Visual hallucinations (VH) are particularly frequent in Parkinson's disease (PD), PD with dementia (PDD) and Dementia with Lewy bodies (DLB). Beside parkinsonism, the clinical features of PDD and DLB crucially include visual hallucinations and cognitive impairment. VH in PD, PDD and DLB typically progress along a clinical spectrum ranging from vivid dreams to frank psychosis, which is associated with the development of dementia and institutionalization. Understanding mechanisms of VH is crucial in detecting new targets for novel therapeutic approaches in patients with VH. The brain mechanisms underlying VH in PD, PDD and DLB are largely unclear. VH might reflect a failure in recruiting the dorsal attentional network (DAN) during periods of conflict resolution in visual processing. The DAN is composed of widespread neural circuits including regions within the frontal eye fields (FEF), and the intraparietal sulcus (IPS) in the right hemisphere. Transcranial magnetic stimulation (TMS) is a neurostimulation technique able to assess brain functions and disease-associated dysfunction. Recently introduced combined TMS-EEG approaches would provide an interesting window in the investigation of abnormal brain dynamics responsible for VH. In this study, we will use TMS-EEG to investigate excitability and connectivity abnormalities in each of the single nodes within the DAN (FEF and IPS) and the visual cortex, in patients with VH and in age-matched healthy subjects. Finally, given the pathophysiological role of decreased cortical cholinergic transmission in patients with VH, we will also assess the link between changes in the DAN network connectivity and changes in short-afferent inhibition (SAI), a non-invasive TMS measure of the cortical cholinergic tone.
The prevalence of VH in PD has been reported to range between 6% and 60% (Goetz et al. 2010). VH generally occur during the second half of the disease's course and have a persistent and progressive nature (Williams et al., 2005). The development of VH in PD commonly occurs in both demented and non-demented patients and leads to a high degree of burden on primary caregivers (Grossi et al., 2005; Aarsland et al., 2007). Moreover, VH usually heralds the development of dementia (Goetz CG, 2010; Hely MA 2008).
The present study has been designed to uncover network dysfunctions specific of VH development in patients with PD, PDD and DLB. One of potential use of TMS-EEG might be in the identification of individuals in the prodromal phase, prior to the manifestation of significant VH. From a theoretical perspective EEG, as a functional marker of neuronal and synaptic integrity, may be sensitive to VH related subtle and early cortical excitability and connectivity changes that precede overt large-scale degenerative changes leading to dementia. In addition to the search for specific abnormalities of the presence of VH, the set of collected neurophysiological data could help to differentiate clinical conditions characterized by wide overlap such as PDD and DLB (disease biomarker). Furthermore, clarifying the relationship between cholinergic alterations and parameters of excitability and network functionality can provide objective indicators of therapeutic efficacy of drugs oriented to the regulation of cholinergic tone such as acetylcholinesterase inhibitors. This aspect is of particular relevance given the key role that cholinergic alterations also play in determining the therapeutic response to dopaminergic drugs, fundamental in the treatment of PD. Finally, the use of EEG neurophysiological biomarkers in PD, PDD and DLB patients might be the development of new therapeutic treatments. In fact, the study of the individual nodes of the retentive network responsible for VH could identify the network node on which to apply invasive and / or non-invasive neurostimulation approaches able to improve the patient's symptoms. Today, in fact, we have advanced repetitive magnetic stimulation techniques known to induce long-term plasticity-like phenomena. Therefore the study is a fundamental prerequisite for a non-invasive neurostimulation intervention aimed at the symptomatic treatment of VH in patients with VH.
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