The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity
Rainer Kraehenmann, André Schmidt, Karl Friston, Katrin H. Preller, Erich Seifritz, Franz X. Vollenweider
NeuroImage : Clinical, 2016, 11, 53–60
a b s t r a c t
Stimulation of serotonergic neurotransmission by psilocybin has been shown to shift emotional biases away from negative towards positive stimuli. We have recently shown that reduced amygdala activity during threat processing might underlie psilocybin’s effect on emotional processing. However, it is still not known whether psilocybin modulates bottom-up or top-down connectivity within the visual-limbic-prefrontal network underlying threat processing.We therefore analyzed our previous fMRI data using dynamic causal modeling and used Bayesian model selection to infer how psilocybin modulated effective connectivity within the visual–limbic–prefrontal network during threat processing. First, both placebo and psilocybin data were best explained by a model in which threat affect modulated bidirectional connections between the primary visual cortex, amygdala, and lateral prefrontal cortex. Second, psilocybin decreased the threat-induced modulation of top-down connectivity from the amygdala to primary visual cortex, speaking to a neural mechanism that might underlie putative shifts towards positive affect states after psilocybin administration. These findings may have important implications for the treatment of mood and anxiety disorders.
Keywords : Serotonin, Psilocybin, Depression, fMRI, Dynamic causal modeling
Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter within neural networks related to emotion processing. We have recently shown that 5-HT2A receptor activation by psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) attenuates amygdala activation in response to threat-related visual stimuli in healthy volunteers and that the reduction of amygdala blood oxygen level-dependent (BOLD) signal is related to psilocybin3s mood-enhancing effect (Kraehenmann et al., 2014). Here, we addressed the hypothesis that connectivity changes between the amygdala (AMG) and visual and prefrontal cortical (PFC) areas contribute to the observed effects of psilocybin on threat processing previously observed (Kraehenmann et al., 2014). This hypothesis is based on evidence showing that the processing of threat-related visual stimuli may be modulated via feedback connections from the amygdala to the visual cortex (Furl et al., 2013). Such top-down input from the amygdala to the visual cortex may be an important mechanismat the interface between emotion processing and visual perception—given that theamygdala has been implicated in tuning visual processing to allocate resources towards sensory processing of – and coordinating responses to – emotionally salient stimuli (Morris et al., 1998). Furthermore, processing of threat signals may be modulated via inhibitory feedback connections from the PFC to the AMG (Hahn et al., 2011; Aznar and Klein, 2013). Using DCM for fMRI, Sladky et al. (2015) recently analyzed the effects of the selective serotonin reuptake inhibitor (SSRI) (S)-citalopramonamygdala–PFC effective connectivity in healthy volunteers. They found that the PFC exhibited a down-regulatory effect on amygdala activation, and that this effect was significantly increased by the antidepressant (S)-citalopram.
Importantly, the inhibitory feedback fromthe PFC to the AMG has been found to be correlated with 5-HT2A receptor stimulation (Fisher et al., 2009). Therefore, it is conceivable that the psilocybin induced attenuation of amygdala activation (Kraehenmann et al., 2014) might be caused by increased inhibitory connectivity from the PFC to the AMG. Finally, given the abundance of feed-forward projections from visual input regions (e.g. primary visual cortex, V1) to the AMG (Pessoa and Adolphs, 2010) and from the AMG to the PFC (Volman et al., 2013), bottom-up connectivity changes may also contribute to psilocybin3s effects on threat processing.
To test these hypotheses,we analyzed the functionalmagnetic resonance imaging (fMRI) data of our previous study (Kraehenmann et al., 2014) using dynamic causal modeling (DCM) (Friston et al., 2003) and Bayesian model selection (BMS) (Stephan et al., 2009). DCMis a general framework for inferring hidden mechanisms at the neuronal level from measurements of brain activity such as fMRI. Recent studies have demonstrated its sensitivity to detect pharmacological manipulations in fMRI data (Grefkes et al., 2010; Schmidt et al., 2013b); in particular, after serotonergic stimulation (Volman et al., 2013). BMS is an essential aspect of DCM studies, as it can be used to test competing hypotheses (different DCMs) about the neuralmechanisms generating data.We applied DCM and BMS to address the following questions : First, which is the most likely mechanism underlying threat processing, (1) threatinduced modulation of bottom-up connectivity, (2) threat-induced modulation of top-down connections, or (3) modulation of both bottom-up and top-down connections by threat stimuli. Secondly, which of these mechanisms – changes in bottom-up or top-down connectivity – contributed to the psilocybin-induced reduction of AMG (Kraehenmann et al., 2014) and V1 activation (Schmidt et al., 2013a) in response to threat-related visual stimuli.