Hallucinations Under Psychedelics and in the Schizophrenia Spectrum

An Interdisciplinary and Multiscale Comparison

Pantelis Leptourgos; Martin Fortier-Davy; Robin Carhart-Harris; Philip R. Corlett; David Dupuis; Adam L. Halberstadt; Michael Kometer; Eva Kozakova; Frank LarØi; Tehseen N. Noorani; Katrin H. Preller; Flavie Waters; Yuliya Zaytseva; Renaud Jardri


Schizophr Bull. 2020;46(6):1396-1408. 

In This Article

Brain-imaging Markers

At the network level, SCZs and psychedelics exhibit interesting commonalities and differences. A first line of work comes from fMRI capture studies which compare ON and OFF periods for hallucinations and detect the phasic neural changes associated with hallucinatory ON states. In SCZs, these studies suggest a role for modality-dependent associative cortex overactivations during hallucinations.[26–30] When recruited, the primary cortices were associated with more vivid experiences.[28] Interestingly, the onset of hallucinations has been found associated with various aberrant activation/deactivation patterns. Hyperactivity was found in the hippocampal complex, as well as within associative cortices related to the hallucinatory content, while the default-mode network was found concomitantly deactivated.[28,31]

Brain imaging studies conducted to explore psychedelic states did not try to specifically capture hallucinatory events, but rather focused on neural changes in relation to sensory experiences during the psychedelic intoxication, making links with hallucinations more indirect. Regarding visual hallucinations (VH), a greater cerebral blood flow was measured in the visual cortex under LSD.[32] Increased early visual activity but decreased processing in associative visual areas was also observed after psilocybin administration,[33] suggesting that a combination of enhanced early sensory and reduced associative processing may contribute to the psychedelic experience.[23,34]

The second contribution comes from large-scale neural connectivity analyses, based on functional connectivity (FC; correlations between signals measured in different brain areas that define intrinsic brain networks), and effective connectivity, namely the effect one neuronal system exerts over another. We first look at FC studies and then briefly look at selective changes in directed effective connectivity.

A well-replicated finding in healthy individuals is an antagonistic activity between the default-mode resting-state network (DMN) and the task-related central-executive network (CEN).[35–40] Some authors proposed that the orthogonality of these networks might break down in psychotic states.[41] A functional disconnection between the nodes of the DMN and CEN might notably engender impaired self-monitoring as observed in SCZs[42] and manifest as weak anti-correlation between these intrinsic brain networks.

According to the triple-network theory,[43] the antagonistic activity of these resting-state networks (DMN and CEN) putatively reflects competing modes of information processing that may be regulated by the salience network (SN).[44] Recent experimental data using intracranial EEG reported temporal profiles of task-evoked activity compatible with the hypothesis of SN acting as a switch between the CEN and DMN.[45] Impairments of the triple-network was proposed broadly involved in psychopathology,[46–48] and more specifically in intrusive experiences, such as flash-backs,[49] obsessive ideas,[50] or hallucinations in SCZs.[31] In this vein, it has been proposed that SN impairments may reflect a disturbance in ascribing salience properly,[51] while DMN instabilities seem to be a shared characteristic across multiple sensory domains in patients with hallucinations.[41]

Classical psychedelics also induce pervasive changes in network-dynamics that can generally be described as a transition from regularity to increased instability. The coherence of classical resting-state networks was found diminished (disintegrated), while FC of the primary visual cortex expanded—desegregated.[32,52] In complement to its reduced activity-level, the DMN was found to potentially co-activate with the CEN, a phenomenon which may underlie the reported confusion between internally and externally generated mental contents.[53] Analyzing global brain connectivity with fMRI after the administration of LSD and psilocybin also revealed an increased integration of sensory and somatomotor information together with a disintegration of information from associative networks.[23,54] Additionally, a general decrease in directed FC, and concurrently an increase in undirected FC after the administration of LSD was observed using MEG imaging and may point to increased instability in psychedelic states.[55]

Another influential theory in SCZs is the thalamic filter hypothesis (wherein the thalamus gates sensory information to prevent the information overflow in the cortex[56]). Resting-state fMRI studies in patients at various stages of the illness showed that prefrontal–thalamic FC was decreased, while thalamic FC with somatosensory and motor areas was strengthened during disease progression, in a manner that correlates with positive symptoms.[57,58] However, findings regarding the exact relationship between thalamocortical dysconnectivity and clinical symptoms are mixed.[59]

Thalamocortical connectivity was found altered in psychedelic states. Specifically, LSD was found to selectively increase effective connectivity from the thalamus to certain DMN areas, while other connections are attenuated.[60] Furthermore, increased thalamic connectivity with the right fusiform gyrus and the anterior insula correlated with visual and auditory hallucinations (AH), respectively.[61]

In summary (see Table 2), hallucinations relate more to associative network overactivations in SCZs, while they are linked with primary cortex overactivations under psychedelics. Second, in both cases, the experience is associated with reduced internal integration of functional networks, an enhanced correlation between internally and externally oriented networks as well as an impaired thalamocortical connectivity. This phenomenon may notably blur the differentiation between self-generated and perceived mental contents.