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.
Psychedelics and ketamine/esketamine show promise for treating depressive disorders by inducing rapid and sustained antidepressant effects. The review examines their biological mechanisms, including modulation of glutamate and serotonin systems, promotion of neuroplasticity, and changes in brain connectivity and network function. Neuroimaging studies reveal alterations in default mode network, fronto-limbic connectivity, and thalamic activity. Clinical changes are associated with these brain alterations, though the precise relationships remain under investigation. The work synthesizes current evidence on how these compounds produce observable brain changes and symptom improvement, highlighting the need for further research to clarify mechanisms and optimize therapeutic applications.