Exploring resting-state EEG brain oscillatory activity in relation to cognitive functioning in multiple sclerosis
Introduction
Multiple sclerosis (MS) is one of the most common chronic neurological diseases and is associated with a variety of functional deficits. Due to an autoimmune response that corrupts myelinc sheaths and leads to axonal loss in the central nervous system, MS may involve diverse deficits in e.g. gross- and fine-motor skills (Squillace et al., 2015, Yozbatiran et al., 2006), coordination, walking capacity and balance (Burschka et al., 2012, Burschka et al., 2014, Hofstadt-van Oy et al., 2015, Keune et al., 2015a, Keune et al., 2015a, Keune et al., 2017), autonomic functions (Racosta and Kimpinski, 2016), as well as sensory disturbances (Lucassen et al., 2016), fatigue and depression (Boeschoten et al., 2017, Rottoli et al., 2017).
Cognitive deficits are also frequent in MS, with prevalence estimates ranging between 40 and 65% (Hansen et al., 2015, Korakas and Tsolaki, 2016). Deficits have been described as domain-specific rather than reflecting global cognitive or intellectual decline (Hoffmann et al., 2007). Symptoms may arise in numerous domains such as information processing speed and attention, executive functions and working memory, as well as verbal and visuo-spatial memory (Amato et al., 2010, Hansen et al., 2017, Korakas and Tsolaki, 2016, Prakash et al., 2008). Impaired performance on tests addressing information processing speed and attention, as well as executive functions has been described as the most robust finding in this context (Hoffmann et al., 2007).
It is assumed that impaired cognition in MS may be attributed to white matter lesions, as well as the disruption of essential fibre tracts that may be critical for the connectivity of cortical nodes (Calabrese et al., 2009, Harrison et al., 2015, Llufriu et al., 2017). While this reasoning represents a contemporary accepted notion, initial results obtained with magnetic resonance imaging (MRI) did not always converge with those of cognitive tests. In an early study for example, the administration of immune-modulating medication was shown to be associated with stable MRI lesion load, yet patients improved on tests addressing visuospatial memory performance throughout a course of two to four years (Pliskin et al., 1996). In another study, the administration of immune-modulating medication was associated with stable or improved cognitive performance two years after treatment initiation, while there was no significant relation between MRI measures and global cognitive performance in the domains of attention, learning and memory, language, and visuo-spatial functions (Lanzillo et al., 2006). In this context, recent work involving functional MRI and connectivity analyses has revealed the presence of ongoing cortical reorganization, representing compensatory mechanisms (Llufriu et al., 2017). These compensatory mechanisms may be particularly effective during early stages of the disease, when lesion burden is still relatively low, however may be exhausted as the disease progresses and cognitive deficits consolidate (Llufriu et al., 2017, Rocca et al., 2016).
While elaborate imaging techniques may address neural correlates of cognitive dysfunction in MS, they are often not available for routine clinical examinations. Recently, it has been suggested that brain oscillatory activity may be useful as a correlate of cognitive performance and for aiding the diagnostic process (Babiloni et al., 2016, Hardmeier et al., 2012, Tewarie et al., 2013, Van der Meer et al., 2013, Vecchio et al., 2017). In a pioneering study using magnetoencephalographic (MEG) recordings, Van der Meer et al. (2013) reported increased power in the alpha-1 and decreased power in the alpha-2 band in 21 MS patients, relative to 17 matched controls, as well as a lower alpha peak frequency. In this study, global alpha-1 activity also showed a negative correlation with overall cognitive performance, driven by a negative correlation with information processing speed on a test commonly employed in MS (Symbol Digit Modalities Test, SDMT; Smith, 1982, Benedict et al., 2017).
A compatible notion frequently examined in research focusing on resting-state electroencephalographic (EEG) parameters is that an increase in spectral power of slow-wave activity (e.g. theta power, 4–7 Hz) and a decrease of fast-wave activity (beta power, 13–30 Hz), may be associated with attenuated attentional control. Such a pattern, reflected by an increased theta/beta ratio, particularly in frontal brain regions, might also be indicative of a deterioration in information processing speed and attention performance, as previously observed in healthy participants and patients with attention-deficit/hyperactivity disorder (ADHD; Barry et al., 2003, Ogrim et al., 2012, Putman et al., 2010, Putman et al., 2014). For example, Putman et al. (2014) reported on a negative relation between the theta/beta ratio and trait attentional control, examined by the Attentional Control Scale (Derryberry and Reed, 2002), in a non-clinical group. The authors replicated related previous findings obtained in ADHD (Barry et al., 2003, Loo and Makeig, 2012) and in accord with previous notions, they also suggested that the theta/beta ratio may reflect prefrontally mediated attentional control processes (Knyazev, 2007, Schutter and Van Honk, 2005). In another replication of the negative relation between the theta/beta ratio and attentional control, the ratio marker was further described as being highly test-retest reliable in a group of healthy adults (Angelidis et al., 2016).
