Regular articleLevodopa may affect cortical excitability in Parkinson's disease patients with cognitive deficits as revealed by reduced activity of cortical sources of resting state electroencephalographic rhythms
Introduction
Parkinson's disease (PD) is characterized by motor symptoms but often goes hand in hand with subtle mild cognitive impairment at the disease onset. This cognitive dysfunction is progressive in most of patients (Muslimovic et al., 2005). Indeed, the percentage of PD patients progressing to dementia in 20 years is included between 60% (Aarsland et al., 2003, Buter et al., 2008, Hughes et al., 2000, Levy et al., 2000) and more than 80% (Hely et al., 2008).
The pathoetiology of the cognitive deficits in PD is heterogeneous and thus patients may need personalized treatments to mitigate the cognitive decline. Ideally, this monitoring should be done with biomarkers reflecting those neuropathological processes or the effects of those processes on brain functions. Among various candidates, resting state eyes-closed electroencephalographic (rsEEG) rhythms are cost-effective, noninvasive, and can be repeated several times. For this reason, they have extensively been studied as biomarkers to evaluate the neurophysiological mechanisms of dementing disorders (Breslau et al., 1989, Briel et al., 1999).
A prominent application of quantitative rsEEG techniques in PD patients was the computation of power (density) of rsEEG rhythms in standard frequency bands from delta (<4 Hz) to gamma (>30 Hz) at scalp electrodes placed over the whole scalp, as a neurophysiological biomarker of thalamocortical and corticothalamic neural synchronization of oscillatory cycles of cellular excitation and inhibition. Results have shown that when compared to normal healthy elderly (Nold) individuals, PD patients with cognitive deficits (PDCD) were characterized by widespread higher power in delta and theta (4–7 Hz) rhythms and some reduction of alpha power (Bonanni et al., 2008, Bosboom et al., 2006, Bosboom et al., 2009, Caviness et al., 2016, Fünfgeld, 1995, Kamei et al., 2010, Melgari et al., 2014, Pugnetti et al., 2010, Serizawa et al., 2008). PDCD also showed lower frequency of the alpha (8–12 Hz) power peak, greater global theta and delta power, and lower power in the alpha and beta (13–30 Hz) frequency bands even compared with a PD group with normal cognitive status (Caviness et al., 2007).
The above rsEEG techniques have received some validation for clinical applications in individual patients. A stepwise method using an input of 20 discriminant rsEEG power and coherence for a statistical pattern recognition procedure exhibited an accuracy of classification (area under the receiving operator characteristic curve) of 0.90 between participants with dementia due to AD (ADD) and PD (PDD; Engedal et al., 2015). Another study using a multimodal combination of rsEEG variables with clinical, cerebrospinal fluid, neuroimaging, neuropsychological, and visual EEG data reached a classification accuracy of 0.87 in the discrimination between ADD, PDD, and dementia with Lewy bodies (DLB) individuals (Dauwan et al., 2016). Finally, a rsEEG study in a small database obtained a 100% classification accuracy of individuals with PDD/DLB, ADD, and frontotemporal dementia using 25 discriminant variables based on scalp rsEEG power and interrelatedness (i.e., Granger causality) as an input to a support vector machine (Garn et al., 2017).
In summary, compared with Nold individuals, PDCD show a reduced activation of posterior cortical sources of alpha rhythms in quiet wakefulness, which is associated with increased widespread delta rhythms. It is well known that such reduced alpha rhythms reflect cortical over-excitability in quiet wakefulness (Babiloni et al., 2015), but the relationship of this effect with dopamine neuromodulation is poorly known. This is particularly pertinent, given PDCD are affected by neurodegenerative neuropathology of subcortical projection to cerebral cortex lobe including deposition of α-synuclein in Lewy bodies and neurites, loss of tegmental dopamine cell populations, loss of basal forebrain cholinergic projection to the cortex, and a variable degree of coexisting AD neuropathology (Barker and Williams-Gray, 2016, Irwin et al., 2017).
