Alexandra Vassilieva

Background: Glutamate is the main excitatory neurotransmitter in the brain, and extracellular levels of glutamate and glycerol (a breakdown product of cell damage) increase after severe acute brain injury. Previous studies report that increased intracerebral glutamate—measured using cerebral microdialysis (CMD)—is associated with unfavorable outcome, and that both increased glutamate and glycerol are associated with mortality in patients with severe acute brain injury. We investigated the association between CMD levels of glutamate and glycerol to episodes of neuroworsening, in‐hospital mortality, and functional outcome at 6 months postinjury. Methods: This single‐center retrospective cohort study included patients with subarachnoid hemorrhage (SAH) or traumatic brain injury (TBI) monitored with CMD and in whom at least five vials of microdialysate were analyzed. Using mixed‐effects linear regression, we compared CMD‐glutamate and ‐glycerol leading up to episodes of neurological worsening (9–12 h vs. 0–3 h before) as well as 0–3 h before and after episodes of neurological worsening. Additionally, CMD‐glutamate and ‐glycerol were analyzed for an association with in‐hospital mortality and functional outcome 6 months after injury, and we explored predictive thresholds of CMD‐glutamate and ‐glycerol for unfavorable functional outcome 6 months after brain injury. Results: A total of 172 patients were included. Neither CMD‐glutamate nor ‐glycerol changed up to or after a neuroworsening episode, nor were they associated with unfavorable outcome at 6 months. We could not establish a predictive threshold of neither CMD‐glutamate or ‐glycerol for 6‐month clinical outcomes. However, CMD‐glycerol was increased in patients who died during hospitalization compared to those who survived (mean difference: 55; 95% CI: 30–81 μmol/L). Conclusion: CMD‐glutamate and ‐glycerol did not predict episodes of neuroworsening or 6‐month functional outcome in patients with SAH or TBI. CMD‐glycerol was associated to in‐hospital mortality. Editorial Comment: Serial measurements of local markers after acute brain injury might help to understand if brain condition is worsening or improving. This study assessed localized microdialysis‐based collection and measurement of a neurotransmitter and cell injury marker to test how well serial measures of these follow clinical brain recovery after injury. Findings confirm that more extracellular glycerol as sampled here is common in more severe brain injuries. Trail Registration: Clinicaltrials.gov identifier: NCT06302244.

Psychedelics such as psilocybin have been linked to enhanced neuroplasticity and symptom relief in affective disorders, but the neurobiological mechanisms and impact of environmental context remain unclear. Here, we tested whether a single dose of psilocybin (0.3 mg/kg) alters synaptic density in healthy individuals and whether setting-dependent subjective experience shapes this effect. Fifteen healthy participants had a psilocybin-induced psychedelic experience either inside an MRI scanner or in a therapeutic-like room. We assessed synaptic density changes by measuring the Synaptic Vesicle glycoprotein 2A in the frontal cortex and hippocampus with [¹¹C]UCB-J PET at baseline and one-week post-dose, and assessed subjective experiences immediately afterwards and at three months. Overall, we found no statistically significant increase in SV2A density. However, participants treated in the therapeutic-like setting exhibited more intense mystical-type experiences, longer-lasting psychological benefits, and greater increases in synaptic density than those dosed in the MRI scanner. These findings indicate that psilocybin’s neuroplastic effects are modulated by environmental context, with important implications for psychedelic-assisted therapies. ClinicalTrial : NCT03289949.

