49 Theoretically, an impairment of thalamic filtering should result in sensory overload of the cortex, leading to a breakdown of integrative cortical functions, and subsequently to positive symptoms such as delusions, hallucinations, thought disturbances, persecution, and loss of a coherent ego experience. In addition, various negative symptoms, such as emotional and social withdrawal, could result from – and be understood as – efforts to protect from input overload. Figure 3. The limbic cortico-striato-thalamic-cortical (CSTC)

feedback loops are involved in memory, learning, and self-nonself discrimination Inhibitors,research,lifescience,medical by linkage of cortically categorized exteroceptive perception with internal stimuli of the value system. The filter function … On the basis of these findings and the thalamic filter model, ACSs induced by hallucinogens and NMDA antagonists in humans can be conceptualized Inhibitors,research,lifescience,medical as complex disturbances that arise from more elementary deficits of sensory information processing in corticostriato-thalamo-cortical (CSTC) feedback loops.6,50 The model proposes that NMDA antagonists may disrupt thalamic filter functions and produce sensory overload of cortical areas, particularly of the prefrontal cortex, by blocking NMDA receptors located on corticostriatal pathways, while serotonergic hallucinogens may alter thalamocortical Inhibitors,research,lifescience,medical transmission by stimulation

of 5-HT2 receptors located in several Selleck Afatinib components of the CSTC loop, including the prefrontal

cortex, striatum, nucleus accumbens, and thalamus (for details, see reference 49). Brain imaging studies Until recently, many neural circuit models were based on animal studies, and implications for the effects of hallucinogenic Inhibitors,research,lifescience,medical drugs or disease models in humans were based on inferences from these studies. However, functional neuroimaging studies enable one to examine these neural circuit models directly and test specific hypotheses about the role of specific neural systems in the expression of ASC. PET with the radiotracer 18F-fluorodcoxyglucose (18FDG) was used Inhibitors,research,lifescience,medical to assess drug-induced changes in the regional cerebral metabolic rate of glucose (CMRglu), as an index of cerebral activity. We found that a hallucinogenic dose of racemic ketamine increased neuronal activity in the prefrontal cortex (hyperfrontality) and associated limbic regions, as well as in striatal and thalamic structures in healthy volunteers, giving the first unless evidence that functional alterations in CSTC loops may underlie the symptomatology of drug-induced ASC.50 This hyperfrontality finding was corroborated and extended in subsequent studies in healthy volunteers in which the effects of hallucinogens and NMDA antagonists including psilocybin, racemic ketamine, and S-ketamine were compared. In particular, we found that, despite different primary mechanisms of action, the two classes of drugs produced strikingly similar brain activation patterns as indexed by normalized CMRglu.