Claus Svarer

Lysergic acid diethylamide (LSD) is a potent psychedelic with increasing therapeutic interest, yet qualification of target engagement using in vivo neuroimaging has not yet been performed. Using simultaneous positron emission tomography–magnetic resonance imaging technology, we describe multiple brain actions of LSD in seven healthy volunteers blinded to LSD dose received. Here we show that LSD occupies 5-HT2AR with a high affinity and increases both global cerebral blood flow (CBF) and internal carotid artery flow. LSD also decreases global connectivity, which was negatively associated with changes in CBF. We observe an anticlockwise hysteresis loop between plasma drug levels and subjective effects, suggesting atypical pharmacodynamic mechanisms. We contrast our CBF and global connectivity findings and their relation in a separate cohort of 25 participants administered psilocybin, highlighting key consistencies and differences. By establishing the dose–occupancy relation of LSD in humans, our findings provide insights for the clinical development of psychedelic compounds and demonstrate unique neurophysiological effects that distinguish LSD from psilocybin.

Purpose: Neurodegenerative parkinsonism is characterized by degeneration of the dopaminergic nigrostriatal pathways and a reduction in nigral neuromelanin. Dopamine transporter (DAT) imaging assesses presynaptic striatal dopaminergic function and is typically performed with [ ¹²³ I]FP-CIT SPECT-CT, but has recently also become available with [ ¹⁸ F]FE-PE2I PET-CT. Magnetic resonance imaging (MRI) can explore disease-related changes by quantifying neuromelanin and iron deposition associated with the loss of nigral neurons. Methods: In this study, we conducted a head-to-head comparison of [¹²³I]FP-CIT SPECT, [¹⁸F]FE-PE2I PET, and nigral MRI in 35 patients referred for diagnostic DAT imaging. Nigral MRI was performed with neuromelanin-sensitive gradient echo magnetization-transfer contrast MRI and iron-sensitive STrategically Acquired Gradient Echo (STAGE) MRI. Patient satisfaction with SPECT and PET was recorded via questionnaires. Results: Eighteen patients were diagnosed with neurodegenerative parkinsonism with a median symptom duration of 29 months. DAT availability as measured with SPECT and PET showed complete concordance across cases, correlated strongly, and demonstrated equally excellent diagnostic performance. Patient questionnaire items were either not different between modalities or in favor of SPECT. Nigral neuromelanin content was reduced in patients with neurodegenerative parkinsonism and provided intermediate diagnostic accuracy, with indications of lower neuromelanin with disease duration. Midbrain iron content did not differ between groups and provided no diagnostic information. Conclusion: Our findings indicate that in early-stage parkinsonism, DAT neuroimaging with SPECT and PET provides comparable and superior diagnostic value relative to nigral MRI.

Introduction: Anesthesia is known to modulate glymphatic clearance and cerebrospinal fluid (CSF) transport in rodents, but how these effects translate to a larger, gyrencephalic brain is unknown. With its anatomical similarity to the human brain, the pig offers a valuable translational model for examining anesthesia-dependent CSF-to-brain transport. Methods: We used dynamic in vivo SPECT/CT imaging for six hours following cisterna magna injection of [99mTc]-DTPA to quantify CSF-to-brain tracer transport in pigs under two anesthesia regimens: ketamine/dexmedetomidine (K/D, n=5) which previously has been shown in rodents to enhance glymphatic influx relative to GABAergic anesthesia, and propofol (PRO, n=5). Brain and CSF spaces were delineated using a data-driven non-negative matrix factorization approach, and tracer kinetics were quantified using a one-tissue compartment model. Results: Brain influx could be stably estimated from 2 hours post-injection. Hierarchical sub-division of the brain parenchyma identified two kinetically distinct components with different anatomical distributions: a surface component, located ventrally and within the interhemispheric fissure, showed faster kinetics than the anatomically deeper and lateral-dorsal component. Consistent with rodent findings, K/D-anesthetized pigs showed 62% (p=0.002) greater brain tracer accumulation than PRO-anesthetized pigs. However, while the brain influx rates did not differ substantially (p=0.047), a 52% higher cumulative CSF tracer concentration (p=0.047) could account for most of the difference by providing greater tracer availability for brain entry. Conclusions: In the larger gyrencephalic pig brain, we found higher brain tracer accumulation under K/D anesthesia compared to PRO anesthesia. A significant portion of this difference is readily explained by higher CSF retention, likely driven by a slower CSF turnover. This underscores the necessity of dynamic CSF tracer concentration measurements when assessing CSF-brain influx, a factor we suggest that future glymphatic studies should take into account.

