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

Mihai Avram, Helena Rogg, Alexandra Korda, Christina Andreou, Felix Müller and Stefan Borgwardt

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.

Keywords : resting-state FC-fMRI, cortico-thalamic connectivity, psychotic states, psychedelic states, serotonergic psychedelics

INTRODUCTION

The idea of investigating drug-induced effects that mimic symptoms of psychiatric disorders (i.e., psychosis) was spurred by the discovery of lysergic acid diethylamide (LSD) in 1943, which led to the first substance-induced model of psychosis (1), and later catalyzed the serotonin hypothesis of schizophrenia (2) [for further details see (3, 4)]. Although this hypothesis lacks supporting evidence, more recent models have suggested that drug-induced effects may shed light on the mental state of emerging psychosis and that the idea of using drug-induced effects as a model for psychosis might be still worth exploring (2, 5, 6). With the recent revival of psychedelic research, newly generated theories and supporting data may clarify whether the converging phenomena seen in both drug-induced states and endogenous psychosis share neurophysiological mechanisms.

Classic psychedelics or serotonergic hallucinogens (e.g., psilocybin, dimethyltryptamine (DMT), and LSD) are substances that can induce powerful psychoactive effects, by acting as agonists or partial agonists on serotonin 2A (5-HT2A) receptors (7–9). These psychoactive effects constitute so-called altered states of consciousness (ASC), which reflect temporary changes in an individual’s mental state, and are characterized by distortions or alterations in several neurocognitive processes (e.g., perception, thoughts, mood) (10, 11). A variety of experiences can be elicited in this manner, which are influenced by several factors such as dose, environment, but also individual factors (12). We refer to psychedelic-induced ASC in this review as psychedelic states. Similarly, psychosis is a clinical syndrome including several symptoms such as alterations in perception (e.g., hallucinations), abnormal thinking (e.g., delusions), and bizarre behaviors (13), which are characterized by impaired reality testing, reflecting the ability to differentiate the external environment from one’s internal world (14). While psychosis can be drug-induced (13), we refer to psychotic states as acute phases of so-called psychotic disorders (unless otherwise specified). In a sense, psychotic states can be understood as ASC (10, 15). Although psychotic states have mainly been associated with alterations in dopamine function, recent research indicates that other neurotransmitter systems may also be involved. For instance, substantial evidence demonstrates that alterations in glutamatergic transmission are relevant for schizophrenia—ranging from postmortem findings to in vivo imaging—and, importantly, that antagonists (e.g., ketamine) to specific glutamate receptors [i.e., N-methyl-D-aspartate (NMDA)] induce psychotic symptoms (16).

Psychedelic and psychotic states are accompanied by a plethora of phenomena, some of which are shared by both while other phenomena are distinct [(4, 17); for details see below]. For instance, a core characteristic of both altered states are perceptual disturbances, mainly hallucinations, however, other perceptual alterations (e.g., of time and space) and experiences with a higher power (e.g., mystical experiences) can also occur (4). Nevertheless, the perceptual disturbances are mainly characterized by distinct features in psychedelic and psychotic states, i.e.,—they are predominantly visual in psychedelic states and auditory in psychotic states (2). Furthermore, reality testing is not impaired in psychedelic states, meaning that subjects are (usually) aware that the experienced phenomena are drug-induced (4, 17); in contrast, patients suffering from psychosis are not able to trace the phenomena—which is considered real—to their medical condition (i.e., reality testing is impaired) (14). It remains to be determined, whether psychedelic and psychotic states reflect distinct or overlapping neural mechanisms. Following the “thalamic filter” model (18), a potential candidate for a shared neural mechanism in psychotic and psychedelic states is a disrupted thalamic filter function. In more detail, this model posits that the thalamic filtering of sensory information to the cortex is modulated by several sources (i.e., cortico-striatal pathways), which are, in turn, modulated by distinct neurotransmitter systems (e.g., dopaminergic, serotonergic). Aberrant modulation may lead to filtering deficits, resulting in an overload of exteroceptive and interoceptive stimuli, thereby bringing about psychedelic or psychotic phenomena (e.g., hallucinations). For a schematic of this model see Figure 1. This model has received recent support from functional magnetic resonance imaging (fMRI) studies pertaining both to psychotic and psychedelic states (22, 27–30). Indeed, recent efforts made to corroborate neuroimaging findings regarding altered perceptions concerning psychotic disorders and psychedelic substances, have highlighted altered thalamocortical connectivity—measured via resting- state fMRI (rsfMRI) functional connectivity—as a common finding (17). This review aims to discuss these recent findings of thalamocortical dysconnectivity, the putative extension of thalamocortical dysconnectivity to CSPTC circuitry, and clinical implications along with future directions.

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