Background: Invasive multimodal neuromonitoring (MMNM) is standard of care in many neuro-intensive care units for patients with severe acute brain injury. MMNM is used for monitoring of early signs of secondary brain injury. Still, the safety of this approach is only partly clarified. This study aimed to investigate the prevalence and types of MMNM-related complications. Methods: For this single-centre retrospective study, we included all patients admitted to the Neurointensive Care Unit at Rigshospitalet from March 2017 to December 2023, who were monitored using MMNM probes in the brain, i.e. monitoring of intracranial pressure (ICP) in combination with brain tissue oxygen tension (PbtO ₂ ) and/or cerebral microdialysis (CMD). Medical records and computed tomography (CT) or magnetic resonance imaging (MRI) of the head were reviewed for MMNM-related complications and functional outcome at 6 months after ictus. Results: A total of 223 patients with severe acute brain injury underwent monitoring with MMNM. Imaging was done after insertion in 196 patients (88%) of all who received MMNM. In these, haemorrhage related to the insertion was observed in 25 patients (13%), suboptimal location in 70 (36%), bone fragments in 25 (13%), and pneumocephalus in 71 (36%); none of these necessitated intervention. Among the entire cohort of 223 patients, infection related to MMNM occurred in one patient (0.4%); malfunction was reported by clinicians in 64 patients (29%) and verified in 26 (12%). After MMNM removal, 162 patients (73%) had a CT or MRI scan, of whom 11 patients (6.8%) had a new parenchymal haemorrhage; one patient (0.4%) underwent surgical haematoma evacuation. Six months functional outcome did not differ between patients with and those without MMNM-related complications. Conclusion: In this retrospective study, a high number of MMNM-related complications was found, of which the vast majority did not cause clinical concern and did not affect patient treatment or outcomes.

Background: Hyperlactatemia is common during brain tumor craniotomy, although the pathophysiology and association to outcome are unclear. We prospectively investigated prevalence and risk factors for perioperative hyperlactatemia (S-lactate ≥2.2 mM) as well as its association with short-term outcomes in patients undergoing elective brain tumor craniotomy. Methods: In 450 patients, arterial lactate was measured hourly from the first surgical incision until 6 hours postoperatively. The primary outcome was a change in the level of neurological disability, measured by the modified Rankin Scale preoperatively and at 30 days after surgery. Secondary outcomes were length of hospital stay, new neurological deficits at discharge, days alive and out of hospital at 30 days, and 30-day mortality. Hyperlactatemia was analyzed both as a dichotomous (≥1 measurement of S-lactate ≥2.2 mM) and as a continuous variable (lactate load). We used both a multivariable regression and a backward stepwise regression analysis to identify risk factors for hyperlactatemia and factors associated with postoperative outcomes. Results: Hyperlactatemia was seen in 66% of the study participants. No association was found between hyperlactatemia and modified Rankin Scale change from baseline to 30 days or any other clinical outcome. Independent factors associated with hyperlactatemia were mean perioperative glucose (0.14; 95% CI: 0.09-0.18; P P P =0.004), and inverse noradrenaline dose (−0.02; 95% CI: −0.04 to −0.006, P =0.006). Conclusions: We did not find an association between perioperative hyperlactatemia and short-term outcomes in patients undergoing brain tumor craniotomy. Preoperative glucocorticoids, perioperative glucose, malignant CNS tumor, and noradrenaline dose were independently associated with hyperlactatemia.

Psychedelics such as psilocybin have been linked to enhanced neuroplasticity and symptom relief in affective disorders, but the neurobiological mechanisms and impact of environmen-tal context remain unclear. Here, we tested whether a single dose of psilocybin alters synap-tic density in healthy individuals and whether setting-dependent subjective experience shapes this effect. Fifteen healthy participants had a psilocybin-induced psychedelic experi-ence either inside an MRI scanner or in a therapeutic-like room. We assessed synaptic densi-ty changes by measuring the Synaptic Vesicle glycoprotein 2A in the frontal cortex and hip-pocampus with [¹¹C]UCB-J PET at baseline and one-week post-dose, and assessed subjective experiences immediately afterwards and at three months. Participants treated in the thera-peutic-like setting exhibited more intense mystical-type experiences, longer-lasting psycho-logical benefits, and greater increases in synaptic density than those dosed in the MRI scan-ner. These findings indicate that psilocybin’s neuroplastic effects are modulated by envi-ronmental context, with important implications for psychedelic-assisted therapies.

