Combined dysfunction of the amygdala and nucleus basalis underlies visual hallucinations in Parkinson's disease   

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Why are visual hallucinations in Parkinson’s disease so important? 

Visual hallucinations are common in Parkinson’s disease, affecting up to 70% of patients over time. These experiences can range for minor misperceptions to more complex hallucinations and may progress to more pervasive psychosis involving delusions. What is most concerning about visual hallucinations is that they can signal faster cognitive decline and are one of the strongest predictive factors for earlier nursing home placement. Unfortunately, effective treatment options are currently quite limited, which places emphasis on the crucial need for a more detailed understanding of their underlying pathophysiology. 

What are some of the mechanisms that have been suggested to explain visual hallucinations? 

A common thread across many of the models proposed to explain hallucinations is that these abnormal perceptual experiences arise from an imbalance between bottom-up sensory input and top-down influences on perception, broadly defined as expectations or predictions shaped by prior experiences. Attention plays a key role in both bottom-up and top-down aspects of perception, functioning to prioritize incoming sensory information relevant to internal expectations. Our team’s neurobiological model emphasizes how dysfunction within large-scale attentional networks may disrupt this balance, increasing vulnerability to misperceptions and hallucinations.  

What inspired our research question? 

As highlighted in our recent review, growing evidence suggests that degeneration within the cholinergic system, particularly the nucleus basalis of Meynert (NBM), plays a central role in the mechanisms underlying visual hallucinations in Parkinson’s disease. At the same time, neuropathological studies have demonstrated an association between visual hallucinations and an elevated Lewy body burden within the amygdala, a region highly vulnerable to degeneration. While both nuclei have been implicated independently, how the functional consequences of these pathological alterations intersect remains unclear.  

Therefore, we firstly wanted to determine whether visual hallucinations are associated with abnormal amygdala functional connectivity with the visual and attentional networks. Then, considering the cholinergic system’s role in regulating attention, we examined whether the relationship between amygdala-attentional network dysfunction and hallucinations is dependent on changes to NBM connectivity. 

What did our study reveal? 

Using resting-state functional MRI, we found that individuals with Parkinson’s disease who experience visual hallucinations showed reduced amygdala connectivity with both visual and attentional networks. Importantly, the link between dysfunctional amygdala-attentional network interactions and hallucinations was mediated by reduced connectivity between the NBM and the ventral attention network. This suggests that, taken alone, amygdala dysfunction may not be sufficient to fully account for visual hallucinations but rather its influence depends on concurrent disturbances within the cholinergic system. 

How do these findings advance our understanding of visual hallucinations? 

Our findings support network-based models proposing that visual hallucinations emerge from disrupted coordination between visual and attentional systems and highlight the potential contributions of neurotransmitter dysfunction and localized pathology. Extending prior work that has examined the cholinergic system and amygdala in isolation, our results emphasize that it is the “double hit” that appears to be key, underscoring the importance of considering how multiple pathologically affected circuits converge to produce hallucinations. 

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