This study presents a novel in vivo neuroimaging approach using dynamic single photon emission computed tomography (SPECT/CT) to investigate cerebrospinal fluid (CSF) dynamics in pigs, a translationally relevant model due to their human-like brain structure. The distribution, brain penetration of [99mTc]-DTPA and subsequent clearance were followed by brain SPECT for three hours after injection into the cisterna magna of anesthetized pigs and rats. To investigate the effects of anesthesia and across-species effects, we examine CSF dynamics under two types of anesthesia, propofol and ketamine/dexmedetomidine (K/D), and compare the outcome in pigs to that of rats, in which we also compared isoflurane. Propofol and K/D produced largely similar tracer distribution patterns across both pigs and rats: In both species, K/D was associated with higher tracer penetration into the dorsal striatum compared to propofol while neither species showed a tracer accumulation difference in the thalamus. K/D also increased intracranial radiotracer retention and reduced urinary tracer clearance in rats, but not in pigs. In rats, propofol and isoflurane showed similar tracer distribution, reflecting their shared GABAergic mechanism of action. The differences observed between pigs and rats may reflect species-specific physiology, differences in anesthesia dosing, or methodological factors. The work demonstrates the feasibility of using SPECT/CT to study CSF transport in the large gyrencephalic pig brain to advance understanding of human brain fluid dynamics.

Cognitive impairment is a debilitating feature of mood disorders (MD) linked to decreased neuroplasticity. Moderate hypoxia upregulates neuroplasticity and may improve cognition when combined with cognitive training. In this outcome assessor-blinded randomized controlled trial, we investigate the effects of three weeks of repeated hypoxia (12% O ₂ ) with concurrent cognitive training (H-CT) for 3.5 hours, 5-6 days per week compared with treatment as usual (TAU). Cognitively impaired individuals with remitted MD were randomized to H-CT or TAU and assessed at baseline, treatment completion, and one-month follow-up. The primary outcome was a broad cognitive composite measure. Additional cognitive, functioning, blood-based, and neuroimaging (SV2A as a presynaptic marker with [ ¹¹ C]UCB-J positron emission tomography (PET) and neural activity during working memory functional magnetic resonance imaging (fMRI)) outcomes were assessed. Sixty-four participants were randomized to H-CT ( n =34) or TAU ( n =30), and 26 H-CT and 29 TAU completed the intervention and assessments. There was no effect of H-CT on the primary outcome ( ps≥ 0.24) but H-CT induced improvements in the secondary executive function outcome (treatment effect=0.76, 95% CI=[0.23;1.28], adj. p =0.02) that prevailed at follow-up (treatment effect=1.07, 95% CI=[0.36;1.77], adj. p =0.02). Executive function improvement was accompanied by H-CT-related lower presynaptic [ ¹¹ C]UCB-J binding in the nucleus accumbens ( p =0.03). H-CT also produced sustained improvements in everyday functioning (adj. ps ≤0.049). No effects were observed on dorsolateral prefrontal cortex activity or real-life cognitive skills ( p s≥0.54). Two serious but treatment-unrelated adverse events occurred. In conclusion, H-CT produces robust effects on executive functions, but not broader cognition, in MD, and H-CT may thus be particularly promising for targeting executive dysfunction in this population.

