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Cognitive and physical training for the elderly:

Evaluating outcome efficacy by means of
neurophysiological synchronization

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Psychophysiology · January 2014
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Cognitive and physical training for the elderly: evaluating outcome efficacy
by means of neurophysiological synchronization

Christos A. Frantzidis, Aristea-Kiriaki I. Ladas, Ana B. Vivas, Magda

Tsolaki, Panagiotis D. Bamidis

PII: S0167-8760(14)00036-1
DOI: doi: 10.1016/j.ijpsycho.2014.01.007
Reference: INTPSY 10761

To appear in: International Journal of Psychophysiology

Received date: 9 May 2013

Revised date: 17 January 2014
Accepted date: 20 January 2014

Please cite this article as: Frantzidis, Christos A., Ladas, Aristea-Kiriaki I., Vivas, Ana
B., Tsolaki, Magda, Bamidis, Panagiotis D., Cognitive and physical training for the
elderly: evaluating outcome efficacy by means of neurophysiological synchronization,
International Journal of Psychophysiology (2014), doi: 10.1016/j.ijpsycho.2014.01.007

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 ACCEPTED MANUSCRIPT

Cognitive and physical training for the elderly: evaluating

outcome efficacy by means of neurophysiological
synchronization
Christos A. Frantzidisa, Aristea-Kiriaki I. Ladasb, Ana B. Vivasb, Magda

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Tsolakic and Panagiotis D. Bamidisa, *

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a
Laboratory of Medical Informatics, Medical School, Aristotle University of
Thessaloniki, Greece (christos.frantzidis@gmail.com, bamidis@med.auth.gr)

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b
Psychology Department, The University of Sheffield International
Faculty, City College, Thessaloniki, Greece (arladas@seerc.org,

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vivas@city.academic.gr)
c
3rd Department of Neurology, Medical School, Aristotle University of Thessaloniki,
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Greece (tsolakim@med.auth.gr)

keywords: age-related intervention, cognitive & physical training, dementia,

electroencephalography, relative wavelet entropy, resting-state synchronization
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*Corresponding author at: Medical School, Aristotle University of Thessaloniki,

54124 Thessaloniki, Greece, tel: +302310999310, e-mail: bamidis@med.auth.gr
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Abstract

Recent neuroscientific research has demonstrated that both healthy and pathological

aging induces alterations in the co-operative capacity of neuronal populations in the

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brain. Both compensatory and neurodegenerative mechanisms contribute to

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neurophysiological synchronization patterns, which provide a valuable marker for

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age-related cognitive decline. In this study, we propose that neuroplasticity-based

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training may facilitate coherent interaction of distant brain regions and consequently

enhance cognitive performance in elderly people. If this true, this would make

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neurophysiological synchronization a valid outcome measure to assess the efficacy of
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non-pharmacological interventions to prevent or delay age-related cognitive decline.

The present study aims at providing an objective, synchronization-based tool to assess

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cognitive and/or physical interventions, adopting the notion of Relative Wavelet

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Entropy. This mathematical model employs a robust and parameter-free

synchronization metric. By using data mining techniques, a distance value was

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computed for all participants so as to quantify the proximity of their individual profile
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to the mean group synchronization increase. In support of our hypothesis, results

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showed a significant increase in synchronization, for four electrode pairs, in the

intervention group as compared to the active control group. It is concluded that the

novel introduction of neurophysiological synchronization features could be used as a

valid and reliable outcome measure; while the distance-based analysis could provide a

reliable means of evaluating individual benefits.

1. Introduction
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Healthy as well as pathological aging is associated with neuroanatomical and

functional changes in the brain (Ewers et al., 2011; Zhang et al., 2012). For instance,

studies involving healthy elderly participants have reported reduced activity in neural

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networks that are active at rest (resting-state networks - RSNs) and form the anterior

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part of the default mode network (DMN) (Damoiseaux et al., 2008). Diminished

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DMN activity may be attributed to an overall grey matter (GM) reduction, which has

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been mostly observed in the frontal and the parietal cortex (Koch et al., 2010). Studies

have also shown that degeneration of cortico-cortical projections, in both healthy and

