Bridging the Gap? Altered Thalamocortical Connectivity in Psychotic and Psychedelic States

This review article (2021) explores the changes in brain function that are induced by psychedelics. It was concluded that some aspects of psychosis can be modelled by psychedelics as a result of the changes to neurocognitive processes and the biological mechanisms underlying these changes.

Abstract

“Psychiatry has a well-established tradition of comparing drug-induced experiences to psychotic symptoms, based on shared phenomena such as altered perceptions. The present review focuses on experiences induced by classic psychedelics, which are substances capable of eliciting powerful psychoactive effects, characterized by distortions/alterations of several neurocognitive processes (e.g., hallucinations). Herein we refer to such experiences as psychedelic states. Psychosis is a clinical syndrome defined by impaired reality testing, also characterized by impaired neurocognitive processes (e.g., hallucinations and delusions). In this review we refer to acute phases of psychotic disorders as psychotic states. Neuropharmacological investigations have begun to characterize the neurobiological mechanisms underpinning the shared and distinct neurophysiological changes observed in psychedelic and psychotic states. Mounting evidence indicates changes in thalamic filtering, along with disturbances in cortico-striato-pallido-thalamo-cortical (CSPTC)-circuitry, in both altered states. Notably, alterations in thalamocortical functional connectivity were reported by functional magnetic resonance imaging (fMRI) studies. Thalamocortical dysconnectivity and its clinical relevance are well-characterized in psychotic states, particularly in schizophrenia research. Specifically, studies report hyperconnectivity between the thalamus and sensorimotor cortices and hypoconnectivity between the thalamus and prefrontal cortices, associated with patients’ psychotic symptoms and cognitive disturbances, respectively. Intriguingly, studies also report hyperconnectivity between the thalamus and sensorimotor cortices in psychedelic states, correlating with altered visual and auditory perceptions. Taken together, the two altered states appear to share clinically and functionally relevant dysconnectivity patterns. In this review we discuss recent findings of thalamocortical dysconnectivity, its putative extension to CSPTC circuitry, along with its clinical implications and future directions.”

Authors: Mihai Avram, Helena Rogg, Alexandra Korda, Christina Andreou, Felix Müller & Stefan Borgwardt

Summary

INTRODUCTION

The idea of using drug-induced effects as a model for psychosis was spurred by the discovery of LSD in 1943. Although this hypothesis lacks supporting evidence, more recent models suggest that this idea is still worth exploring.

Classic psychedelics or serotonergic hallucinogens can induce powerful psychoactive effects, by acting as agonists or partial agonists on serotonin 2A (5-HT2A) receptors. These psychoactive effects can be characterized by distortions or alterations in several neurocognitive processes, and are influenced by several factors such as dose, environment, but also individual factors.

Psychedelic and psychotic states are characterized by perceptual disturbances, mainly hallucinations, however, other perceptual alterations and experiences with a higher power can also occur.

In psychedelic states, subjects are aware of the drug-induced phenomena, whereas in psychosis, patients are not able to trace the phenomena to their medical condition. This review focuses on the thalamic filter model, which posits that a disrupted thalamic filter function may underlie psychotic and psychedelic states.

THE THALAMOCORTICAL SYSTEM

The thalamocortical system is composed of reciprocally connected pathways between the cortex and thalamus, organized topographically. First-order thalamic nuclei receive excitatory input from peripheral or subcortical structures, and higher-order thalamic nuclei receive driving input from layer V cortical neurons.

The thalamus modulates both bottom-up sensory- and top-down cortical-information via glutamatergic neurotransmission, which is in turn modulated by other neurotransmitter systems.

The human thalamocortical system has been investigated via diffusion tensor imaging and functional connectivity with rsfMRI, in both patients and healthy subjects. Dysconnectivity is a decrease in coherence of infra-slow fluctuations of ongoing brain activity.

