressure probe incorporating a thermal sensor. Patients with BT ≥38.5°C requiring TTM were randomized to BT-targeted or ST-targeted (bladder temperature) TTM. BT and ST were recorded every minute for 12 hours.ResultsThirty-four patients were included (17 per group). Median age was 46 years (IQR 42-53), and 68% were men. During the maintenance phase (H3-H12), the median proportion of time with BT within the target range (36.0-37.0°C) was 84% (IQR 53-99) in the BT-targeted group and 89% (IQR 63-92) in the ST-targeted group (primary outcome, p=0.89). Target attainment at H3 was similar (p=0.49). The BT-ST gradient increased from 0.11±0.07°C during induction to 0.30±0.06°C during maintenance. Per-protocol analyses were consistent.ConclusionBT-targeted TTM did not improve BT control compared with ST-targeted TTM.

Diffuse cerebral gliomas are the most common malignant brain tumors in adults. In the present work we conducted a narrative review on the role of blood oxygen level-dependent (BOLD)-MRI in diffuse glioma imaging, from historical and clinical applications to recent translational studies including approaches to detect vascular and metabolic alterations as well as its expanding potential to enhance tumor infiltration assessment and treatment surveillance. Task-based and resting-state BOLD-MRI enable localization of eloquent cortical areas and assessment of functional reorganization, though their accuracy is challenged by neurovascular uncoupling and patient-related variability. Combination with vasoactive stimuli allows cerebrovascular reactivity mapping to uncover vascular dysfunction propagating beyond visible tumor margins, correlating with tumor grade and hemodynamic impairment. Quantitative and calibrated BOLD approaches as well as oxygen modulation during BOLD sequence acquisition provide noninvasive biomarkers of tissue hypoxia, oxygen metabolism, and tumor aggressiveness. Despite extensive research, BOLD contrast holds unexploited potential for enhancing glioma diagnosis and management by capturing critical vascular and metabolic alterations. Although challenges remain pertaining to accuracy and standardization, emerging techniques offer substantial potential for the assessment of tumor infiltration extent and therapy surveillance. Advancing clinical integration will require robust standardization, large-scale validation, and correlation with clinical, molecular, and histopathological data.

Endovascular thrombectomy restores macrovascular patency but fails to achieve tissue-level perfusion in approximately 30% of cases, likely because of the no-reflow phenomenon. Even after optimized hemodynamic management, 40% of patients with angiographically successful recanalization fail to achieve functional independence, revealing a biological ceiling beyond blood pressure optimization. I propose that pericyte contraction via endothelin-1/ET-A receptor signaling, neutrophil CD11b/CD18-dependent capillary plugging, and platelet microthrombus, mechanisms operating orthogonally to systemic hemodynamics, define this ceiling. I review imaging and biomarker strategies for identifying microvascular failure and discuss endothelin receptor antagonism, integrin blockade, and intra-arterial thrombolysis as therapeutic priorities for next-generation of post-thrombectomy trials.

Does glucose oxidation yield 6 or 10 H2O? Debated 30 years ago and revived in 2025, the question underlies a brain metabolic water budget built on C6H12O6 + 6O2 → 6CO2 + 10H2O, which does not satisfy the law of conservation of mass. The balanced form, C6H12O6 + 6O2 + 4ADP[3][-] + 4HPO4[2][-] + 4H[+] → 6CO2 + 10H2O + 4ATP[4][-], combines combustion (6H2O) with substrate-level phosphorylation (4H2O). This reconciles both answers, resolving the controversy. How much water is secreted per glucose depends on the fate of ATP; choosing 6 or 10 changes estimates of brain metabolic water by two-thirds.

Gamma entrainment using sensory stimuli (GENUS) uses 40Hz-pulsed sensory stimuli to entrain neural activity in the gamma band (30-150Hz). However, the effect of GENUS on low-frequency vascular oscillations has not been fully explored. The objective of this study is to elucidate the effect of GENUS on vasomotion in healthy mice and potential confounds for future application in disease studies. Head-fixed, awake C57Bl/6 mice (n=18; 9M 9F) aged between 18 to 60 weeks were subjected to white light of either 40Hz visual flicker (GENUS), or constant stimulus (control). Blood flow was imaged using laser speckle contrast imaging (LSCI) before, during, immediately after 1 hour of stimulus, and 30min after the stimulus termination. A linear mixed-effects model showed that GENUS enhanced the magnitude of 0.2-0.4Hz blood flow oscillations by 38% during stimulation and by 30% at 30 minutes after stimulation compared to control when controlled for age, sex, and other factors. The effect on vasomotion was distributed across the surface of many cortical regions not limited to visual areas. These results support the exploration of GENUS for increasing vasomotion in therapeutic contexts.

Remote ischemic conditioning(RIC) is a promising neuroprotective strategy for ischemic stroke, but reliable pharmacodynamic biomarkers confirming its biological activity are lacking. In this translational sub-study of the multicenter randomized phase II TRICS-9 trial, we profiled five circulating microRNAs (miR-181b,miR-150,miR-143,miR-223, and let-7a) in 42 acute stroke patients assigned to RIC or standard medical therapy at 24 hours and 72 hours post-randomization.At 24 hours, miR-143,miR-150, and let-7a were significantly lower in RIC patients, with miR-143 and miR-150 showing strong pharmacodynamic biomarker performance in receiver operating characteristic analysis. At 72 hours, miR-181b was significantly elevated in RIC patients, while let-7a and miR-223 remained suppressed.Longitudinal paired analysis revealed significant within-patient temporal increases in miR-181b,miR-150, and miR-143 from 24 to 72 hours in RIC patients consistent with a biphasic molecular response to conditioning. These findings identify miR-143, miR-150, let-7a, and miR-181b as candidate pharmacodynamic biomarkers of RIC biological activity. Importantly, none of the candidate miRNAs demonstrated significant correlation with stroke severity, discharge NIHSS, or 90-day functional outcome, consistent with their role as pharmacodynamic rather than prognostic markers. These results provide mechanistic support for translational convergence between preclinical and clinical RIC neuroprotection research and highlight the need for external validation in larger outcome-linked cohorts.