Hippocampal dysfunction underlies delusions of control in schizophrenia

Abstract

Current treatments for delusions in schizophrenia are only partly effective, and a better understanding of delusional pathophysiology would lead to new treatments. This study hypothesizes that delusions of control (DOCs), such as the belief that one’s thoughts or actions are under external control, as seen in schizophrenia, can arise from reduced activity in the hippocampal monosynaptic pathway (MSP), that is, between the entorhinal cortex (EC) and the CA1 region of the hippocampus. One CA1 function is to compare new environmental information received from the EC with the cortical memory received via the CA3 region of the hippocampus. One of the consequences of reduced MSP activity is that the hippocampal CA1 region does not receive sufficient environmental information from the EC to match the cortical memory information sent via CA3. The subjective equivalent of this is the sensation that memories occur without environmental stimulation, without explanation. The repetition of this experience results in DOCs. People with DOCs may also develop non-DOC paranoid delusions to explain why they have DOCs. For example, people who believe that their thoughts are under external control might conclude that others are plotting against them. Since there are currently functional MRI(fMRI) techniques for measuring EC-CA1 connectivity, using blood oxygen-level dependent (BOLD) indices, the hypothesis of this study can be tested by comparing EC-CA1 connectivity in normal subjects to people with schizophrenia and DOCs, during an encoding and retrieval task. Since reduced acetylcholine(ACH) or N-methyl-D-aspartate (NMDA) receptor activity both decrease activity of the MSP, it is possible that an acetylcholine or NMDA agonist would increase EC-CA1 connectivity and decrease DOCs in people with schizophrenia. If the defective MSP theory is validated, it would provide a measure of the pathophysiology underlying DOCs and related delusions, and could lead to therapeutic regimens providing a more personalized, symptom-specific treatment of people with illnesses that include DOCs. Better understanding of how MSP defects occur could lead to increased knowledge about the biological basis for psychosis in schizophrenia.