THALAMOCORTICAL CONNECTIVITY IN PSYCHOTIC STATES

The thalamus is altered in psychotic disorders, particularly in schizophrenia, including lower cell count, volume reduction, altered activity during cognitive tasks, and reduced structural thalamocortical connectivity. A study found that patients with psychotic disorders have altered thalamocortical connectivity, with increased functional connectivity between the thalamus and sensorimotor regions and decreased functional connectivity between the thalamus and prefrontal and cerebellar regions. Although different approaches have been used to investigate thalamocortical connectivity, findings indicate that sensorimotor areas are preferentially hyperconnected with ventral lateral/posterior nuclei, whereas prefrontal areas show hypoconnectivity primarily with mediodorsal/ anterior nuclei. Moreover, this hyperconnectivity pattern is associated with psychotic symptoms.

Studies have shown that altered thalamocortical connectivity, corticostriatal connectivity, and cortico-pallidal connectivity are also associated with altered brain function in psychotic states. These findings suggest that altered dopaminergic transmission modulates CSPTC circuitry, including thalamocortical dysconnectivity.

THALAMOCORTICAL CONNECTIVITY IN PSYCHEDELIC STATES

The thalamus is involved in serotonergic transmission and might be induced via modulatory effects of 5-HT2A receptors located presynaptically on thalamocortical afferents to the prefrontal cortex. Furthermore, thalamic glucose metabolism and cerebral blood flow are altered in psychedelic states.

Recent evidence of thalamic involvement in psychedelic states comes from rsfMRI-based neuropharmacological investigations, which typically employ a crossover design. These studies mainly rely on the investigation of functional connectivity, and a pattern of altered thalamocortical connectivity has emerged.

Carhart-Harris et al. (79) found no changes in connectivity between the thalamus and the default-mode network (DMN) after psilocybin administration, but did observe an increase in connectivity between the thalamus and the task-positive network (TPN).

In a study by Tagliazucchi et al. (80), thalamocortical hyperconnectivity was found after LSD administration. This hyperconnectivity was found after psilocybin administration, suggesting that this phenomenon is a broader psychedelic-induced phenomenon.

Muller et al. (27) found that LSD administration increased thalamocortical connectivity with many brain regions, particularly with primary sensory regions, and that this increased connectivity was positively associated with alterations in sensory perceptions.

Preller et al. (28) investigated the effect of LSD on brain connectivity, and found that LSD-induced changes in connectivity were blocked by ketanserin, indicating that LSD effects are elicited via 5-HT2A receptors.

HYPERCONNECTIVITY AS THE COMMON DENOMINATOR IN PSYCHOTIC AND PSYCHEDELIC STATES

Thalamic hyperconnectivity with sensorimotor cortices appears to be a common denominator in psychotic and psychedelic states, possibly reflecting a shared biological mechanism involved in abnormal perception.

LSD modulated resting-state effective connectivity of the CSPTC circuitry, which can be used to infer the direction of connectivity. The authors found that LSD increased connectivity from the thalamus to the posterior cingulate cortex (PCC) and decreased connectivity from the PCC to the thalamus. Furthermore, thalamocortical hyperconnectivity with sensorimotor cortices might have functional relevance regarding altered perceptions.

VARIATIONS OF PSYCHOTIC AND PSYCHEDELIC STATES

Despite sharing common features, psychotic and psychedelic states differ regarding phenomenology (e.g., perceptual disturbances), neural correlates, duration of the experience, type of perceptual distortion, and the presence of negative symptoms and cognitive disturbances.

In addition to altered perception, psychotic and psychedelic states are accompanied by a plethora of phenomena. However, in this review we focused on phenomena that are characteristic and shared by both altered states, and that are functionally relevant for thalamocortical connectivity changes.

Thalamocortical hyperconnectivity with sensorimotor cortices is only transient in subjects receiving psychedelics, but is stable in psychotic states. Furthermore, thalamocortical hyperconnectivity with sensorimotor cortices predicts later transition to full-blown psychosis in subjects at clinical high risk. In contrast to psychedelic states, structural connectivity studies revealed a similar pattern of thalamocortical dysconnectivity in patients with psychosis: reduced structural connectivity between the thalamus and prefrontal areas and increased structural connectivity between the thalamus and sensorimotor areas.