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pathological aging, influences coherent firing of neuronal circuits, thereby affecting
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their synchronization (Koenig et al., 2005). Although there is no a unique disturbance

pattern regarding the brain’s co-operative activity, most studies report a reduction of
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synchronization associated with cognitive decline in elderly people relative to healthy

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controls. Specifically, a decrease in synchronization is most prominent within the

alpha band frequency spectrum (Koenig et al., 2005). Several studies have also shown
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less beta-band synchronization during early stages of Alzheimer’s disease (AD)

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(Koenig et al., 2005; Park et al., 2008) by means of the Global Field Synchronization
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(GFS) and the Synchronization Likelihood (SL) techniques (Stam et al., 2003).

Furthermore, it has been suggested that the loss of gamma band synchronization

found in AD may be responsible for the deficient integration of synchronized activity

among distant brain regions (Koenig et al., 2005). All together these findings may

account for the functional disconnection among distant brain regions that

characterizes AD neuropathology (Delbeuck et al., 2003). However, in some cases an

increase instead of a decrease of synchronization is associated with pathological

aging. For instance, studies have reported a synchronization increase in the delta band

due to cholinergic deafferentiation (Koenig et al., 2005), and hyper synchronization of

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the parieto-temporal cortex in preclinical stages of AD (Knyazeva et al., 2013). The

latter finding has been attributed to compensatory mechanisms observed within the

theta frequency bands, and linked with poor memory performance (Sankari et al.,

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2011). Overall, these findings suggest that EEG synchronization could be a valid and

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valuable biological marker of early neurodegeneration signs.

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In the last decades there is a growing interest at investigating whether the

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negative effects of aging can be ameliorated, or even delayed, with cognitive or/and

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physical training (Colcombe et al., 2006; Boyke et al., 2008; Smith et al., 2009;

Erickson et al., 2011; Simon et al., 2012). At the base of all these cognitive
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interventions is the concept of neuroplasticity: the brain is able to adjust and

compensate for brain and cognitive alterations by strengthening existing connections

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or creating new ones (Erickson et al., 2011; Mahncke et al., 2006). An example of
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such interventions is the IMPACT study, which randomly assigned 487 healthy old

adults to one of two groups: the intervention and the active control group (Smith et al,
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2009). In the intervention group, participants were intensively trained (40 training

hours in two months) with auditory stimuli by means of computer software named
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Brain Fitness. This standardized training program consists of six computerized

exercises with varying levels of difficulty, which tap mostly on auditory processing.

Participants in the active control group were also exposed to a computerized task that

did not train specific cognitive processes and received the same hours of “training” as

the intervention group. The study reported statistically significant improvements on

the cognitive processes directly trained, in the intervention group relative to the active

control group. Most important, there were also significant spillover effects to other

measures that were not directly trained. The authors concluded that the intervention

was effective in improving cognitive performance in old adults. Despite this and other
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positive findings, there are still some outstanding questions such as finding the most

effective type, and optimal duration of cognitive training, as well as, what the long-

term effects of these interventions might be.

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Evidence regarding the effects of physical activity on healthy aging appears to

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be more robust (Boyke et al., 2008; Billis et al., 2010). There have been several

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hypotheses put forward to explain the striking positive effects of physical activity on

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healthy aging (Colcombe et al., 2006; Erickson et al., 2011). For instance, it has been

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reported that aerobic training induces hippocampal neurogenesis (Erickson et al.,

2011). Physical activity is also related to the decrease of β-amyloid deposition

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(Lazarov, et. al., 2005) and the reduction of risk factors that may accelerate

neurodegeneration (Cotman, 2007). Finally, the oxygenation hypothesis proposes that

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brain perfusion can account for the beneficial effect of physical activity on cognitive
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function (Obisesan et al., 2012).

