Dottorato in NEUROSCIENZE CLINICO-SPERIMENTALI E PSICHIATRIA

Titolo della tesi: ABNORMAL REACTIVITY OF RESTING-STATE EEG ALPHA RHYTHMS DURING EYES OPEN IN PATIENTS WITH ALZHEIMER’S AND LEWY BODY DISEASES

Previous studies suggest that resting-state electroencephalographic (rsEEG) rhythms recorded in old patients with dementia due to different neurodegenerative diseases have a significant heuristic and clinical potential in identifying peculiar abnormalities of the ascending activating systems and reciprocal thalamocortical circuits in which oscillatory (de)synchronizing signals dynamically underpin cortical arousal in the regulation of quiet vigilance. In the present PhD program, a new methodological approach based on rsEEG cortical source estimation and individually-based frequency bands was used to test the hypothesis of significant abnormalities in the neurophysiological oscillatory mechanisms underlying the regulation of the quiet vigilance during the transition from an eyes-closed to an eyes-open condition in patients with the most prevalent neurodegenerative dementing disorders such as Alzheimer’s disease and Lewy Body and Parkinson’s diseases and initial abnormalities in the prodrormal stage of ADD, characterized by mild cognitive impairment. Three rsEEG studies were performed for that purpose. In the first study, we tested if the reactivity of posterior rsEEG alpha rhythms from the eye- closed to the eyes-open condition may differ in patients with dementia due to Lewy Bodies (DLB) and Alzheimer’s disease (ADD) as a functional probe of the dominant neural synchronization mechanisms regulating the vigilance in posterior visual systems. We used clinical, demographical, and rsEEG datasets in 28 healthy elderly (Healthy) seniors, 42 DLB, and 48 ADD participants. The eLORETA freeware estimated rsEEG cortical sources at individual delta, theta, and alpha frequencies. Results showed a substantial (> -10%) reduction in the posterior alpha activities during the eyes-open condition in 24 Healthy, 26 ADD, and 22 DLB subjects. There were lower reductions in the posterior alpha activities in the ADD and DLB groups than in the Healthy group. The reduction in the occipital region was lower in the DLB than in the ADD group. These results suggest that DLB patients may suffer a greater alteration in the neural synchronization mechanisms regulating vigilance in occipital cortical systems compared to ADD patients. In the second study, we hypothesized that the vigilance dysregulation seen in PDD patients might be reflected by altered reactivity of posterior rsEEG alpha rhythms during the vigilance transition from an eyes-closed to an eyes-open condition. We used clinical, demographical, and rsEEG datasets in 28 healthy elderly (Healthy), 73 PDD, and 35 ADD participants. We have applied the same methodology used for the first study. Results showed substantial (> -10%) reduction (reactivity) in the posterior alpha source activities from the eyes-closed to the eyes-open condition in 88% of the Healthy seniors, 57% of the ADD patients, and only 35% of the PDD patients. In these alpha-reactive participants, there was lower reactivity in the parietal alpha source activities in the 5 PDD group than in the Healthy and the ADD groups. These results suggest that PDD is characterized by poor reactivity of mechanisms desynchronizing posterior rsEEG alpha rhythms in response to visual inputs. This finding could be an interesting biomarker of impaired vigilance regulation in quiet wakefulness in PDD patients. Indeed, such biomarkers may provide endpoints for pharmacological intervention and brain electromagnetic stimulations to improve the PDD patients’ general ability to regulate vigilance and primary visual consciousness in the activities of daily living. In the third study, we tested the exploratory hypothesis that rsEEG alpha rhythms may predict and be sensitive to mild cognitive impairment due to AD (ADMCI) progression at a 6-month follow-up (a relevant feature for intervention clinical trials). Clinical, neuroimaging, and rsEEG datasets in 52 ADMCI and 60 Healthy seniors were used. We applied the same methodology used for the first and the second studies. Results showed a substantial (> -10%) reduction in the posterior alpha source activities during the eyes-open condition in about 90% and 70% of the Healthy and ADMCI participants, respectively. In the younger ADMCI patients (mean age of 64.3±1.1) with “reactive” rsEEG alpha source activities, posterior alpha source activities during the eyes closed condition predicted the global cognitive status at the 6-month follow-up. In all ADMCI participants with “reactive” rsEEG alpha source activities, posterior alpha source activities during the eyes-closed condition reduced in magnitude at that follow-up. These effects could not be explained by neuroimaging and neuropsychological biomarkers of AD. These results suggest that in ADMCI patients, the true (“reactive”) posterior rsEEG alpha rhythms, when present, predict (in relation to younger age) and are quite sensitive to the effects of the disease progression on neurophysiological mechanisms underpinning vigilance regulation. The results of the three studies unveiled the significant extent to which the well-known impairments in the cholinergic and dopaminergic neuromodulatory ascending systems could affect the brain neurophysiological oscillatory mechanisms underpinning the reactivity of rsEEG alpha rhythms during eyes open and, then, the regulation of quiet vigilance in ADD, PDD, and DLB patients, thus enriching the neurophysiological model underlying their known difficulties to remain awake in quiet environmental conditions during daytime.