|Title / Titel||VISUAL EMOTION PROCESSING AND BRAIN RESTING STATE DURING AND AFTER NEUROCHEMICAL STIMULATION BY THE 5-HT2A AGONIST PSILOCYBIN: AN FMRI STUDY|
|Abstract (PDF, 14 KB)|
|Summary / Zusammenfassung||Although our knowledge on the effects of serotonergic psychedelics on emotion regulation and its relevance for the treatment of psychiatric disorders is very scant, two recent studies from our lab demonstrate that psilocybin has the ability to enhance mood and shift the processing of negative stimuli towards processing of positive stimuli in healthy human subjects (Schmidt et al. 2012, Kometer et al. 2012). Behavioral and neurophysiological evidence indicate that these emotional effects of psilocybin are primarily mediated via serotonin 5-HT2A receptor activation (Kometer et al. 2012), although a contribution of 5-HT1A or other subtypes of serotonin receptors may also be implicated (Blair et al. 2000, Sard et al. 2005, McKenna et al. 1990). Moreover, theoretical considerations and experimental findings suggest that psilocybin has glutamate and dopamine enhancing effects in neuronal circuitries that are critical for mood regulation (Vollenweider and Kometer 2010). Specifically, LSD and psilocybin increase glutamate concentration in medial prefrontal cortex in animals and activate prefrontal-limbic brain regions in healthy humans that were reported to show reduced extrasynaptic glutamate concentration and metabolic activity in patients with mood disorders (Vollenweider and Kometer 2010; Walter et al. 2008; Scheidegger et al. 2012). Furthermore, there is accumulating evidence that other glutamate modulating agents such as ketamine have rapid and sustained antidepressive properties, presumably via activation of brain-derived neurotropic factor (BDNF), which in turn, promotes synaptic plasticity (Autry et al. 2011). Given that 5-HT2A agonists such as LSD were also found to increase BDNF in rodents, it is conceivable that psilocybin may also have antidepressive properties and may thus shift the well established emotion processing bias observed in major depression (Disner et al. 2011). In support of this assumption, a recent double-blind, placebo-controlled study has shown that moderate doses of psilocybin improved mood and reduced anxiety for up to 6 months in terminal cancer patients (Grob et al. 2011). Although the effects of psilocybin on emotion regulation have not yet been studied in depression, a number of molecular targets and neuronal network functions have been identified that may be critical for the evaluation of the putative antidepressant effects of psilocybin (Krystal et al. 2009; Scheidegger et al. 2012).
In this study, we propose to use functional magnetic resonance imaging (fMRT) and spectroscopy (MRS), partially in combination with electroencephalographic brain mapping (EEG), to investigate the psychological and neuronal basis of psilocybin’s effect emotion regulation as well as its antidepressant potential in healthy human subjects and depressed patients.
Given the recent evidence that abnormal functional activation and network connectivity during emotional challenge is changed concomitantly with alterations in glutamatergic and serotonergic functions in depression, we aim to investigate
1) effective brain network connectivity within the emotion processing network and its modulation by psilocybin in healthy human subjects and patients with major depression (MMD) performing a face affect categorization and attention-emotion interaction task. To achieve this goal, fMRI and statistical parametric mapping (SPM) with dynamic causal modeling (DCM) will be applied (Friston 2006; Dima et al. 2011c; Dima et al. 2011c).
2) to get further inside into the role of 5-HT2A/1A receptor activation in mediating the subjective effects of psilocybin including visual and emotional alterations, the effect of the non-hallucinogenic 5-HT2A/1A agonist ergotamine shall be compared with the effect of hallucinogenic 5-HT2A/1A agonist psilocybin using fMRI and the same emotion categorization task as described under aim 1) above. Specifically, we aim to delineate whether the visionary and self/ego-altering effects of psilocybin are enabling and predisposing and thus necessary conditions for the overall clinical and particularly the emotional and antidepressant effects of psychedelics.
3) given the evidence that glutamate-modulating agents may exert acute and sustained antidepressant effects via large-scale changes in neuronal network plasticity, we aim to investigate functional brain connectivity within emotion, cognition and self processing networks and its acute and postacute modulation by psilocybin in healthy human subjects and patients with major depression in resting state during and after psilocybin administration (Scheidegger et al. 2012).
Putative changes in functional connectivity shall be related to putative changes in regional brain glutamate concentrations. To achieve this goal, 4) resting state fMRI and MRS, statistical parametric mapping (SPM) and MRS spectra analysis (LCModel) will be conducted to assess changes in functional network connectivity and glutamatergic metabolite concentrations in a set of predefined target regions (Friston 2006; Walter et al. 2009; Horn et al. 2010a).
5) Given that baseline prestimulus alpha-activity appears to be predictive for the extent of the electrophysiological response (e.g. visual induced ERP) and the subjective experience in psilocybin states, brain electrical activity will be simultaneously recorded with resting state fMRI using EEG technique (Kometer et al. 2011).
The aims of this study are twofold. First, we aim to delineate psychological and biological mechanisms that contribute to the psychedelic and emotional of effects psilocybin and which may mediate the putative antidepressant of psychedelics. Second, given the heterogeneity of the depressive syndrome, we aim to identify functional (bio)markers that may help to predict individual treatment responses and thus fostering more specific personalized treatments.
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Projektleitung und Kontakte
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|Duration of Project / Projektdauer||Dec 2012 to Mar 2015|