In this study, we investigated EEG alpha reactivity in patients with LBD compared to AD and healthy controls and its relation to cholinergic system integrity as measured by NBM volume. We found a reduction in alpha reactivity in the dementia groups compared to controls which is in line with previous EEG studies in AD [19, 20], and MEG studies in DLB [21] and PDD [22]. Importantly, for the first time we also showed that alpha reactivity is more severely affected in DLB and PDD compared to AD. Furthermore, in agreement with previous findings in healthy participants [17, 18], we found evidence for an involvement of the cholinergic system in modulating alpha reactivity, specifically in PDD patients.
Since alpha reactivity is determined by the difference between eyes-closed and eyes-open alpha power, a reduction in alpha reactivity as observed in the dementia groups, can occur in two different ways (see Fig. 5). In AD, eyes-closed alpha power was reduced compared to controls while eyes-open alpha power was not significantly different from healthy control levels. In the LBD group, the opposite was the case: while eyes-closed alpha power was not significantly reduced compared to controls (after taking into account individual alpha peak frequencies), eyes-open alpha power was significantly increased compared to controls and AD. Furthermore, in AD, there was a strong positive correlation between alpha reactivity and individual alpha peak frequency, indicating that the reduction in alpha reactivity in this group might be more related to general alpha power reduction and alpha slowing [26]. In contrast, in LBD, even though the general EEG slowing was slightly more severe than in AD, there was no significant correlation between alpha reactivity and alpha slowing, indicating that the loss of alpha reactivity might be a process that is more independent from general EEG slowing than in AD. Instead, loss of alpha reactivity in LBD might be more related to a lack of neuronal desynchronization upon opening the eyes.
In the healthy human brain, opening of the eyes normally leads to a suppression of alpha power due to neuronal desynchronization [15, 16]. This state of low alpha power has been associated with highest levels of cortical responsiveness and has been suggested to be a more externally oriented brain state in which it is easiest for external stimuli to reach the cortex [32]. In contrast, higher eyes-open alpha power indicates a more internally oriented state making it harder for external stimuli to be perceived [32]. Evidence comes from studies of pre-stimulus alpha power which showed that performance is highest if pre-stimulus alpha power is low [33]. However, the extent of alpha power suppression is not only important for processing of visual stimuli, but has also been related to attention and cognitive performance more generally. Low alpha power has been associated with higher activity in attention networks [34]. Furthermore, the extent of alpha suppression upon eyes opening has been shown to be positively correlated with cognitive performance [35] and has been related to attention and cognitive load [36]. Simultaneous EEG-fMRI studies have reported a negative relationship between blood oxygen level dependent (BOLD) signal and alpha power indicating a simultaneous occurrence of occipital alpha power decrease and neuronal activation in the occipital cortex and other cortical areas [37, 38].
The increase in eyes-open alpha power in LBD might therefore indicate a specific impairment in neuronal desynchronization. Instead of activating neurons in primary and secondary visual areas when opening the eyes, the cortex of LBD patients seems to stay in a more synchronised state which might lead to a loss of cortical responsiveness. This in turn might lead to problems with attention and cognition [35, 36].
Several previous studies have investigated the mechanisms that lead to neuronal desynchronization when opening the eyes and thereby modulate alpha reactivity. There is compelling evidence for a role of the cholinergic system [17, 18]. The suppression of alpha power from eyes closed to eyes open has been shown to be related to an increase in functional connectivity between the NBM and primary visual areas [17]. Furthermore, white matter integrity along fibre tracts connecting the NBM with occipital areas was negatively correlated with alpha reactivity. These findings suggest that cholinergic drive from the NBM might play an important role in modulating the reduction in alpha power from eyes closed to eyes open [17]. Additionally, Osipova et al. [18] showed that alpha power suppression upon opening the eyes was impaired when cholinergic neurotransmission was temporarily blocked by the cholinergic antagonist scopolamine, further suggesting that the integrity of the cholinergic system is crucial for alpha power suppression.
In the present study, across all groups and in the PDD group in particular, loss of alpha reactivity was related to volume loss within the NBM. The failure to activate neural sources in occipital cortex upon opening the eyes might therefore be due to a loss of cholinergic drive from the NBM which is in line with these previous studies [17, 18]. The lack of a specific association between alpha reactivity and NBM volume in DLB might be due to the fact that functional impairment within the cholinergic system can precede structural abnormalities; in particular it has been shown that even prior to neurodegeneration, alpha-synuclein can reduce cholinergic neurotransmitter production [9]. In contrast, PDD patients with a comparable level of cognitive impairment typically have a longer disease duration which might lead to structural abnormalities within the cholinergic system playing a greater role in the loss of alpha reactivity in these patients. Furthermore, PDD patients show less AD co-pathology than patients with DLB [39], making PDD a “purer” alpha-synucleinopathy which might explain the discrepant findings in these two groups.
Contrary to our hypothesis, alpha reactivity was not significantly correlated with measures of cognitive fluctuation severity in LBD. This might be due to the fact that alpha reactivity was quite severely reduced in most patients and most of them had cognitive fluctuations, which might have led to a floor effect. The fact that AD patients, who have less severe cognitive fluctuations compared to LBD [25], showed a less severe reduction in alpha reactivity, might indicate that loss of alpha reactivity is related to the presence of cognitive fluctuations, while a relationship between alpha reactivity and cognitive fluctuation severity is more difficult to establish based on the present results.
We decided to use individual alpha peak frequencies to determine alpha power instead of using a fixed alpha frequency band (usually from 8–12 Hz) [21, 22]. This was done to account for a shift of the alpha peak to slower frequencies in AD and LBD [26, 27]. Nevertheless, we showed that alpha reactivity differences between groups and the association with NBM volume remained the same when repeating the analysis using the standard alpha frequency band.
A potential limitation of the present study is the fact that most dementia patients were taking cholinesterase inhibitors which have been shown to influence the cortical EEG signal [40]. Due to the low number of patients not taking these medications, it was not possible to study the effect of cholinesterase inhibitors on the present results nor would it be ethical to withdraw these medications. However, investigating the effect of cholinergic medication on alpha reactivity in AD and LBD will be an important step of future research which will also help to better understand the relationship between alpha reactivity and cholinergic neurotransmission.