Psilocybin induces sustained alterations in cortical and hippocampal dynamics
Poster No:
1665
Submission Type:
Abstract Submission
Authors:
Nikitas Koussis1, Richa Phogat1, Joshua Siegel2, T. Rick Reneau3, Nico Dosenbach3, Michael Breakspear1
Institutions:
1University of Newcastle, New Lambton Heights, NSW, 2New York University, New York, NY, 3Washington University, St Louis, MO
First Author:
Co-Author(s):
Introduction:
The psychedelic compound psilocybin has garnered significant interest for its profound effects on brain function and its potential therapeutic applications. Recent findings have heavily indicated the role of the hippocampus and its interaction with the cerebral cortex in the effect that psilocybin has on brain activity (Siegel et al., 2024). This study investigated the impact of the drug on the spatiotemporal dynamics of the cortex and hippocampus using a geometric eigenmode approach, where the spatiotemporal activity was described in terms of its geometry. These modes are linked to neural field theory equations and therefore are immediately informative about the excitability of the system, i.e., the brain in response to the drug.
Methods:
Seven (7) healthy volunteers with a previous psychedelic experience underwent psilocybin (PSIL) and methylphenidate (MTP) administration in a randomized cross-over design. This design consisted of: (1) three baseline scans; (2) drug 1 session (either PSIL or MTP), (3) one between scan for 3 weeks; (4) drug 2 session (PSIL/MTP, whichever wasn't administered at session 2), and (5) one between scan for 3 weeks. Each scanning session consisted of structural T1 and T2 weighted MRI and resting-state multi-echo (5-echo) multi-band fMRI at 2 mm isotropic resolution and 1.4 s TR. After preprocessing and nonlinear registration to the MNI152 template, fMRI scans were projected to the fsLR32k surface and decomposed with a general linear model (Fig. 1) into geometric eigenmode coefficients (Pang et al., 2023). Every volume of fMRI was decomposed independently, producing a timeseries of modal coefficients for each mode for each condition.
Results:
Brain activity of rs-fMRI during psilocybin is characterized by a drastic shift to shorter wavelength eigenmodes (higher spatial frequencies). Compared to normal brain activity, the characteristic spatial wavelengths of psilocybin activity were significantly higher in modes with wavelengths shorter than 50 mm rather than lower-order modes at 50 mm (r = -0.65, p < 0.001, d.f. = 248). In the same analysis, hippocampus modal coefficients show a similar pattern to cortex. Higher-order modes are significantly associated with higher power in PSIL (r = -.38, p = 0.013, d.f. = 48). Just as the cortex, this shift is reflected in the projection of the PSIL significant coefficients onto their modes in the hippocampus.
The use of eigenmodes in the brain extends their spatiotemporal nature across surfaces, mapping modes on one surface to another via coupling (Robinson et al., 2016). For each modal timeseries on the cortex we correlate every modal timeseries on the hippocampus. This results in cross-correlation matrices T of dimensions (250x50) (Fig. 2a-e). Mode coupling is minimal at baseline (Fig. 2a: T ̅_BASE= 0.0226±0.0002; note (±) pertains to standard error of the mean), increasing in psilocybin (Fig. 2b: T ̅_PSIL= 0.0401±0.0012). This effect is sustained in follow-up sessions (Fig. 2c-e: T ̅_POST1= 0.0361±0.0005; T ̅_POST2= 0.0397±0.0008; T ̅_POST3= 0.0361±0.0005). Repeated measures ANOVAs indicated a significant increase in mode coupling in PSIL and post-PSIL sessions at long wavelengths (>50 mm; Fig. 2f: F=982.282, p<<0.001, d.f.=24) and short wavelengths (<50 mm; Fig. 2g: F=256.184, p<<0.001, d.f.=24).
The use of eigenmodes in the brain extends their spatiotemporal nature across surfaces, mapping modes on one surface to another via coupling (Robinson et al., 2016). For each modal timeseries on the cortex we correlate every modal timeseries on the hippocampus. This results in cross-correlation matrices T of dimensions (250x50) (Fig. 2a-e). Mode coupling is minimal at baseline (Fig. 2a: T ̅_BASE= 0.0226±0.0002; note (±) pertains to standard error of the mean), increasing in psilocybin (Fig. 2b: T ̅_PSIL= 0.0401±0.0012). This effect is sustained in follow-up sessions (Fig. 2c-e: T ̅_POST1= 0.0361±0.0005; T ̅_POST2= 0.0397±0.0008; T ̅_POST3= 0.0361±0.0005). Repeated measures ANOVAs indicated a significant increase in mode coupling in PSIL and post-PSIL sessions at long wavelengths (>50 mm; Fig. 2f: F=982.282, p<<0.001, d.f.=24) and short wavelengths (<50 mm; Fig. 2g: F=256.184, p<<0.001, d.f.=24).
Conclusions:
We identified that resting fMRI activity is shifted to higher spatial frequencies and shorter timescales, and this effect lasts for several days to weeks. These spatiotemporal phenomena suggest a sustained psilocybin-based imbalance of excitation and inhibition in the brain. Validation of these findings in clinical studies is needed to further understand its putative mechanisms for treatment of depression and other disorders.
Modeling and Analysis Methods:
Task-Independent and Resting-State Analysis 1
Perception, Attention and Motor Behavior:
Perception and Attention Other 2
Keywords:
Other - Psilocybin; Serotonin; Cortico-subcortical interactions;
1|2Indicates the priority used for review
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Healthy subjects only or patients (note that patient studies may also involve healthy subjects):
Was this research conducted in the United States?
Were any human subjects research approved by the relevant Institutional Review Board or ethics panel? NOTE: Any human subjects studies without IRB approval will be automatically rejected.
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Provide references using APA citation style.
Pang, J. C. et al. Geometric constraints on human brain function. Nature 618, 566–574 (2023).
Robinson, P. A. et al. Eigenmodes of brain activity: Neural field theory predictions and comparison with experiment. NeuroImage 142, 79–98 (2016).