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The aforementioned beneficial effects of both cognitive and physical training

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on cognitive performance and daily functioning, led to a plethora of non-

pharmaceutical training programs aiming to prevent dementia onset. The evaluation

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of these approaches and the validation of their effectiveness are currently top research

priorities. For instance, only a few studies (Boyke et al., 2008; Colcombe et al., 2006;

Engvig et al., 2010; Erickson et al., 2011) have actually looked at the functional

changes or structural changes in brain activity associated with this type of

interventions. One may expect structural changes such as increases in cortical

thickness of specific regions (Boyke et al., 2008; Colcombe et al., 2006; Engvig et al.,

2010; Erickson et al., 2011). In line with this hypothesis, it has been reported that

intensive verbal memory training with the Method of Loci was associated with an

increase of the cortical thickness in the right fusiform and lateral orbitofrontal cortex
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among other regions (Engvig et al., 2010). Another study demonstrated that visuo-

motor learning may also induce the plasticity of the mature human brain (Boyke et al.,

2008). Twenty-five healthy old adults were trained for three months in three-ball

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cascade juggling that, according to the authors, requires dynamic storage and

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processing of complex visual stimuli, and visuomotor coordination. The study found

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that senior citizens who participated in the training group demonstrated a significant

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increase in grey matter on the middle temporal area of the visual cortex, on the left

hippocampus and on the nucleus accumbens, as compared to the control group.

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However, the aforementioned effects were not sustained during the 3-month follow-
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up period (Boyke et al., 2008).

Studies have also reported brain changes related with physical training.
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Colcombe et al. (2006) conducted MRI scans in a group of 59 healthy elderly

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participants, who were trained in aerobic exercises during 6 months. The active

control group was trained during the same period with whole-body stretching and
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toning exercises. The authors reported an increase in size of the anterior hippocampus

in the intervention group relative to the active control group. These findings were
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further supported by a recent randomized controlled trial. It adopted a similar design

regarding the groups. It involved 120 healthy older adults who were randomly

assigned to one of two groups described above. The training parameters were three

days per week and the program lasted for one year (Erickson et al., 2011). However, it

was not clear what the functional relevance of these structural changes might be.

We propose that studies assessing the impact of cognitive and/or physical

interventions must take into account changes in functional activity or connectivity

between regions, which seem to be a valid index of cognitive performance. Recently,

there is a growing interest in the study of the functional synchronization among

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distant brain regions. In one related study, Pons et al. (2010) measured structural and

functional alterations associated with aging, using a neural mass model. The authors

focused on thalamocortical alpha oscillations at resting state (eyes closed), and

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reported a long-range reduction of synchronization among thalamo-cortical and

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cortico-cortical brain regions in healthy and pathological (Mild Cognitive Impairment,

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MCI) aging. Similarly, Han et al. (2012) reported abnormal functional connectivity

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values in patients suffering from MCI as compared with healthy control individuals.

In addition, we propose that quantitative electroencephalogram (qEEG) is a suitable

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tool for studying interactions among brain regions since it is a non-invasive, relatively
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easy to use and cheap technique.

In the present study we measured synchronization changes associated with a

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combined cognitive and physical intervention in a sample of senior citizens. We

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employed a neurophysiological resting state synchronization evaluation framework

based on the notion of relative wavelet entropy (RWE). The mathematical model
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adopted employs a simple, accurate, robust and parameter free mathematical notion,

which is combined with a decision making scheme in order to consider both the group
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and participant level. To our knowledge, this is the first study that used a

synchronization-based technique to measure the impact of a cognitive and physical

intervention on the brain activity of senior citizens. Based on the aforementioned

literature findings on both physiological and pathological aging, the current study

hypothesizes that a neuroplasticity-based intervention program is expected to induce

increased synchronization among distant brain regions. Since, the proposed

mathematical model does not focus on a specific frequency band but on the relative

energy distribution of the EEG signal, we expect increased synchronization among

regions across the two hemispheres.

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2. Methods

2.1 The Long Lasting Memories (LLM) Training Program

The participants of the LLM training program performed both cognitive and physical

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exercise, whereas the ACTIVE protocol was also computerized and had the same

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duration / intensity with the intervention protocol (Konstantinidis et al., 2010;

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Bamidis et al., 2011).

