Scientific Understanding of Consciousness
Hallucinogen Drug Action
Toward a Science of Consciousness III The Third Tucson Discussions and Debates
Neural Correlates of Hallucinogen-induced Altered States of Consciousness
F. X. Vollenweider, A. Gamma, and M. F. I. Vollenweider-Scherpenhuyzen
Psychiatric University Hospital Zurich Research Department
CH-8029 Zurich, Switzerland
The study of hallucinogens ("psychedelics") and related substances offers a promising avenue to investigate biological correlates of altered states of consciousness (ASC). In combination with functional brain imaging techniques and pharmacological methodologies, these compounds are remarkable molecular probes into the biochemistry and functional organization of the brain in nonordinary states. The study of hallucinogens in humans is important firstly because they profoundly affect a number of brain functions that characterize the human mind, including cognition, volition, emotion, ego and self-awareness, which cannot be reliably studied in behavioral animal models. Secondly, they are important because they elicit a clinical syndrome resembling in several aspects the first manifestation of schizophrenic disorders. The various forms of ego alterations are especially prominent features of psychedelic and naturally occurring psychoses. These alterations may range from a slight loosening of ego boundaries to a dissolving of ego into an ecstatic oneness with the cosmos. The dissolution of the self as a center of reference, however, can also evoke anxiety and feelings of fragmentation, confusion and disorganization resembling the core features of schizophrenic ego disorders. Hence, studies of the neuronal mechanisms of hallucinogen action should provide not only novel insights into the pathophysiology of psychiatric disorders and their treatment, but, in a broader sense, into the biology of consciousness as a whole, for example, into the biology of ego structuring processes.
In the present contribution, we wish to summarize some of our recent results and advances in hallucinogen research, which are the result of human studies conducted in our group. We have developed different strategies to explore the pharmacological effects of hallucinogens on brain functions. The basic approaches are to investigate hallucinogen-induced metabolic changes with fluorodeoxyglucose (FDG) and to characterize functional interactions of neurotransmitter systems by assessing hallucinogen-induced displacement of specific radiolabeled receptor ligands using positron emission tomography (PET). A human model of sensory gating deficits, the cortico-striato-thalamo-cortical (CSTC) loop model, will be introduced to provide a perspective how current knowledge about hallucinogen drug action could be visualized within a synthetic framework to explain its subjective effects in humans. Hypotheses derived from this model were tested in several FDG-PET studies, and correlational analyses between hallucinogen-induced brain activity changes and phenomenological dimensions of ASC were computed to elucidate the neuronal correlates of ASC.
The CSTC Model of Sensory Information Processing and ASC
Based on the available neuroanatomical evidence and pharmacological findings of psychedelic drug action, we propose a cortico-subcortical model of psychosensory information processing that can be used as a starting point to analyze and integrate the effects of different chemical types of hallucinogens at a system level. The model advances that psychedelic states can be conceptualized as complex disturbances arising from more elementary deficits of sensory information processing in corticostriato-thalamo-cortical (CSTC) feedback loops. The model is not entirely new, it incorporates the idea that psychotic symptoms might relate to a dopaminergic and/ or dopaminergic-glutamatergic neurotransmitter dysbalance in mesolimbic and/or mesolimbic-corticostriatal pathways, but it extends this hypothesis, insofar that the serotonergic and GABAergic neurotransmission are also brought into the scheme.
Five CSTC loops have been identified, and each loop, functioning in parallel, is thought to mediate a different set of functions; the motor, the oculomotor, the prefrontal, the association and the limbic loop. The limbic loop is involved in memory, learning and self-nonself discrimination by linking of cortical categorized exteroceptive perception and internal stimuli of the value system. The limbic loop originates in the medial and lateral temporal lobe and hippocampal formation and projects to the ventral striatum. Projections from this region then converge on the ventral pallidum and feed back via the thalamus to the anterior cingulate and the orbitofrontal cortex.
The CSTC model posits that the thalamus acts as a filter or gating mechanism for the extero- and interoceptive information flow to the cerebral cortex and that deficits in thalamic gating may lead to a sensory overload of the cortex, which in turn may cause the sensory flooding, cognitive fragmentation and ego-dissolution seen in drug-induced ASC and endogenous psychotic states. The filter capability of the thalamus is thought to be under the control of cortico-striato-thalamic (CST) feedback loops. Specifically, it is hypothesized that the striatum and pallidum exert an inhibitory influence on the thalamus. Inhibition of the thalamus should result in a decrease of sensory input to the cortex and in a reduction of arousal, protecting the cerebral cortex from sensory overload and breakdown of its integrative capacity. The striatal activity is modulated by a number of subsidiary circuits and neurotransmitter systems, respectively. The mesostriatal and mesolimbic projections provide an inhibitory dopaminergic input to the striatum. Under physiological conditions, the inhibitory influence of the dopaminergic systems on the striatum is, however, thought to be counterbalanced by the glutamatergic excitatory input from cortico-striatal pathways. This assumption implies that an increase in dopaminergic tone (e.g., by amphetamine) as well as a decrease in glutamatergic neurotransmission (e.g., by ketamine) should lead to a reduction of the inhibitory influence of the striatum on the thalamus and result in a opening of the thalamic "filter" and, subsequently, in a sensory overload of the cerebral cortex and psychotic symptom formation. Finally, the reticular formation, which is activated by input from all sensory modalities, gives- rise to serotonergic projections to the components of the CST loops. Excessive activation of the postsynaptic elements of the serotonergic projection sites (e.g., by psilocybin) should also result in a reduction of thalamic gating and, consequently, in a sensory overload of frontal cortex and psychosis.
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