Psychedelics disrupt hierarchical propagations in the default mode network of humans and mice
Poster No:
2123
Submission Type:
Abstract Submission
Authors:
Adam Pines1, Xue Zhang1, John Kochalka2, Sam Vesuna1, Isaac Kauvar2, Divya Rajasekharan1, T. Rick Reneau3, Teddy Akiki1, Laura Hack1, Joshua Siegel4, Leanne Williams1
Institutions:
1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, 2Department of Bioengineering, Stanford University, Stanford, CA, 3Washington University, St Louis, MO, 4New York University, New York, NY
First Author:
Adam Pines, PhD
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Co-Author(s):
Xue Zhang, PhD
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Sam Vesuna
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Divya Rajasekharan, BS
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Teddy Akiki, MD, PhD
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Laura Hack, MD, PhD
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Leanne Williams
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Introduction:
The hierarchical organization of the cortex affords bottom-up sensory integration and top-down control (Mesulam, 1998; Siegle et al., 2021). Bottom-up hierarchical processing definitionally requires activity propagating through space from lower- to higher-order areas. However, studies of hierarchical processing near-ubiquitously quantify activity fluctuations in fixed regions over time rather than propagations over space. This gap is crucial for studies of psychedelics, as leading but opposed theories posit that psychedelics either broadly increase (Carhart-Harris & Friston, 2019; Gattuso et al., 2023) or decrease (Corlett et al., 2019; Shine et al., 2022) bottom-up activity movement into higher-order cortical networks, principally the Default Mode Network (DMN). We sought to resolve this incongruence with computer vision and three high-quality psychedelic datasets across two species and imaging modalities, as well as six control conditions (Zhang et al. 2024; Siegel et al., 2024; Vesuna et al., 2020).
Methods:
fMRI scans were used for humans (MDMA, PSIL), whereas widefield calcium imaging was utilized in mice (LSD). Control comparisons for human data included baseline scans, inert placebos, and methylphenidate as an active placebo. Comparisons for mouse data included pre/post-drug scans, as well as two active controls: diazepam and dexmedetomidine. Drug versus no-drug comparisons were also available across all datasets.
After quality control, we retained 169 scans from study 1 (MDMA), 226 scans from study 2 (PSIL) and 80 scans from study 3 (LSD). We used optical flow to delineate the movement of activity and regularized non-negative matrix factorization to delineate the DMN in humans as prior and in mice separately. For analysis of activity movement directionality, the gradient of the DMN (∇) was used as a reference direction for hierarchical ascent (bottom-up) over space. Procedures were approved by their respective regulatory bodies.
After quality control, we retained 169 scans from study 1 (MDMA), 226 scans from study 2 (PSIL) and 80 scans from study 3 (LSD). We used optical flow to delineate the movement of activity and regularized non-negative matrix factorization to delineate the DMN in humans as prior and in mice separately. For analysis of activity movement directionality, the gradient of the DMN (∇) was used as a reference direction for hierarchical ascent (bottom-up) over space. Procedures were approved by their respective regulatory bodies.
Results:
The magnitude of optical flow vectors captures the degree of signal displacement from frame-to-frame (Fig. 1a). Aggregate activity movement in the DMN was lower in MDMA as compared to all control conditions (Fig. 1b, 1c, 1d, 1e). This effect replicated in the PSIL dataset in all comparisons (Fig. 1f, 1g, 1h, 1i). DMN propagation magnitudes also decreased in LSD administration in mice across all comparisons (Fig. 1j, 1m, 1k, 1l, 1n, 1o).
The percentage of bottom-up propagations represents the balance of bottom-up versus top-down moving activity on the cortical mantle (Fig. 2a). Bottom-up propagations in the DMN were attenuated in MDMA as compared to all control conditions (Fig. 2b, 2c, 2d, 2e). This effect replicated in the PSIL dataset in all comparisons (Fig. 2f, 2g, 2h, 2i). Bottom-up propagations in the DMN also broadly decreased in LSD administration in mice across all comparisons (Fig. 2j, 2m, 2k, 2l, 2n, 2o).
The impact of psychedelics on propagations was not attributable to in-scanner head motion or previously-established functional neuroimaging measures.
Bottom-up propagation prominence uniquely captured negative valence in self-report within drug sessions, correlating with reported Dread of Ego Dissolution (r. = 0.72, pFDR = 0.004) and Impaired Control (r = 0.71, pFDR = 0.004) and surviving correction for multiple comparisons across all DMN measurements.
The percentage of bottom-up propagations represents the balance of bottom-up versus top-down moving activity on the cortical mantle (Fig. 2a). Bottom-up propagations in the DMN were attenuated in MDMA as compared to all control conditions (Fig. 2b, 2c, 2d, 2e). This effect replicated in the PSIL dataset in all comparisons (Fig. 2f, 2g, 2h, 2i). Bottom-up propagations in the DMN also broadly decreased in LSD administration in mice across all comparisons (Fig. 2j, 2m, 2k, 2l, 2n, 2o).
The impact of psychedelics on propagations was not attributable to in-scanner head motion or previously-established functional neuroimaging measures.
Bottom-up propagation prominence uniquely captured negative valence in self-report within drug sessions, correlating with reported Dread of Ego Dissolution (r. = 0.72, pFDR = 0.004) and Impaired Control (r = 0.71, pFDR = 0.004) and surviving correction for multiple comparisons across all DMN measurements.
·Figure 1: Psychedelics attenuate the magnitude of cortical propagations within the Default Mode Network (DMN)
·Figure 2: Psychedelics attenuate bottom-up cortical propagations within the Default Mode Network (DMN)
Conclusions:
Psychedelics reduce the prominence of cortical propagations within the DMN broadly and hierarchically ascending propagations specifically. These results replicated across different psychedelics, drug-contrast approaches, species, and imaging modalities. Reductions in bottom-up propagations were associated with impaired control and dread of ego dissolution within psychedelic sessions. These results suggest that psychedelics disrupt the procession of activity along the cortical sheet in a potentially anxiogenic fashion and offer strong support for theories positing attenuation of bottom-up cortical activity in the psychedelic state.
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Anatomy and Functional Systems
Novel Imaging Acquisition Methods:
BOLD fMRI
Multi-Modal Imaging 2
Imaging Methods Other
Physiology, Metabolism and Neurotransmission:
Pharmacology and Neurotransmission 1
Keywords:
ADULTS
Anxiety
Computational Neuroscience
Cortex
Cross-Species Homologues
Data analysis
FUNCTIONAL MRI
OPTICAL
Pharmacotherapy
Other - Psychedelics
1|2Indicates the priority used for review
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Corlett, P. R. et al., (2019). Hallucinations and Strong Priors. Trends in Cognitive Sciences, 23(2), 114–127. https://doi.org/10.1016/j.tics.2018.12.001
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Zhang, X., et al., (2024). Negative affect circuit subtypes predict acute neural, behavioral, and affective responses to MDMA: a randomized trial.