How Psychedelics Affect Neurovascular Function
Post by Shireen Parimoo
The takeaway
Psychedelics like psilocybin exert their hallucinogenic effects by acting on 5HT2A serotonin receptors in the brain, and fMRI has been used to measure how this is reflected in neuronal activity. This research shows that psychedelics affect not only neuronal activity but also vascular activity (i.e., blood vessel activity) in the brain in distinct ways, meaning both need to be considered when using fMRI.
What's the science?
Psychedelic compounds like psilocybin have seen a surge of interest in recent years due to their potential to treat mood and substance use disorders. Many psychedelics have hallucinogenic effects through their action on serotonin receptors (5HTRs) in the brain. These serotonin receptors are primarily located in brain areas associated with higher-order cognitive functions, such as the default-mode network regions, including the retrosplenial cortex. In humans, functional magnetic resonance imaging (fMRI) studies show that psychedelics reduce functional connectivity within DMN regions but increase connectivity between the DMN and other areas of the brain.
Functional MRI records the hemodynamic response that occurs following neural activity, but is not well-suited to differentiate between neural activity and vascular activity in the brain. Moreover, 5HTRs are located on both neurons that give rise to neural activity and astrocytes, which are involved in vascular coupling between neurons and blood vessels. Thus, it is presently unclear whether psychedelics exert their effects by modulating neural activity, vascular responses, or both. This week in Nature Neuroscience, Padawer-Curry and colleagues used optical imaging techniques to investigate the neurovascular origins of psychedelic-induced hemodynamic responses and functional connectivity in the brain.
How did they do it?
The authors performed wide-field optical imaging in mice during a whisker stimulation task and during rest. This technique can be used to measure both neural activity via calcium imaging and vascular or hemodynamic activity simultaneously. Mice were injected with either (i) 2,5-dimethoxy-4-iodoamphetamine (DOI), a hallucinogenic agonist of the 5HT2A receptor, (ii) MDL, a selective antagonist of 5HT2A receptors, (iii) DOI + MDL, (iv) saline, or (v) lisuride, a non-hallucinogenic 5HT2A receptor agonist. Notably, administering DOI and MDL together enabled them to determine whether the effects of psychedelics are specific to the 2A serotonin receptor, while administering lisuride helped determine whether these receptors were important for hallucinogenic as compared to non-hallucinogenic receptor activation.
To distinguish between vascular and neuronal origins of the HRF, they recorded changes in hemodynamic and neural activity in response to whisker stimulation (i.e., task) and at rest. Power spectral density (PSD) was used as a measure of neural and hemodynamic activity across different frequency bands. The authors examined PSD in the infraslow (0.01-0.08 Hz), intermediate (0.08 – 0.50 Hz), and the delta frequency bands (0.50 – 4.00 Hz), which helped distinguish the neural and hemodynamic responses at different timescales. Finally, resting-state functional connectivity between regions was calculated from the neuronal and hemodynamic responses to obtain measures of intra- and inter-network connectivity.
What did they find?
Administration of DOI altered hemodynamic and neuronal activity in a regionally specific manner. For instance, hemodynamic responses increased in regions like the somatosensory and auditory cortex. In contrast, neuronal activity in the retrosplenial cortex and somatosensory regions was reduced. The shape of the HRF following DOI was narrower, while simultaneous injection of MDL and DOI did not have this effect on the HRF, indicating that DOI disrupts neurovascular coupling through its effect on 5HT2A receptors.
There was a divergence in the effects of DOI on neuronal compared to hemodynamic activity across frequency bands. Specifically, global neuronal activity increased in the delta band but decreased in the intermediate frequency band following DOI injection. Global hemodynamic activity, on the other hand, only increased in the delta band. At a regional level, neuronal activity in the infraslow band increased in frontal and motor regions, while hemodynamic activity increased in somatosensory regions. In the intermediate frequency band, neuronal activity showed broad reductions but an increase in frontal and cingulate regions, whereas hemodynamic activity decreased in the frontal and cingulate cortex. In the delta band, both neuronal and hemodynamic activity increased in response to DOI, but in different regions.
Finally, DOI altered network-level organization as measured by neuronal responses. Across most of the cortex, DOI reduced intra-network connectivity and increased inter-network connectivity, while the cingulate cortex showed greater intra-network connectivity with the DMN. Conversely, hemodynamic-based network dynamics showed minimal connectivity changes in response to DOI. Interestingly, co-administration of MDL largely reversed the effects observed following DOI administration alone. This demonstrates that DOI acts specifically through the 5HT2A receptors and differentially disrupts vascular and neuronal processes in the brain.
What's the impact?
This study found that psychedelics disrupt both neuronal and vascular responses through their action on 5HT2A receptors in the brain, identifying a potential mechanism through which psychedelics induce changes in brain network connectivity. Importantly, this indicates that hemodynamic measures of brain activity – such as those measured using fMRI in humans – may be capturing signals other than neural activity in psychedelic states.