In sum, pioneering work by Van der Meer et al. (2013) suggested that MEG alpha-1 activity may represent a marker of attention in MS, but these results remain to be replicated by means of EEG recordings. Such a replication appears particularly important with regard to the implementation of more available methods for routine monitoring purposes. Further, an extensive body of research has provided support for the EEG theta/beta ratio as a neurophysiologic correlate of attentional control processes in healthy and clinical groups. However, to date attempts to transfer this notion and to examine whether the theta/beta ratio could also be used as a marker of attention performance in MS are scarce.
Based on these considerations, in the current study it was examined whether the previously reported association between increased MEG alpha-1 activity and lower attention performance (Van der Meer et al., 2013) could be replicated by means of EEG assessments. The latter authors observed such an association for global alpha-1 activity, therefore no regional specificity was inferred. In the current work, also alpha-2 activity was considered, due to the lower signal-to-noise ratio of the EEG.
Additionally, it was tested whether an increased theta/beta ratio would also be associated with lower attention performance in MS. We intended to examine whether such an association would be particularly pronounced for frontal brain regions, as previously suggested (Putman et al., 2014). Complementary, it was explored whether the theta/beta ratio displays sufficient test-retest reliability in MS, as previously reported for healthy participants (Angelidis et al., 2016). This point was addressed since the observation of an association between an increased theta/beta ratio and impaired cognitive performance might also qualify the theta/beta ratio as a monitoring parameter in routine clinical practice, given its test-retest reliability. As EEG alpha activity is known to involve sufficient test-retest reliability (Tenke et al., 2017), this analysis was restricted to the theta/beta ratio.
The analyses outlined above address the association between resting-state EEG parameters and attention performance in MS, operationalized by means of the SDMT as previously implemented by Van der Meer et al. (2013). In an additional exploratory analysis, both resting-state EEG parameters, i.e. alpha activity and the theta/beta ratio were further examined with regard to their potential sensitivity to cognitive clinical status. To this end, besides the SDMT, also the Test of Attention Performance (TAP; Zimmermann and Fimm, 1992) was implemented and patients with and without clinically relevant deficits on the involved tests were compared with regard to alpha-1 activity, alpha-2 activity and the theta/beta ratio. The TAP provides healthy population norm-values that may be used to determine cognitive clinical status. It was expected that patients with clinically relevant deficits in attention performance would display significantly increased alpha activity, based on results by Van der Meer et al. (2013), as well as a significantly increased theta/beta ratio, compared to patients without cognitive deficits.
Section snippets
Participants
Patients were recruited as a convenience sample during the routine clinical process in the Department of Neurology, Klinikum Bayreuth GmbH, Germany. Participants were visiting the clinic for various reasons, including routine monitoring and rehabilitative purposes, administration of cyclic steroid therapy, as well as potentially necessary adjustments in the medical treatment regime. All participants provided written informed consent and the study was approved by the ethics committee of the
Alpha activity and attention performance
Descriptive correlations between alpha-1 and alpha-2 activity for frontal, central and parietal regions on the one hand and SDMT performance on the other hand, are presented in Table 2.
For global alpha-1 and alpha-2 activity, significant negative correlations with SDMT performance emerged (alpha-1: r = −0.428, p = 0.016; alpha-2: r = −0.401, p = 0.024; Fig. 1a and b). This implies that increased global alpha activity was associated with worse performance on the SDMT (slower processing speed). A
Discussion
Cognitive deficits are observable in 40–65% of MS patients and require continuous monitoring. Neuropsychological standard procedures which may be economically implemented in routine clinical practice have been established to assess these deficits on a behavioral level (Hansen et al., 2015, Hansen et al., 2017, Langdon et al., 2012). Neurophysiologic correlates of cognition, on the other hand, are not as easily obtained, which may be attributed to compensatory cortical reorganization,
Conclusions
In sum, results of the current work suggest that EEG alpha activity and the theta/beta ratio may serve as markers of attention performance in MS. Particularly the frontal theta/beta ratio might represent a marker involving potential sensitivity to clinically relevant cognitive deficits. As the EEG theta/beta ratio may be easily obtained during the routine clinical process, we suggest that future studies should further examine its clinical utility in MS in context of monitoring and intervention
Acknowledgments
The current work was supported by Genzyme GmbH (Sanofi-Genzyme), Germany. Further support occurred through a research grant provided to Dr. Keune by the Klinikum Bayreuth GmbH (2015–2017).
Conflicts of interest: The authors declared that there is no conflict of interest.
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