Thalamic hypoconnectivity was not found in sensorimotor areas, suggesting that thalamocortical hyperconnectivity is specifically associated with disorder-related processes. Thalamic hyperconnectivity persists despite treatment with antipsychotic medication in psychotic states.

HIERARCHICAL PREDICTIVE CODING IN PSYCHOTIC AND PSYCHEDELIC STATES

Both psychotic and psychedelic states have been discussed in the context of hierarchical predictive coding, which relies on glutamatergic projections and weighting of prediction errors via neuromodulators such as dopamine, serotonin, and acetylcholine. The thalamocortical system organizes both feedforward and feedback information processing. First-order and higher-order thalamic nuclei play different roles in these processes, as well as striato-pallidal projections, which are themselves modulated by cortical projections or distinct neuromodulators.

Psychedelics alter the bottom-up/top-down balance by acting on 5-HT1A and 5-HT2A receptors, which in turn change the activity of other cortical areas. This changes the control over the bottom-up information-flow, possibly leading to hallucinations. The REBUS model (i.e., relaxed beliefs under psychedelics) suggests a top-down mechanism, whereas the thalamic filter model (18) suggests a bottom-up mechanism. However, layer V pyramidal neurons can also alter thalamic activity.

FUTURE DIRECTIONS AND CONCLUSIONS

In psychedelic states, the involvement of specific thalamic nuclei in the hyperconnectivity with sensorimotor cortices is unclear. Future studies should investigate the connectivity from distinct cortical areas to the thalamus in a voxel-wise manner, which could reveal how the mechanisms leading to thalamocortical hyperconnectivity might differ in the two altered states.

It is not yet known whether the mediodorsal nucleus is hyperconnected to prefrontal areas in humans, but this would be in contrast to psychosis findings, which report hypoconnectivity for this nucleus. Furthermore, the hypoconnectivity of this nucleus with prefrontal areas is well in line with the topographical organization of the thalamocortical system.

Although dopamine appears to play a central role in the pathophysiology of psychosis, there is substantial evidence indicating that the two systems are highly interconnected. Moreover, some 5-HT2A receptor agonists appear to modulate dopamine release in the striatum of healthy volunteers.

Perceptual deprivation techniques have been reported to induce subjective experiences that differ both qualitatively and quantitatively from psychedelic-induced experiences, and may also reflect an imbalance between typical top-down signaling and atypical bottom-up input.

LSD studies dominate the findings of thalamocortical dysconnectivity in psychedelic states, and there are few studies investigating the acute effects of other classic psychedelics such as DMT and mescaline. Ketamine is not a “classic” psychedelic, but rather a hallucinogenic anesthetic, which elicits its effects mainly via NMDA antagonism. Ketamine has been associated with both psychotic- and negative-like symptoms in healthy volunteers, and thus reflects the most comprehensive model of schizophrenia up to date. Several substances can cause psychotic-like phenomena, but psychedelics also have long-lasting positive effects. These effects include increased optimism and trait openness, and enhanced self-reported positive behavioral changes that last up to 1 year.

Evidence suggests that the pattern of altered connectivity seen in psychotic and psychedelic states is consistent with schizophrenia and bipolar disorder, and that this pattern is more substantial in schizophrenia than in major depression disorder.

Thalamocortical dysconnectivity is present in patients with psychotic disorders, but it is also present in unmedicated individuals at clinical high risk and in drug-naive adolescents with early-onset schizophrenia.

Drug-induced alterations in distinct neurocognitive processes are highly relevant for psychotic research. Thalamocortical hyperconnectivity with sensorimotor areas appears to be a shared biological mechanism between psychedelic and psychotic states, whereas thalamocortical hypoconnectivity with prefrontal cortices is not observed in psychedelic states. The findings reviewed in our paper indicate that some aspects of psychosis can be modeled by psychedelics, but additional research is needed to establish valid models.