EEG markers are associated to gray matter changes in thalamus and basal ganglia in subjects with mild cognitive impairment
Highlights
► Association of EEG alpha3/alpha2 and theta/gamma ratio with changes in thalamus and basal ganglia in subjects with MCI. ► EEG markers-driven analysis. ► Increase of alpha3/alpha2 ratio ssociated with minor atrophy of caudate, accumbens and pulvinar nuclei. ► Increase of theta/gamma ratio associated with minor atrophy of putamina bilaterally.
Introduction
EEG has been demonstrated a reliable diagnostic tool in dementia research (Babiloni et al., 2006, Dauwels et al., 2010a, Dauwels et al., 2010b, Lizio et al., 2011, Rossini et al., 2008, Stam et al., 2003). The increase of high alpha relative to low alpha power has been recently demonstrated a reliable EEG marker of hippocampal atrophy as well as conversion of patients with mild cognitive impairment (MCI) in Alzheimer's disease (AD; Moretti et al., 2009c). Moreover, the increase of the theta/gamma ratio has been found associated to the atrophy of amygdala complex as well as to the conversion of MCI patient in non-AD dementias (Moretti et al., 2009a, Moretti et al., 2009b).
fMRI and PET-based studies, approaching the large scale neural connectivity issue, showed that impaired visual working memory correlated with brain activity within the posterior parietal association cortex, prefrontal cortex, as well as thalamus nuclei in AD (Bokde et al., 2009, Collette et al., 1997, Desgranges et al., 1998). A study using an associate memory task with healthy controls, mildly cognitive impaired subjects (MCI) and AD patients (Celone et al., 2006), found a pattern of activation in the hippocampus-related network in healthy controls, of hyperactivation in more mildly impaired MCI subjects, of hypoactivation in more severe MCI subjects and no activation in AD patients. The non-linear changes in activation in the network across the various groups provided further evidence of a previous study suggesting this non-linear dynamic in the hippocampus (Dickerson et al., 2005, Moretti et al., 2007a). Other studies of interest found that the activation during a task was not altered between the MCI subjects and the healthy controls (Bokde et al., 2008), suggesting that connectivity within a network is first altered due to the putative AD neuropathology and then changes in activation occur in the brain. It may be that before recruitment of compensatory regions for a cognitive task, functional connectivity would be the first step leading to increased activation in a region that would activate as a compensatory mechanism.
The large neural network altered in AD encompasses also thalamic structure (Frisoni et al., 2006, Frisoni et al., 2007, Frisoni et al., 2008, Frisoni et al., 2009, van Strien et al., 2009). In particular, atrophy of the thalamus and basal ganglia has been demonstrated to be involved in AD and in the symptomatic development (Canu et al., 2010, Cherubini et al., 2010). Alzheimer's disease (AD) is associated with neuronal loss not only in the hippocampus and amygdala but also in the thalamus and basal ganglia. Anterodorsal, centromedial, and pulvinar nuclei are the main sites of degeneration in AD (Zarei et al., 2010). Moreover, volumes of putamen and thalamus were found significantly reduced in patients diagnosed with probable Alzheimer's disease and the decrease in volume correlated linearly with impaired global cognitive performance (de Jong et al., 2008) . These findings strongly suggest that, beside neo-cortical atrophy, deep gray matter structures in Alzheimer's disease suffer structural changes and that degenerative processes in the basal ganglia and thalamus may contribute to cognitive decline in Alzheimer's disease.
The relationship between the sources of different EEG rhythms and thalamus–basal ganglia structure has been widely studied and accepted. For instance, findings in human and animal studies suggest that coordinated simultaneous theta activity is observed in two networks linked, respectively to striatal nucleus (Llinas et al., 1999) and to the frontal-anterior thalamic system (Gevins and Smith, 2000, Kirk and Mackay, 2003, Schmiedt et al., 2005). The alpha rhythm generation is quite more complex. The alpha dominant rhythm arises from the continuous interplay between posterior thalamus, posterior cingulated and parieto-occipital cortical areas (Cantero et al., 2009, Steriade, 2006). As a consequence, the alpha rhythm is more linked to the thalamus so the a3/a2 ratio is expected to be more associated with the thalamic or thalamus-related structure modifications. On the contrary the theta/gamma ratio is more associated with fronto-basal ganglia networks and it could more associated with modifications in these structures. Accordingly, different EEG oscillations based on different anatomical networks have been suggested to have different functions. Specifically, synchrony of theta oscillations, impinging on fronto-striatal circuits plays a crucial role in top-down modulated higher order visual processing. On the other hand, changes in alpha and gamma oscillatory activity, impinging on thalamo-cortical posterior networks, have been shown to play a relevant functional role during perceptual, executive and mnemonic processes (Klimesch, 1997; Gevins et al., 2000). As a consequence, modifications in theta/gamma and alpha3/alpha2 ratio would like to reflect anatomopathological changes in those deep brain structures.
In the present study the association of EEG indexes with gray matter (GM) changes in thalamus and basal ganglia has been studied in subjects with MCI. The working hypothesis was that modifications of both EEG markers could be underpinned by different deep brain structures, unveiling the possibility to identify different MCI populations. Results show that subjects with higher a3/a2 ratios when compared to subjects with lower and middle a3/a2 ratios showed minor atrophy in the ventral stream of basal ganglia (head of caudate nuclei and accumbens nuclei bilaterally) and of the pulvinar nuclei in the thalamus; subjects with higher t/g ratio showed minor atrophy in putamina nuclei bilaterally than subjects with middle ratio.
Section snippets
Subjects
For the present study, 74 subjects with MCI were recruited from the memory Clinic of the Scientific Institute for Research and Care (IRCCS) of Alzheimer's and psychiatric diseases ‘Fatebenefratelli’ in Brescia. The data of the same subjects were used in previously published works of our group (Moretti et al., 2009c).
Diagnostic criteria
Patients were taken from a prospective project on the natural history of MCI. The project was aimed to study the natural history of non-demented persons with apparently primary
Low-a3/a2 group
Subjects with low a3/a2 ratio exhibited a region of GM more atrophic than subjects with high a3/a2 ratios located in the head of caudate, specifically in the ventral part and accumbens nuclei bilaterally, slightly wider on the left side (see Fig. 1).
No regions of GM tissue loss were found when patients with low a3/a2 ratio were compared to those with middle a3/a2 ratio.
Middle a3/a2 group
Subjects with middle a3/a2 ratio, contrasted to individuals with high a3/a2 ratios, showed the same cerebral atrophic areas
Preliminary remarks
In this study we have considered the GM changes of deep brain structures, basal ganglia and thalamus, based on brain electrical activity markers. As a consequence, the analysis of anatomical structural changes in MCI patients was EEG marker-driven. This is a crucial point for considering the results of the present study. Indeed, it is not a simple detection of atrophy pattern between two clinically different populations of subjects, but it would investigate the association of EEG markers with
Conclusion
The integrated analysis of EEG and morpho-structural markers could be useful in the comprehension of anatomo-physiological underpinning of the MCI entity.
Conflict of interest statement
Moretti D V: I state that I have no actual or potential conflicts of interest.
Paternicò D: I state that I have no actual or potential conflicts of interest.
Binetti G: I state that I have no actual or potential conflicts of interest.
Zanetti O: I state that I have no actual or potential conflicts of interest.
Frisoni G B: I state that I have no actual or potential conflicts of interest.
Acknowledgments
The work is funded by Fatebenefratelli Association for Research.
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On the behalf of all coauthors I declare that appropriate approval and procedures were used concerning human subjects.