Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the subacute impact of psilocybin on brain function in two clinical trials of ...depression. The first was an open-label trial of orally administered psilocybin (10 mg and 25 mg, 7 d apart) in patients with treatment-resistant depression. Functional magnetic resonance imaging (fMRI) was recorded at baseline and 1 d after the 25-mg dose. Beck's depression inventory was the primary outcome measure ( MR/J00460X/1 ). The second trial was a double-blind phase II randomized controlled trial comparing psilocybin therapy with escitalopram. Patients with major depressive disorder received either 2 × 25 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo ('psilocybin arm') or 2 × 1 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram (10-20 mg) ('escitalopram arm'). fMRI was recorded at baseline and 3 weeks after the second psilocybin dose ( NCT03429075 ). In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in fMRI brain network modularity, implying that psilocybin's antidepressant action may depend on a global increase in brain network integration. Network cartography analyses indicated that 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after psilocybin treatment. The antidepressant response to escitalopram was milder and no changes in brain network organization were observed. Consistent efficacy-related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: global increases in brain network integration.
The laws governing cannabis are evolving worldwide and associated with changing patterns of use. The main psychoactive drug in cannabis is Δ9-tetrahydrocannabinol (THC), a partial agonist at the ...endocannabinoid CB1 receptor. Acutely, cannabis and THC produce a range of effects on several neurocognitive and pharmacological systems. These include effects on executive, emotional, reward and memory processing via direct interactions with the endocannabinoid system and indirect effects on the glutamatergic, GABAergic and dopaminergic systems. Cannabidiol, a non-intoxicating cannabinoid found in some forms of cannabis, may offset some of these acute effects. Heavy repeated cannabis use, particularly during adolescence, has been associated with adverse effects on these systems, which increase the risk of mental illnesses including addiction and psychosis. Here, we provide a comprehensive state of the art review on the acute and chronic neuropsychopharmacology of cannabis by synthesizing the available neuroimaging research in humans. We describe the effects of drug exposure during development, implications for understanding psychosis and cannabis use disorder, and methodological considerations. Greater understanding of the precise mechanisms underlying the effects of cannabis may also give rise to new treatment targets.
Recent evidence indicates that psilocybin with psychological support may be effective for treating depression. Some studies have found that patients with depression show heightened amygdala responses ...to fearful faces and there is reliable evidence that treatment with SSRIs attenuates amygdala responses (Ma, 2015). We hypothesised that amygdala responses to emotional faces would be altered post-treatment with psilocybin. In this open-label study, 20 individuals diagnosed with moderate to severe, treatment-resistant depression, underwent two separate dosing sessions with psilocybin. Psychological support was provided before, during and after these sessions and 19 completed fMRI scans one week prior to the first session and one day after the second and last. Neutral, fearful and happy faces were presented in the scanner and analyses focused on the amygdala. Group results revealed rapid and enduring improvements in depressive symptoms post psilocybin. Increased responses to fearful and happy faces were observed in the right amygdala post-treatment, and right amygdala increases to fearful versus neutral faces were predictive of clinical improvements at 1-week. Psilocybin with psychological support was associated with increased amygdala responses to emotional stimuli, an opposite effect to previous findings with SSRIs. This suggests fundamental differences in these treatments’ therapeutic actions, with SSRIs mitigating negative emotions and psilocybin allowing patients to confront and work through them. Based on the present results, we propose that psilocybin with psychological support is a treatment approach that potentially revives emotional responsiveness in depression, enabling patients to reconnect with their emotions.
ISRCTN, number ISRCTN14426797.
This article is part of the Special Issue entitled ‘Psychedelics: New Doors, Altered Perceptions’.
•Psilocybin with psychological support was used successfully to treat depression.•Amygdala responses to fearful faces were increased one day after psilocybin session.•Increased amygdala responses predicted positive clinical outcomes.•Psilocybin assisted therapy treats depression by reviving emotional responsiveness.
Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood ...oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other 'psychedelics' yet were related to clinical outcomes. A 'reset' therapeutic mechanism is proposed.
Accelerated functional Magnetic Resonance Imaging (fMRI) with ‘multiband’ protocols is now relatively widespread. These protocols can be used to dramatically reduce the repetition time (TR) and ...produce a time-series sampled at a higher temporal resolution, which may produce benefits in the statistical methods typically used to analyse fMRI data. We tested the effects of higher temporal resolutions for fMRI on statistical outcome measures in a comprehensive manner on two different MRI scanner platforms. Spatial resolution was maintained at a constant of 3 mm isotropic voxels, and an in-plane acceleration factor of 2 was used for all experiments. Experiment 1 tested a range of acceleration factors (1-6) against a standard EPI protocol on a single composite task that mapped a number of basic sensory, motor, and cognitive networks. Experiment 2 compared the standard protocol with acceleration factors of 2 and 3 on both resting-state and two task paradigms (an N-back task, and faces/places task), with a number of different analysis approaches. Results from experiment 1 showed modest but relatively inconsistent effects of the higher sampling rate on statistical outcome measures. Experiment 2 showed strong benefits of the multiband protocols on results derived from resting-state data, but more varied effects on results from the task paradigms. Notably, the multiband protocols were superior when Multi-Voxel Pattern Analysis was used to interrogate the faces/places data, but showed less benefit in conventional General Linear Model analyses of the same data. In general, ROI-derived measures of statistical effects benefitted only modestly from higher sampling resolution, with greater effects seen when using a measure of the top range of statistical values. Across both experiments, results from the two scanner platforms were broadly comparable. The statistical benefits of high temporal resolution fMRI with multiband protocols may therefore depend on a number of factors, including the nature of the investigation (resting-state vs. task-based), the experimental design, the particular statistical outcome measure, and the type of analysis used.
•Comprehensive testing of high temporal-resolution fMRI using multiband sequences•Effects on statistical outcomes vary depending on experimental and analysis design•Resting-state fMRI showed the strongest benefits of higher temporal resolutions•Equivalent effects are seen on two different scanner platforms
An essential function of visual processing is to establish the position of the body in space and, in concert with the other sense systems, to monitor movement of the whole body, or “egomotion.” A key ...cue to egomotion is optic flow. For example, forward motion through the environment generates an expanding pattern of flow on the retina, and (with eyes fixed centrally) the direction of heading corresponds to the center of expansion 1. In macaques, visual cortical area MST is sensitive to optic-flow structure 2, 3, and it has been suggested that MST has a central role in the computation of heading 4. However, here we identify two areas of the human brain that represent visual cues to egomotion more directly than does MST. These areas respond strongly to a single optic-flow stimulus but become relatively unresponsive when the stimulus is surrounded with further flow patches and thereby made inconsistent with egomotion. One is putative area VIP in the anterior portion of the intraparietal sulcus. The other is a new visual area, which we refer to as cingulate sulcus visual area (CSv). Areas V1–V4 and MT respond about equally to both types of flow stimulus. MST has intermediate properties, responding well to multiple patches but with a modest preference for a single, egomotion-compatible patch. We suggest that MST is merely an intermediate processing stage for visual cues to egomotion and that such cues are more comprehensively encoded by VIP and CSv.
Distinguishing between meaningful and meaningless sensory information is fundamental to forming accurate representations of the world. Dopamine is thought to play a central role in processing the ...meaningful information content of observations, which motivates an agent to update their beliefs about the environment. However, direct evidence for dopamine’s role in human belief updating is lacking. We addressed this question in healthy volunteers who performed a model-based fMRI task designed to separate the neural processing of meaningful and meaningless sensory information. We modeled participant behavior using a normative Bayesian observer model and used the magnitude of the model-derived belief update following an observation to quantify its meaningful information content. We also acquired PET imaging measures of dopamine function in the same subjects. We show that the magnitude of belief updates about task structure (meaningful information), but not pure sensory surprise (meaningless information), are encoded in midbrain and ventral striatum activity. Using PET we show that the neural encoding of meaningful information is negatively related to dopamine-2/3 receptor availability in the midbrain and dexamphetamine-induced dopamine release capacity in the striatum. Trial-by-trial analysis of task performance indicated that subclinical paranoid ideation is negatively related to behavioral sensitivity to observations carrying meaningful information about the task structure. The findings provide direct evidence implicating dopamine in model-based belief updating in humans and have implications for understating the pathophysiology of psychotic disorders where dopamine function is disrupted.
