Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life.

BACKGROUND: COMP360 is a proprietary, synthetic formulation of psilocybin being developed for treatment-resistant depression (TRD), a burdensome, life-threatening illness with high global impact. Here, we expand upon the previous report of primary outcomes from a phase 2 study of COMP360 in individuals with TRD-the largest randomised controlled clinical trial of psilocybin-to discuss findings of the exploratory efficacy endpoints. METHODS: In this phase 2, double-blind trial, 233 participants with TRD were randomised to receive a single dose of psilocybin 25 mg, 10 mg, or 1 mg (control), administered alongside psychological support from trained therapists. Efficacy measures assessed patient-reported depression severity, anxiety, positive and negative affect, functioning and associated disability, quality of life, and cognitive function. RESULTS: At Week 3, psilocybin 25 mg, compared with 1 mg, was associated with greater improvements from Baseline total scores in all measures. The 10 mg dose produced smaller effects across these measures. LIMITATIONS: Interpretation of this trial is limited by the absence of an active comparator and the possibility of functional unblinding in participants who received a low dose of psilocybin. CONCLUSIONS: Three weeks after dosing, psilocybin 25 mg and, to a lesser degree, 10 mg improved measures of patient-reported depression severity, anxiety, affect, and functioning. These results extend the primary findings from the largest randomised clinical trial of psilocybin for TRD to examine other outcomes that are of importance to patients.

Sensory-motor integration during speech production localizes to both left and right plana temporale.

Speech production relies on fine voluntary motor control of respiration, phonation, and articulation. The cortical initiation of complex sequences of coordinated movements is thought to result in parallel outputs, one directed toward motor neurons while the "efference copy" projects to auditory and somatosensory fields. It is proposed that the latter encodes the expected sensory consequences of speech and compares expected with actual postarticulatory sensory feedback. Previous functional neuroimaging evidence has indicated that the cortical target for the merging of feedforward motor and feedback sensory signals is left-lateralized and lies at the junction of the supratemporal plane with the parietal operculum, located mainly in the posterior half of the planum temporale (PT). The design of these studies required participants to imagine speaking or generating nonverbal vocalizations in response to external stimuli. The resulting assumption is that verbal and nonverbal vocal motor imagery activates neural systems that integrate the sensory-motor consequences of speech, even in the absence of primary motor cortical activity or sensory feedback. The present human functional magnetic resonance imaging study used univariate and multivariate analyses to investigate both overt and covert (internally generated) propositional and nonpropositional speech (noun definition and counting, respectively). Activity in response to overt, but not covert, speech was present in bilateral anterior PT, with no increased activity observed in posterior PT or parietal opercula for either speech type. On this evidence, the response of the left and right anterior PTs better fulfills the criteria for sensory target and state maps during overt speech production.

Parallel systems in the control of speech.

Modern neuroimaging techniques have advanced our understanding of the distributed anatomy of speech production, beyond that inferred from clinico-pathological correlations. However, much remains unknown about functional interactions between anatomically distinct components of this speech production network. One reason for this is the need to separate spatially overlapping neural signals supporting diverse cortical functions. We took three separate human functional magnetic resonance imaging (fMRI) datasets (two speech production, one "rest"). In each we decomposed the neural activity within the left posterior perisylvian speech region into discrete components. This decomposition robustly identified two overlapping spatio-temporal components, one centered on the left posterior superior temporal gyrus (pSTG), the other on the adjacent ventral anterior parietal lobe (vAPL). The pSTG was functionally connected with bilateral superior temporal and inferior frontal regions, whereas the vAPL was connected with other parietal regions, lateral and medial. Surprisingly, the components displayed spatial anti-correlation, in which the negative functional connectivity of each component overlapped with the other component's positive functional connectivity, suggesting that these two systems operate separately and possibly in competition. The speech tasks reliably modulated activity in both pSTG and vAPL suggesting they are involved in speech production, but their activity patterns dissociate in response to different speech demands. These components were also identified in subjects at "rest" and not engaged in overt speech production. These findings indicate that the neural architecture underlying speech production involves parallel distinct components that converge within posterior peri-sylvian cortex, explaining, in part, why this region is so important for speech production.