bioRxiv Preprint Server
April 28, 2025
Alexander D. Maitland, Nicholas R. Gonzalez, Donna Walther et al.
1 citation
preprint
A new automated method using open-source machine learning toolkits, DeepLabCut and SimBA, accurately quantifies the head twitch response (HTR) in mice from experimental videos. The approach, trained and validated on videos of C57BL/6J mice given various psychedelic drugs, performed best at 50% video resolution and 120 frames per second (precision 95.45%, recall 95.56%, F1 score 95.51%) and also worked well at lower frame rates. When applied to bufotenine, a tryptamine derivative, elevated HTRs occurred only after blocking serotonin 1A receptors (ED50 = 0.99 mg/kg, max counts = 24). HTR counts from the automated method strongly correlated with visual scoring and semi-automated software (r = 0.98–0.99). The method offers a modular, noninvasive, open-source alternative to existing techniques.
bioRxiv Preprint Server
February 10, 2025
Masih Rahmati, Flora Moujaes, Nina Purg Suljič et al.
1 citation
preprint
Working memory deficits in disorders like schizophrenia may stem from disrupted brain cell tuning. Using fMRI, researchers found that ketamine, which blocks NMDA receptors, broadens neural spatial tuning in healthy people, reducing the precision of brain responses across visual, parietal, and frontal areas and worsening spatial working memory accuracy. These tuning changes were more consistent across individuals and brain regions than overall activation changes and correlated with memory performance. The results link NMDA receptor disruption to altered brain circuit dynamics and memory impairment, offering a target for developing treatments.
bioRxiv Preprint Server
December 19, 2024
Evan Lewis-Healey, Carla Pallavicini, Federico Cavanna et al.
1 citation
preprint
A dose of the fast-acting psychedelic DMT rapidly reorganizes conscious experience and brain dynamics, but the link between neural complexity and subjective effects is weaker than previously thought. Nineteen participants received 20 mg or 40 mg of DMT in two sessions. The higher dose produced more extreme visual hallucinations and emotionally intense experiences. Contrary to earlier claims, Lempel-Ziv complexity—a measure of neural signal diversity—was the least strongly associated neural marker of the psychedelic state. The findings suggest the relationship between neural complexity and phenomenology during psychedelic experiences is less clear than originally hypothesized.
bioRxiv Preprint Server
December 12, 2024
Lauri V. Elsilä, Elina Nagaeva, Jari-Pekka Luukkonen et al.
1 citation
preprint
Psychedelic compounds like LSD are often considered non-addictive, but some patterns of use and subjective effects raise questions about their rewarding potential. This study tested whether LSD and a selective 5-HT2A agonist (25CN-NBOH) produce rewarding effects in mice using conditioned place preference and measured changes in synaptic plasticity in dopamine neurons of the ventral tegmental area. No reliable place preference was found for either drug, supporting the idea that psychedelics have at most weak reinforcing effects. However, single doses, especially of LSD, induced synaptic plasticity in medial VTA dopamine neurons, suggesting the midbrain dopamine system may still play a role in their effects.
bioRxiv Preprint Server
December 9, 2024
Clayton R. Coleman, Kenneth Shinozuka, Robert Tromm et al.
1 citation
preprint
Lysergic acid diethylamide (LSD) alters consciousness by affecting brain connectivity, particularly in the dorsolateral prefrontal cortex (DLPFC). Using fMRI and MEG data from healthy participants, the study found that ego dissolution—a hallmark of the psychedelic experience—was positively correlated with increased functional connectivity between the left and right DLPFC, thalamus, and fusiform face area. Emotional arousal was linked to stronger connectivity between the right DLPFC, intraparietal sulcus, and salience network. A confirmatory analysis supported these findings. MEG data showed that LSD increased directed information flow from the thalamus to the DLPFC in the theta band, suggesting disrupted thalamic gating contributes to ego dissolution. These results indicate a key role for the DLPFC in LSD-induced states of consciousness.
bioRxiv Preprint Server
October 25, 2024
Tommaso Bertoni, Giulia Ricci, Jane Jöhr et al.