Hyperlactatemia is common during tumor craniotomy, but the underlying pathophysiology is unclear. This study measured simultaneous arterial and jugular‐bulb lactate concentrations in patients undergoing brain tumor craniotomy to investigate the hypothesis that hyperlactatemia was associated with a net cerebrovascular lactate input. In 20 patients, arterial and jugular‐bulb blood was collected hourly from the start of surgery to 6 h postoperatively for measurement of lactate, glucose, and oxygen concentration. For each marker, data were analyzed using a linear mixed‐effects model with jugular‐bulb concentration as dependent variable, arterial concentration as fixed effect, and patient as random effect. Furthermore, we generated regression lines between arterial and jugular‐bulb concentrations. The slope of the regression line between arterial and jugular‐bulb lactate was 0.95 (95% CI 0.93–0.97, R ² = 0.98), indicating that increasing arterial lactate levels were associated with an increasingly positive net cerebrovascular balance (net input). The line crossed the identity line at 2.86 (95% CI 0.57–5.16) mmol/L, indicating that lower levels of lactate were associated with a negative net cerebrovascular balance (net output). This suggests a switch from net lactate output during normolactatemia towards net input during hyperlactatemia. Hyperlactatemia in tumor‐craniotomy patients probably does not originate from the brain.

Hyperlactatemia occurs frequently after brain tumor surgery. Existing studies are scarce and predominantly retrospective, reporting inconsistent associations to new neurological deficits and prolonged hospital stay. Here we describe a protocol for a prospective observational study of hyperlactatemia during and after elective tumor craniotomy and the association with postoperative outcome, as well as selected pathophysiological aspects, and possible risk factors. We will include 450 brain tumor patients scheduled for elective craniotomy. Arterial blood samples for lactate and glucose measurement will be withdrawn hourly during surgery and until six hours postoperatively. To further explore the association of hyperlactatemia with perioperative insulin resistance, additional blood sampling measuring markers of insulin resistance will be done in 100 patients. Furthermore, in a subgroup of 20 patients, blood from a jugular bulb catheter will be drawn simultaneously with blood from the radial artery to measure the arterial to jugular venous concentration difference of lactate, in order to study the direction of cerebrovascular lactate flux. Functional clinical outcome will be determined by the modified Rankin Scale, length of stay and mortality at 30 days, 6 months, 1 year and 5 years. Clinical outcome will be compared between patients with and without hyperlactatemia. Multivariate logistic regression will be used to identify risk factors for hyperlactatemia. A statistical analysis plan will be publicized to support transparency and reproducibility. Results will be published in a peer-reviewed journal and presented at international conferences.

Background: Levels of consciousness in patients with acute and chronic brain injury are notoriously underestimated. Paradigms based on electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) may detect covert consciousness in clinically unresponsive patients but are subject to logistical challenges and the need for advanced statistical analysis. Methods: To assess the feasibility of automated pupillometry for the detection of command following, we enrolled 20 healthy volunteers and 48 patients with a wide range of neurological disorders, including seven patients in the intensive care unit (ICU), who were asked to engage in mental arithmetic. Results: Fourteen of 20 (70%) healthy volunteers and 17 of 43 (39.5%) neurological patients, including 1 in the ICU, fulfilled prespecified criteria for command following by showing pupillary dilations during ≥4 of five arithmetic tasks. None of the five sedated and unconscious ICU patients passed this threshold. Conclusions: Automated pupillometry combined with mental arithmetic appears to be a promising paradigm for the detection of covert consciousness in people with brain injury. We plan to build on this study by focusing on non-communicating ICU patients in whom the level of consciousness is unknown. If some of these patients show reproducible pupillary dilation during mental arithmetic, this would suggest that the present paradigm can reveal covert consciousness in unresponsive patients in whom standard investigations have failed to detect signs of consciousness.