The present exploratory and observational study tested the hypothesis that the dopamine neuromodulation may affect cortical excitability in PD patients set in quiet wakefulness, as assessed by the examination of resting state cortical alpha rhythms. Our aim therefore was to make use of clinical and rsEEG rhythms in PDD, mild cognitive impairment due to Parkinson's disease (PDMCI), PD with normal cognition, and Nold subjects from an available international archive including all data coming from the PDWAVE Consortium. An assumption of this study was that compared to PD patients without cognitive deficits, those with MCI and dementia have had a longer disease with a consequent progression in the depletion of dopaminergic brain neurons, although the relationship between duration and severity of the disease is not linear. For some of these patients under a standard chronic dopaminergic regimen, clinical and rsEEG rhythms were available before (OFF) and after (ON) about 60 minutes from the administration of 1 daily dose of levodopa. From a methodological point of view, we used exact low-resolution brain electromagnetic tomography (eLORETA) freeware to estimate rsEEG cortical sources at individual frequency bands (Pascual-Marqui, 2007) to improve the topographic analysis of alpha rhythms. In previous studies of our group, this methodology unveiled different characteristics of abnormal cortical delta and alpha source activity in PDCD in relation not only to Nold subjects but also to patients with cognitive deficits due to AD and DLB (Babiloni et al., 2017a, Babiloni et al., 2017b, Babiloni et al., 2018a, Babiloni et al., 2018b). Compared with Nold subjects, PDCD showed a reduced activation in posterior cortical sources of alpha rhythms, associated with increased widespread delta source activation. Furthermore, such increment in delta source activation was greater than that observed in AD and DLB patients. In contrast, PDCD patients exhibited less reduction in alpha source activation than that observed in AD and DLB patients. Keeping in mind, these previous data, the present methodology may provide quite sensitive markers of cortical neural synchronization and excitability in PD patients as a function of cognitive deficits, which are a rough but useful index of PD progression and dopamine depletion severity over time.
Section snippets
Subjects and diagnostic criteria
In the present exploratory and observational study, clinical and rsEEG data in age-, sex-, and education-matched groups of PD patients and Nold subjects were taken from an international archive formed by the Clinical Units of our Consortium. Specifically, the groups were formed by 35 PDD, 50 PDMCI, 35 PD with normal cognition, and 35 Nold individuals. Table 1 summarizes the most relevant demographic features (i.e., age, gender, education) and global cognitive status (i.e., Mini-Mental State
Statistical comparison of the EEG cortical sources in the Nold, PD, PDMCI, and PDD groups
Table 4 reports the mean values of TF and IAF for the 4 groups (i.e., Nold, PD, PDMCI, and PDD), together with the results of the statistical comparisons between the groups (ANOVA, p < 0.05). The mean TF was 6.2 Hz (±0.1 SE) in the Nold group, 5.8 Hz (±0.2 SE) in the PD group, 5.5 Hz (±0.2 SE) in the PDMCI group, and 4.7 Hz (±0.2 SE) in the PDD group. Furthermore, the mean IAF was 9.5 Hz (±0.1 SE) in the Nold group, 8.6 Hz (±0.2 SE) in the PD group, 8.5 Hz (±0.2 SE) in the PDMCI group, and
Discussion
In the present exploratory and observational study, we assessed whether dopamine modulation may reflect cortical excitability in PD patients. When compared to the Nold group, the PD groups without and with cognitive deficits (i.e., PDMCI and PDD) showed reduced activity in posterior alpha sources, which was associated with increased activity in widespread delta (<4 Hz) sources. In relation to the PD group, the PDMCI and PDD groups showed a greater reduction in occipital low-frequency alpha
Methodological remarks
There are a number of methodological limitations to our study.
First, the relatively small number of the patients in the PD, PDMCI, and PDD groups (N = 35-50) did not allow to adequately covary or contrast for a number of potential factors, which are known to affect the EEG such pharmacological intervention (e.g., cholinergic, dopaminergic, serotoninergic), the severity of dementia and motor symptoms, and/or the disease duration.
In this retrospective study, data were collected without a single
Conclusions
In this observational and retrospective study, we hypothesized that dopamine neuromodulation may affect cortical excitability in PDCD set in quiet wakefulness, as revealed by rsEEG rhythms at alpha frequencies. Our results showed that widespread frontal and temporal alpha source activities exhibited an increase in magnitude in the PDD compared with the PDMCI and PD groups, as a possible function of dopamine depletion severity, which is typically greater in the former than the latter groups. In
Acknowledgements
The present study was developed based on the data of the informal European Consortium PDWAVES and European Consortium of Dementia with Lewy Body. The members and institutional affiliations of the Consortia are reported in the cover page of this article. The research activities of the Unit of University of Rome “La Sapienza” were partially supported by the H2020 Marie S. Curie ITN-ETN project with the short title “BBDiag” (http://bbdiag-itn-etn.eu). The authors thank Mrs. Jessica Janson and Mrs.
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