1 citation
preprint
Conscious experience includes not only awareness of external objects but also a sense of the embodied self, which relies on integrating multisensory stimuli near the body, a process involving the Peripersonal Space (PPS) system. Using high-density EEG in awake participants, a neural marker of PPS—high-beta oscillations in centroparietal regions during audiotactile integration near versus far from the body—was identified. This marker persisted during dreaming and waking conscious states but was absent during dreamless, unconscious states. In patients with disorders of consciousness, the same index predicted behavioral measures of consciousness and clinical outcome, suggesting that multisensory integration within PPS is tightly linked to conscious experience.
bioRxiv Preprint Server
August 7, 2024
Yana Vella, Kateřina Syrová, Aneta Petrušková et al.
1 citation
preprint
Psychedelics can produce rapid and lasting antidepressant effects, likely through neuroplasticity, though the precise molecular mechanisms are not yet understood.
bioRxiv Preprint Server
June 2, 2024
Francesca Siclari
1 citation
preprint
Non-REM parasomnias like sleepwalking are not uniformly unconscious or automatic. Interviews with 35 adult patients revealed a graded spectrum of consciousness during episodes. While 36% of patients frequently or always experienced minimal consciousness with automatic behaviors, 65% reported preserved conscious experiences with delusional thinking, often about impending danger. Hallucinations occurred in 53%, impaired insight in 77%, negative emotions in 75%, and pronounced amnesia in 30%. Patients described the state as 'awake dreaming,' where surroundings were either realistically perceived, misinterpreted, or entirely hallucinated. The findings indicate that consciousness and sensory disconnection in these disorders are variable and can resemble dreaming, offering a model for studying consciousness and sleep-related sensory disconnection.
bioRxiv Preprint Server
May 10, 2024
Christina Maher, Lea Tortolero, Daniel D. Cummins et al.
1 citation
preprint
Loving-kindness meditation (LKM) increases gamma power and alters the duration of beta and gamma oscillatory bursts in the amygdala and hippocampus of first-time meditators. These changes were specific to periodic features of neural activity, not aperiodic ones. The findings reveal how LKM modulates limbic brain activity, offering insight into the neural basis of meditation's effects on emotional regulation and well-being.
bioRxiv Preprint Server
January 30, 2024
Marcelo N. Costa, Livia Goto-Silva, Juliana M. Nascimento et al.
1 citation
preprint
Proteomic analysis of human cerebral organoids reveals that lysergic acid diethylamide (LSD) alters proteins involved in proteostasis, energy metabolism, and neuroplasticity-related pathways. LSD exposure changed protein synthesis, folding, autophagy, and proteasomal degradation, suggesting complex regulation of neural cell function. It also modulated glycolysis and oxidative phosphorylation, which are crucial for cellular energy management and synaptic function. Complementary experiments showed LSD enhanced neurite outgrowth in vitro, confirming its impact on neuroplasticity. These findings provide insight into molecular mechanisms through which LSD may affect neuroplasticity and potentially contribute to therapeutic effects for neuropsychiatric disorders.
bioRxiv Preprint Server
December 17, 2023
Abdelmoneim Eshra, Noa Lipstein, Stefan Hallermann
1 citation
preprint
Ketamine rapidly and persistently increases glutamate release from presynaptic terminals in a cerebellar synapse, an effect that lasts more than 30 minutes after the drug is removed. This enhancement results from increased calcium influx and a greater number of vesicles ready for release. Another NMDAR blocker, MK-801, did not affect glutamate release, indicating a mechanism distinct from postsynaptic NMDAR blockade. The findings reveal a rapid presynaptic action of ketamine that may inform the development of faster-acting antidepressants.
bioRxiv Preprint Server
August 8, 2023
Ruixiang Wang, Zeru Peterson, Nagalakshmi Balasubramanian et al.
1 citation
preprint
Social deficits in schizophrenia may stem from underactivity in a specific brain region called the lateral septum (LS). In mice given chronic ketamine to model schizophrenia-like symptoms, the LS showed reduced activation during social encounters. Artificially stimulating the LS restored normal social behavior, while silencing it in healthy mice caused social impairments. Genetic analysis of LS neurons revealed dysregulation of genes linked to neuronal excitability and cell death, with 38 genes overlapping those implicated in human schizophrenia. Activating LS neurons triggered activity in brain areas involved in reward, fear, and sensory processing. The findings suggest the LS acts as a central hub for social behavior, and its dysfunction may underlie social challenges in schizophrenia, pointing to potential targets for new therapies.
bioRxiv Preprint Server
July 27, 2023
Paulina Clara Dagnino, Javier A. Galadí, Estela Càmara et al.