Moderate hypoxia is increasingly recognized as a physiological driver of neuroprotection and neuroregeneration. In this first randomised, double-blind, controlled, four-arm trial, we demonstrate the cognitive and neuroplastic effects of cognitive training under moderate inspiratory hypoxia in humans. Healthy volunteers underwent three weeks of either cognitive or sham training under normobaric hypoxia (12% O ₂ ) or normoxia (20% O ₂ ) for 3.5 hours daily, six days per week. Participants were assessed at baseline, treatment completion, and one-month follow-up. The primary outcome was change in a broad cognitive composite score. Additional cognitive, blood-based, and neuroimaging outcomes were assessed, including measurement of the presynaptic protein SV2A with [ ¹¹ C]UCB-J positron emission tomography (PET) and neural activity through functional magnetic resonance imaging (fMRI). In total, 126 participants were randomised to hypoxia-cognitive training (H-CT: n =36), hypoxia-sham training (H-ST: n =30), normoxia- cognitive training (N-CT: n =30), or normoxia-sham training (N-ST: n =30). Intention-to-treat analyses showed no effect of H-CT relative to N-ST in the primary outcome at treatment completion (primary endpoint; treatment effect=0.11, 95% CI=[-0.06;0.28], p =0.19), but improvements emerged at follow-up (treatment effect=0.17, 95% CI=[0.01;0.34], p =0.04). N-CT induced transient improvement in the primary outcome at treatment completion (treatment effect=0.20, 95% CI=[0.02;0.38], p =0.03), which rendered non-significant at follow-up. Finally, H-ST showed no significant cognitive change relative to N-ST. Moderate hypoxia was safe and well-tolerated. Cognitive benefits were accompanied by decreased hippocampal presynaptic density measured with [ ¹¹ C]UCB-J PET. In conclusion, three weeks of H-CT can enhance cognition with associated effects on neuroplasticity, although with a delayed onset of effects on cognition.

In this study, we provide the first study to integrate molecular and functional neuroimaging during psychedelic drug effects in humans. Using simultaneous PET-MRI technology, we describe multiple brain actions of lysergic acid diethylamide (LSD) in healthy volunteers. We quantify the occupancy of LSD at cerebral serotonin 2A receptors and show that LSD increases global cerebral blood flow and internal carotid artery flow without affecting the diameter of the internal carotid artery, opposite effects to those observed following psilocybin. Functional connectivity analyses showed widespread decreases in global connectivity, particularly in visual networks, alongside increases in network-wise sample entropy and spatial complexity. We observed an anticlockwise hysteresis loop between plasma drug levels and subjective effects, suggesting atypical pharmacodynamic mechanisms. By establishing the dose-occupancy relation of LSD in humans, our findings provide critical insights for the clinical development of psychedelic compounds and demonstrate unique neurophysiological effects that distinguish LSD from related psychedelics. Our findings challenge the leading hypotheses of psychedelic brain-action, until now thought to be instrumental for therapeutic efficacy.

By brain imaging repositories (e.g., OpenNeuro (Markiewicz et al., 2021), PublicnEUro (Public nEUro, 2023)), data management tools (e.g., COINS (Landis et al., 2016), XNAT (Marcus et al., 2007)) and computational platforms (e.g. BrainLife (Hayashi S, 2023)). BIDS allows data to be shared much more efficiently, enables the development of automated data analysis pipelines, and improves reproducibility.

Synapses are fundamental to the function of the central nervous system and are implicated in a number of brain disorders. Despite their pivotal role, a comprehensive imaging resource detailing the distribution of synapses in the human brain has been lacking until now. Here, we employ high-resolution PET neuroimaging in healthy humans (17F/16M) to create a 3D atlas of the synaptic marker Synaptic Vesicle glycoprotein 2A (SV2A). Calibration to absolute density values (pmol/ml) was achieved by leveraging postmortem human brain autoradiography data. The atlas unveils distinctive cortical and subcortical gradients of synapse density that reflect functional topography and hierarchical order from core sensory to higher-order integrative areas—a distribution that diverges from SV2A mRNA patterns. Furthermore, we found a positive association between IQ and SV2A density in several higher-order cortical areas. This new resource will help advance our understanding of brain physiology and the pathogenesis of brain disorders, serving as a pivotal tool for future neuroscience research.