Psychosis in Parkinson's disease and Dementia with Lewy Bodies shares underlying mechanisms with altered states of consciousness seen in REM sleep, psychiatric disorders, and psychedelic drug use. Dysregulated activity in high-order thalamic nuclei, driven by ThalamoCortical Dysrhythmia (TCD), is proposed as a crucial trigger. TCD disrupts finely tuned cortico-cortical modulations normally supported by the thalamus, leading to aberrant Default Mode Network (DMN) activity. This process alters thalamic filtering of internal and external information, causing cortical input overload and DMN decoupling from task-positive networks. These changes destabilize brain metastability, producing dreamlike, dissociative, or altered states. Psychedelic drugs similarly modulate thalamic-cortical pathways. Understanding this pathophysiology bridges neurology and psychiatry, offering promising avenues for investigation and therapy.
LSD selectively alters the functional connectivity between specific thalamic nuclei and sensory and associative cortical areas. Using structural and resting-state functional MRI in healthy volunteers under acute LSD administration, researchers found increased coupling of the ventral complex, pulvinar, and non-specific thalamic nuclei with somatosensory and auditory cortices, as well as with associative cortex regions rich in serotonin 2A receptors. At subcortical levels, LSD increased connectivity among these thalamic nuclei but decreased striatal-thalamic connectivity. These nucleus-specific changes help explain LSD's modulation of subcortical-cortical circuits and associated behavioral effects.
LSD alters brain functional connectivity and local signal amplitude in opposite directions depending on the type of serotonin receptor involved. In healthy volunteers, LSD increased activity and connectivity in cortical regions of the default mode and attention networks, which have high densities of 5-HT2A receptors; these changes correlated with visual hallucinations. Conversely, LSD decreased activity and connectivity in limbic areas rich in 5-HT1A receptors. The spatial patterns of these functional changes overlapped with the distribution of the two serotonin receptor subtypes, suggesting distinct receptor-mediated mechanisms underlie LSD's reorganization of brain networks.
States of consciousness can be ordered along a single dimension defined by the entropy of spontaneous neural activity, as proposed by the Entropic Brain Theory. Applying the same analytical pipeline to pharmacological (psychedelics, modafinil, propofol anaesthesia) and clinical (schizophrenia) fMRI datasets, the temporal irregularity of brain network topology was quantified. Propofol anaesthesia occupied the low-entropy end; psychedelic states and schizophrenia occupied the high end. This ordering tracks combined modulations of the level and content of consciousness, from reduced awareness under anaesthesia to heightened arousal and expanded experience under psychedelics and disorganised processing in schizophrenia. The result was not reducible to fluctuations in mean functional connectivity and was supported by convergent reorganisation of higher-order association cortex.