1 citation
preprint
Meditation produces distinct whole-brain dynamics compared to rest, particularly in the triple-network model (executive control, salience, and default-mode networks). Using a causal mechanistic framework, researchers defined probabilistic metastable substates from dynamic brain patterns and adjusted a whole-brain model of the resting state to simulate transitions to meditation. They successfully induced the meditative state through localized artificial perturbations, primarily shifting areas in the somatomotor and dorsal attention networks. The work suggests meditation can be studied as a practice for health and as a potential therapy for brain disorders.
bioRxiv Preprint Server
June 3, 2023
Yue Hu, Wenjie Du, Jiangtao Qi et al.
1 citation
preprint
Ketamine and isoflurane, two common general anesthetics, produce unconsciousness through different brain mechanisms. Ketamine activates many cortical and subcortical regions involved in sensory, motor, emotional, and reward processing, with the temporal association areas acting as a strong hub, suggesting a top-down mechanism affecting consciousness by targeting higher-order cortical networks. Isoflurane predominantly influences hypothalamic regions controlling neuroendocrine, autonomic, and homeostatic functions, with the locus coeruleus as a connector hub, indicating a bottom-up mechanism. Both anesthetics also share effects on sensory, memory, reward, and autonomic pathways.
bioRxiv Preprint Server
December 29, 2022
Marc Duque, Alex B. Chen, Eric Hsu et al.
1 citation
preprint
Ketamine, a mood-altering compound, suppresses passivity induced by futility in larval zebrafish, similar to effects in rodent learned helplessness models. Brain-wide imaging in behaving zebrafish shows ketamine elevates intracellular calcium in astroglia for many minutes, followed by persistent calcium downregulation after washout. This calcium elevation depends on astroglial α1-adrenergic receptors and is required for suppression of passivity. Chemo- and optogenetic experiments show that the aftereffects of glial calcium elevation are sufficient to suppress passivity by inhibiting neuronal-astroglial integration of behavioral futility. Imaging in mouse cortex reveals ketamine elevates astroglial calcium through conserved pathways, suggesting ketamine exerts its behavioral effects by persistently modulating evolutionarily ancient neuromodulatory systems spanning neurons and astroglia.
bioRxiv Preprint Server
February 14, 2022
Tudor M. Ionescu, Mario Amend, Tadashi Watabe et al.
1 citation
preprint
MDMA, a psychedelic compound being tested for treating post-traumatic stress disorder, inhibits brain activity rather than exciting it, according to fMRI studies. However, interpreting these hemodynamic changes is complicated by MDMA's potent vascular effects. This study used simultaneous PET/fMRI in rats to relate BOLD-fMRI hemodynamic changes to glucose utilization and serotonin transporter occupancy measured by [18F]FDG fPET and [11C]DASB PET. The findings help clarify how MDMA affects brain function, challenging earlier assumptions of mainly excitatory effects.
bioRxiv Preprint Server
January 25, 2022
Erika Vazquez Juarez, Ipsit Srivastava, Maria Lindskog
1 citation
preprint
Mistuning of synaptic transmission may contribute to psychiatric disorders. Inhibiting glutamate transporters in hippocampal slices caused synaptic retuning, reducing synaptic strength and lowering the threshold for long-term potentiation (LTP). A rat model of depression with decreased glutamate transporters also showed a reduced LTP threshold. The antidepressant ketamine counteracted the effects of increased glutamate on synaptic retuning, suggesting its mechanism of action is restoring adequate synaptic tuning.
bioRxiv Preprint Server
May 26, 2021
Grace N Jang, M Bruce MacIver
1 citation
preprint
Ketamine, a fast-acting and long-lasting antidepressant, alters brain cell activity at the synaptic, neuronal, and circuit levels. Its antidepressant effects involve interactions with key brain receptors, specifically N-methyl-D-aspartate (NMDA) receptors, though the exact cellular mechanisms remain unclear. This study examined how ketamine changes the excitability of individual neurons and networks, and the duration of these effects, to better understand the therapeutic mechanism behind its rapid and lasting antidepressant benefits.
bioRxiv Preprint Server
January 5, 2021
Beatrice M. Jobst, Selen Atasoy, Adrián Ponce-Alvarez et al.