ABSTRACT Background Depression, a condition commonly comorbid with multiple sclerosis (MS), is associated more generally with elevated inflammatory markers and hippocampal pathology. We hypothesized ...that neuroinflammation in the hippocampus is responsible for depression associated with MS. We characterized the relationship between depressive symptoms and hippocampal microglial activation in patients with MS using the 18-kDa translocator protein radioligand 18 FPBR111. To evaluate pathophysiologic mechanisms, we explored the relationships between hippocampal neuroinflammation, depressive symptoms, and hippocampal functional connectivities defined by resting-state functional magnetic resonance imaging. Methods The Beck Depression Inventory (BDI) was administered to 11 patients with MS and 22 healthy control subjects before scanning with positron emission tomography and functional magnetic resonance imaging. We tested for higher 18 FPBR111 uptake in the hippocampus of patients with MS relative to healthy control subjects and examined the correlations between 18 FPBR111 uptake, BDI scores, and hippocampal functional connectivities in the patients with MS. Results Patients with MS had an increased hippocampal 18 FPBR111 distribution volume ratio relative to healthy control subjects ( p = .024), and the hippocampal distribution volume ratio was strongly correlated with the BDI score in patients with MS ( r = .86, p = .006). Hippocampal functional connectivities to the subgenual cingulate and prefrontal and parietal regions correlated with BDI scores and 18 FPBR111 distribution volume ratio. Conclusions Our results provide evidence that hippocampal microglial activation in MS impairs the brain functional connectivities in regions contributing to maintenance of a normal affective state. Our results suggest a rationale for the responsiveness of depression in some patients with MS to effective control of brain neuroinflammation. Our findings also lend support to further investigation of the role of inflammatory processes in the pathogenesis of depression more generally.
Psychedelic-assisted psychotherapy with psilocybin is an emerging therapy with great promise for depression, and modern psychedelic therapy (PT) methods incorporate music as a key element. Music is ...an effective emotional/hedonic stimulus that could also be useful in assessing changes in emotional responsiveness following PT.
Brain responses to music were assessed before and after PT using functional Magnetic Resonance Imaging (fMRI) and ALFF (Amplitude of Low Frequency Fluctuations) analysis methods. Nineteen patients with treatment-resistant depression underwent two treatment sessions involving administration of psilocybin, with MRI data acquired one week prior and the day after completion of psilocybin dosing sessions.
Comparison of music-listening and resting-state scans revealed significantly greater ALFF in bilateral superior temporal cortex for the post-treatment music scan, and in the right ventral occipital lobe for the post-treatment resting-state scan. ROI analyses of these clusters revealed a significant effect of treatment in the superior temporal lobe for the music scan only. Voxelwise comparison of treatment effects showed relative increases for the music scan in the bilateral superior temporal lobes and supramarginal gyrus, and relative decreases in the medial frontal lobes for the resting-state scan. ALFF in these music-related clusters was significantly correlated with intensity of subjective effects felt during the dosing sessions.
Open-label trial. Relatively small sample size.
These data suggest an effect of PT on the brain's response to music, implying an elevated responsiveness to music after psilocybin therapy that was related to subjective drug effects felt during dosing.
•Psychedelic therapy is a promising new treatment for depression.•Music can be used to measure effects of psychedelic therapy.•Patients brain responses to music increased after therapy.•This increase was related to the drug effects experienced during the therapy.
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