Thread by @ManojDoss

Although some have speculated that #psychedelics produce enduring enhancements of cognitive flexibility, here we finally show that psilocybin therapy enhances cognitive and neural flexibility in major depressive disorder. However, there's a caveat. 1/10
nature.com/articles/s4139…

As previously reported, depression was reduced (doi.org/10.1001/jamaps…; see variability in single subject data provided here), but also cognitive flexibility (measured as a 𝑑𝑒𝑐𝑟𝑒𝑎𝑠𝑒 in perseverative errors) was enhanced 1 week post-psilocybin therapy. 2/10

Similar to reductions in PCC glutamate 1 day post-ayahuasca (doi.org/10.1093%2Fijnp…) ACC glutamate was reduced 1 week post-psilocybin. We didn't see increased (static) functional connectivity between ACC and PCC but ACC-PCC dynamics of FC (neural flexibility) was increased. 3/10

This is where it starts to get weird. Changes in cognitive and neural flexibility were correlated, but the association was +. That is, the greater the increases in ACC-PCC dynamics, the greater the increases in perseverative errors (i.e., 𝑙𝑒𝑠𝑠 cognitive flexibility). 4/10

To get a better idea of what was going on, I trained a set of predictive models (s/o @monicarosenb). Similar to prior work, baseline (pre-psilocybin) neural flexibility (dynamics of functional connectivity, dFC) was good at predicting baseline cognitive flexibility. 5/10

Also consistent with prior work, of the predictive features (dFC edges) selected in these models, greater neural flexibility was associated with greater cognitive flexibility (i.e., the greater the dynamics, the less the perseverative errors). 6/10

From baseline FC, we could also predict 𝑐ℎ𝑎𝑛𝑔𝑒𝑠 in cognitive flexibility using dynamics. However, we also needed static FC, and the best performing model only required the ACC (a structure important to psychedelic effects and cognitive flexibility). 7/10

But the relationship between predictive features (dFC edges, specifically) and cognitive flexibility was completely flipped! That is, greater baseline neural flexibility was associated with 𝑙𝑒𝑠𝑠 improvements in cognitive flexibility. 8/10

What could be happening here? Perhaps an inverted U. Some neural flexibility might be needed to get out of a depressive rut (e.g., during psychotherapy), but too much neural flexibility might be less beneficial (e.g., not be great for attention, doi.org/10.1016%2Fj.ne…). 9/10

Much 💜 to @monicarosenb, @n_sepeda, @p_fi, @jimpekar, everyone not on Twitter, and especially @FredBarrettPhD for letting me do whatever I wanted to with these datasets. We could have salami sliced the hell out of these data, but together, they tell a much clearer story. 10/10