1 citation
preprint
LSD alters brain dynamics by shifting the brain's global working point further from a stable equilibrium, as shown by consistently higher Perturbational Integration Latency Index (PILI) values after intake. Using a whole-brain computational model perturbed in silico, the largest differences were found in the limbic, visual, and default mode networks. Greater variability of PILI values across brain regions under LSD indicates higher response diversity to external perturbations. These findings provide insights into the brain-wide dynamical changes underlying the psychedelic state and suggest possible clinical applications for psychiatric disorders.
bioRxiv Preprint Server
May 26, 2020
Roberto De Filippo, Benjamin R. Rost, Alexander Stumpf et al.
1 citation
preprint
Serotonin (5-HT) is a key neuromodulator in the mammalian brain, but how it affects synchronized cortical network activity is not fully understood. This work shows that MDMA and fenfluramine, two drugs that release 5-HT, inhibit slow oscillations—a default cortical activity pattern—in the entorhinal cortex of anesthetized mice. The suppression occurs through activation of somatostatin-expressing interneurons via the 5-HT2A receptor. Because 5-HT2A receptor signaling is implicated in psychiatric disorders and mediates effects of serotonergic drugs, this link between these interneurons and serotonin may help clarify these complex topics.
bioRxiv Preprint Server
February 23, 2020
X. Zhao, K. T. Meyers, A. Mcbride et al.
1 citation
preprint
Sleep deprivation for 6-8 hours increases serotonin 2A receptors (5-HT2ARs) in the frontal cortex of mice. This upregulation requires the transcription factor early growth response 3 (Egr3), which binds directly to the Htr2a gene's promoter. The finding suggests a mechanism by which environmental stimuli can rapidly alter levels of a brain receptor involved in the effects of hallucinogenic drugs, antipsychotic medications, and schizophrenia.
bioRxiv Preprint Server
January 22, 2020
Greer McKendrick, Hannah Garrett, Holly E. Jones et al.
1 citation
preprint
Mice conditioned with morphine showed anxiety-like behavior (less time in the open arms of an elevated plus maze) and robust conditioned place preference (CPP) for morphine. A single dose of (R,S)-ketamine given before testing increased open-arm time in both morphine- and saline-conditioned mice. A second ketamine injection before CPP tests blocked morphine-induced CPP, an effect lasting up to 28 days. Sucrose conditioning did not evoke anxiety but produced CPP, which ketamine also attenuated. These results suggest ketamine's blockade of morphine CPP may stem from impairing drug-context memory rather than solely reducing negative affective states.
bioRxiv Preprint Server
May 1, 2019
Paul Dennison
1 citation
preprint
The neural correlates of consciousness (NCC) are often studied via task-based experiments, but these recruit one part of the cortical network to investigate another, limiting what they reveal about consciousness itself. The form of consciousness explored in such research is termed the human default consciousness (DCs), everyday waking consciousness. In contrast, states like anaesthesia, coma, deep sleep, or epilepsy show different cortical activity and are involuntary or unconscious. An exception is Buddhist jhāna meditation, which intentionally withdraws from default consciousness to an inward-directed stillness called jhāna consciousness. Default consciousness is sensorily-based, evaluating outer-world information against personal needs, aligning with Buddhist models and active inference theories minimizing free energy.
bioRxiv Preprint Server
April 4, 2019
Bernd Porr, Alex Trew, Alice Miller
1 citation
preprint
A computational model of the limbic system compares two pharmacological approaches to treating depression: SSRIs, which increase serotonin accumulation, and psychedelics, which stimulate excitatory serotonin receptors. The model simulates a delayed reward paradigm disrupted by low serotonin. Low serotonin allows small signals to pass through decision-making neurons, while high serotonin blocks smaller signals but amplifies larger ones. Behavioral simulations and model checking show SSRIs perform significantly better than psychedelics in this paradigm. However, psychedelics might be more effective in situations where high exploration is beneficial for obtaining rewards.
bioRxiv Preprint Server
April 16, 2018
Eric Edsinger, Gül Dölen
1 citation
preprint
MDMA, also known as ecstasy, increases social behavior in octopuses, despite over 500 million years of evolutionary separation from humans. Octopuses are typically solitary, but when given MDMA, they spent more time in close contact with other octopuses. This effect is linked to a shared serotonin transporter protein, which has a binding site for MDMA that is evolutionarily conserved in the octopus genome. The findings suggest that the neural systems underlying social behavior, particularly those involving serotonin, are ancient and have been preserved across diverse animal lineages.