Neurophysiological mechanisms of quiet vigilance in neurodegenerative diseases: an electroencephalography research program

In the field of neurophysiological research, the term vigilance refers to a variety of mental states of monitoring of external world during wakefulness, related to activities in brain circuits (Steriade, 1999), projections of ascending reticular activating systems (ARASs) using dopaminergic, noradrenergic, serotonergic, histaminergic, cholinergic, and glutamatergic neurotransmitters (Moruzzi and Magoun, 1949). Malfunctioning of these neuromodulatory circuits may cause a variety of behavioural and cognitive dysfunctions as those observed in the most common progressive neurodegenerative dementing disorders such as Alzheimer’s (AD), Parkinson’s (PD), and Lewy Bodies diseases (DLB; Berridge et al., 2003; Gratwicke et al., 2015). AD, PD and DLB suffer of a progressive loss of cognitive functions. Typical clinical manifestation of AD is severe deficits in episodic memory while PD and DLB are both characterized by frontal executive deficits and motor symptoms (Alzheimer’s society 2017; McKeith et al., 2004). Compared with AD and PD patients, DLB patients have more frequent neuropsychiatric symptoms such as psychosis, depression, apathy and abnormalities in sleep behavior (Aarsland et al., 2005). However, there is limited information regarding the prodromal state of these type of dementia, and it need of a clinical markers to support decision-making processes underlying clinical management of AD, PD and DLB patients. The electroencephalography in resting-state condition (rsEEG) can be a valid candidate for this purpose as it can probe cortical arousal in quiet wakefulness, as revealed by the effects of the administration of a pharmacological agent enhancing vigilance (i.e., modafinil) and sleep deprivation on the regulation of brain rsEEG rhythms in humans (Del Percio et al., 2019). The aim of this PhD thesis was to improve our understanding of neurophysiological correlates of the quiet vigilance in patients with the most prevalent neurodegenerative dementing disorders such as AD, PD, and DLB. This aim was pursued by three retrospective rsEEG studies developed in the international clinical and EEG databases of High-resolution EEG Laboratory at the Department of Physiology and Pharmacology “V. Erspamer” at Sapienza University of Rome. These studies were developed in cooperation with the Partners of European Consortium of DLB. In the first study, we tested the hypothesis that resting state eyes-closed electroencephalographic (rsEEG) rhythms might reflect cortical arousal in patients with dementia due to AD (ADD), PD (PDD), and Lewy body disease (DLB). Clinical and rsEEG data of 42 ADD, 42 PDD, 34 DLB, and 40 healthy elderly (Nold) subjects were extracted from our international archive. Demography, education, and Mini Mental State Evaluation score were not different between the patient groups. Individual alpha frequency peak (IAF) determined the delta (< 4 Hz), theta (3-5 Hz), alpha1 (5-7 Hz), alpha2 (7-9 Hz), and alpha3 (9-13 Hz) frequency bands. Fixed beta1 (14-20 Hz), beta2 (20-30 Hz), and gamma (30-40 Hz) frequency bands were also considered. The rsEEG cortical sources were estimated by means of the exact low-resolution brain electromagnetic source tomography and were then classified across individuals, on the basis of the receiver operating characteristic curves. Results were quite interesting at both group and individual levels. At the group level, compared to the Nold subjects, IAF showed marked slowing in the PDD and DLB patients and moderate slowing in the ADD patients. Furthermore, all patient groups over the Nold subjects showed lower posterior alpha 2 source activities. This effect was dramatic in the ADD, marked in the DLB, and moderate in the PDD patients. These groups of patients also showed higher occipital delta source activities, but this effect was dramatic in the PDD, marked in the DLB, and moderate in the ADD patients. At the individual level, the posterior delta and alpha sources allowed good classification accuracy (approximately 0.85-0.90) between the Nold subjects and patients, and between ADD and PDD patients. We concluded that in quiet vigilance, delta and alpha sources unveiled different spatial and frequency features of the cortical neural synchronization underpinning brain arousal in ADD, PDD, and DLB patients. In the second study, we hypothesized that PD patients may show peculiar clinical manifestations related to vigilance (i.e., executive cognitive deficits and visual hallucinations), reflected in rsEEG rhythms. Clinical and rsEEG rhythms in age-, sex-, and education-matched PD (N = 93), AD (N= 70), and Nold (N = 60) subjects were available from the same international archive of the first study. The same methodology for EEG sources estimation was applied as well. Results showed that: (1) compared to the Nold subjects, the AD and PD patients showed higher widespread delta source activities (PD > AD) and lower posterior alpha source activities (AD > PD); (2) the PD patients with the most pronounced motor deficits exhibited very low alpha source activities in widespread cortical regions; (3) the PD patients with the strongest cognitive deficits showed higher delta and alpha source activities in widespread cortical regions; and (4) compared to the PD patients without visual hallucinations, those with visual hallucinations were characterized by higher parieto-occipital alpha sources activities. These results suggest that in PD patients resting in quiet vigilance, abnormalities in cortical neural synchronization at delta and alpha frequencies are differently related to cognitive, motor, and visual hallucinations. The third study tested if cortical sources of rsEEG rhythms may differ as a function of different clinical symptoms in sub-groups of patients with dementia with DLB. Clinical and rsEEG rhythms in age-, sex-, and education-were matched in DLB (N=46), AD (N=60), and Nold (N=20) subjects. Results showed that compared with the Nold subjects, the DLB and AD patients exhibited greater spatially distributed delta source activities (DLB > AD) and lower alpha source activities posteriorly (AD > DLB). In relation to the DLB controls, the DLB patients with (1) rapid eye movement (REM) sleep behavior disorders showed lower delta and alpha source activities in widespread posterior cortical regions; (2) greater cognitive deficits exhibited higher delta source activities posteriorly; (3) visual hallucinations pointed to greater parieto-frontal delta and parietal alpha source activities; (4) cognitive fluctuations manifested higher parietal alpha source activities. These rsEEG results suggest that when prominent, any clinical feature was associated with a different topography of delta and alpha source activities in the DLB patients. In conclusion, the three studies unveiled specific abnormalities in rsEEG rhythms at delta and alpha frequencies in AD, PD, and DLB patients experiencing quiet vigilance. These effects may represent the neurophysiological correlates of abnormalities in ARASs, cortical arousal, and cholinergic and dopaminergic systems probed by EEG techniques in AD, PD, and DLB patients. These effects were strictly related to clinical manifestations of the mentioned diseases. Future studies may cross-validate those results in prospective, harmonized rsEEG studies in AD, PD, and DLB patients followed from prodromal to dementia stages of the diseases.