A Proposed Neural Pathway Associated With Delusions and Hallucinations in Dementia-Related Psychosis

Dr. Stahl: Hello, my name is Dr. Stephen M. Stahl and I am an adjunct professor of psychiatry at the University of California, San Diego, an honorary visiting senior fellow at the University of Cambridge, and director of psychopharmacology for the California Department of State Hospitals. 

Dr. Brunton: And I’m Dr. Stephen Brunton, executive vice president for the Primary Care Education Consortium and associate adjunct clinical professor in the department of family medicine at Touro University in Vallejo, California. In this video, we will discuss a proposed neurobiological mechanism by which cortical damage and/or dysfunction leads to hyperactivation of a neural pathway associated with delusions and hallucinations in dementia-related psychosis.

Dr. Stahl: Let’s begin by discussing the relationship between the cortical damage that is thought to occur in dementia, and the neurotransmitter systems that regulate neural circuits associated with delusions and hallucinations in patients with dementia. 

Dr. Stahl: The pathology of dementia is associated with the loss of cortical neurons.1-5

Dr. Stahl: Such neuronal loss can profoundly affect the surviving neurons and the neurotransmitter systems that regulate them.6 Dysfunction in these neurotransmitter systems may play a key role in the pathophysiology of dementia-related delusions and hallucinations.7 

Dr. Stahl: Dysfunction in neurotransmitter systems can affect the activity of neurons and the neural pathways they comprise. In theory, cortical neurotransmitter dysfunction can lead to neuronal dysregulation in the cortex and activation of the mesolimbic pathway, which projects from the ventral tegmental area to the ventral striatum, as seen here. This network of cortical and mesolimbic neurons comprises a neural pathway that may be associated with delusions and hallucinations.7

Dr. Stahl: It is thought that hyperactivity in this neural pathway may underlie the development of delusions and hallucinations.7 Theoretically, modulation of such pathways may be able to address delusions and hallucinations.7,8

Dr. Brunton: To understand this theory, we must first familiarize ourselves with the role neurotransmitters play in regulating neural activity. Neurotransmitters such as serotonin can modulate neural pathways by binding to their corresponding receptors at neuronal synapses.7-9

Dr. Brunton: When serotonin is released into synapses, it can bind 5-HT2A  serotonin receptors and activate them. 5-HT2A receptors are one member of the serotonin receptor family.7-9

Dr. Brunton: 5-HT2A receptors are thought to modulate the activity of cortical neurons that participate in neural pathways associated with delusions and hallucinations.7,8 Dysregulation of cortical neurons and/or excessive 5-HT2A activity can lead to hyperactivation of such neural pathways, which can theoretically promote the development of delusions and hallucinations.7,8 Thus, blockade of 5-HT2A activity is thought to modulate certain neural pathways associated with delusions and hallucinations.7,8

Dr. Stahl: In summary, the pathology of dementia is associated with the loss of cortical neurons.1-5 Such neuronal loss can profoundly affect the surviving neurons and the neurotransmitter systems that regulate them.6

Dr. Brunton: Dysfunction in neurotransmitter systems can lead to hyperactivation of neural pathways associated with delusions and hallucinations in patients with dementia.7 Blockade of serotonin 5-HT2A receptors is thought to modulate certain neural pathways associated with delusions and hallucinations.7,8

We hope this video has been informative. Please view the other videos in this series, and thank you for watching!

References

    1. Colom-Cadena M, Pegueroles J, Herrmann AG, et al. Synaptic phosphorylated alpha-synuclein in dementia with Lewy bodies. 2017;140(12):3204-3214.
    2. Hamilton RL. Lewy bodies in Alzheimer’s disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol. 2000;10(3):378-384.
    3. Hyman BT, Phelps CH, Beach TG, et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement, 2012;8(1):1-13.
    4. Rosso SM, Donker Kaat L, Baks T, et al. Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study. 2003;126(9):2016-2022.
    5. Jellinger KA, Stadelmann C. Problems of cell death in neurodegeneration and Alzheimer’s disease. J Alzheimers Dis. 2001;3(1):31-40.
    6. Stahl SM. Stahl’s Illustrated Alzheimer’s Disease and Other Dementias. New York, NY: Cambridge University Press; 2019.
    7. Stahl SM. New hope for Alzheimer’s dementia as prospects for disease modification fade: symptomatic treatments for agitation and psychosis. CNS Spectr. 2018;23(5):291-297.
    8. Stahl SM. Parkinson’s disease psychosis as a serotonin-dopamine imbalance syndrome CNS Spectr. 2016;21(5):355-359.
    9. Ballanger B, Strafella AP, van Eimeren T, et al. Serotonin 2A receptors and visual hallucinations in Parkinson’s disease. Arch Neurol. 2010;67(4):416-421.

Faculty

Touro University
Vallejo, CA
University of California, San Diego
La Jolla, CA