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2.1.1 Cognitive Training (CT)

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A Greek-adapted version of the Brain Fitness software (© PositScience, USA),
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developed during the Long Lasting Memories project (www.longlastingmemories.eu)

(Bamidis et al, 2011), was employed for the cognitive part of the training program

(LLM training). The program consists of six (6) exercises with auditory stimuli
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(Smith et al., 2009). Each exercise has self-paced levels of difficulty and lasts for 15

minutes. Each individual training session consisted of four (4) out of the six (6)
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exercises, and lasted for approximately one (1) hour. The whole training protocol
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included 1 hour of cognitive training per day for three (3) to five (5) days / per week
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during a period of eight (8) weeks. This cognitive program was designed to train

processing of auditory-related sensory information, memory, attention and learning

(Mahncke et al., 2006a). Auditory training was selected since the auditory brain

system is better studied than the visual system (Mahncke et al., 2006b) and studies

have shown that age-related cognitive deficits may partially result from reduced

sensory processing in the auditory domain. For instance, it has been shown that high-

frequency auditory loss was associated to impaired speech perception and poor

temporal processing (Mahncke et al., 2006b).

2.1.2 Physical Training (PT)

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Physical training was performed through the FitForAll (FFA) platform, which was an

exergaming environment based on the Nintendo Wii Remote and Balance Board

(Billis et al., 2010; Billis et al., 2011). The program consisted of several simple

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games, carefully designed for senior citizens. These exercises aimed to enhance body

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flexibility and strength, as well as, to improve the participants’ physical endurance

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through aerobic training (Gonzalez-Palau et al., 2013).

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2.2 Active Control (AC) Group

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In order to control for several potential confound factors such as willingness to adopt

an active aging profile, computer skills and socialization, the IMPACT study (Smith
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et al., 2009) included an active control (AC) group rather than a passive control one.

Therefore, it was decided for the purposes of the current piece of work, to also
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introduce a control design similar to the LLM training program with respect to the
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training parameters (computer use, intensity and duration). So, the AC protocol,
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included viewing of YouTube documentaries with topics derived from nature, art and
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history. After the end of the documentary, participants digitally performed a multiple-

choice questionnaire with questions about the documentaries. The AC control group
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did not perform any physical training. The whole protocol was also computerized and

simulated the digital features of CT and Brain Fitness described above.

2.3 Neuropsychological Examination

A complete set of neuropsychological testing took place twice: (a) prior (1-15 days) to

the study initiation and (b) 1-15 days after completing the training. Details about the

impact of LLM training on neuropsychological examination may be found in

(Bamidis et al, 2012; Bamidis et al., 2013).

.
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2.4 Participants

The present study involved 103 participants (53 in the training group and 50 in the

active control group). As mentioned already, the study was part of the multi-centric

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trials piloted during the Long Lasting Memories (LLM) project in five (5) EU

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countries and aiming to promote independent living of senior participants. The

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majority of the participants (75.73%) were females. Inclusion criteria were; i) age

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over 60, ii) MMSE scores above 18 iii) no history of neurological condition (e.g.,

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epilepsy, stroke, etc), severe depression or psychiatric disorder, iv) not being currently

medicated or being medicated for at least 3 months (stable medication) v) normal or

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corrected-to-normal vision and hearing, and vi) being fluent Greek speakers and

committed to the study throughout its duration. Prior to their enrollment, all
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participants were informed about the study and signed an informed consent form.
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During their participation and until the end of the one-year follow up period,

participants were excluded from any other study and/or training program. The study
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was approved by the ethics committee of the Greek Association of Alzheimer’s

Disease and Related Disorders.

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The two groups were matched on age, male-to-female ratio and general

cognitive status as measured by the MoCA and the MMSE tests (see Table 1).

Table 1: Mean age, sex and cognitive status values regarding the LLM training (LLM) and the Active control (AC)

group

Age MMSE MoCA No. of Males

LLM 70.49 ± 5.79 26.09 ± 3.03 22.45 ± 4.30 13/53 (24.53%)

AC 67.30 ± 6.12 25.90 ± 3.72 22.56 ± 4.02 12/50 (24.00%)

Note: all ps > .05

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2.5 Neurophysiological Recordings

Electroencephalographic data were recorded using a Nihon Kohden JE-207A

equipped with active electrodes attached on a cap fitted to the scalp (EASYCAP). The

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device consisted of 57 electrodes recording brain signals, 2 reference electrodes

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attached to the earlobes and a ground electrode placed at a left anterior position. Both

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vertical and horizontal electrooculograms (EOG) as well as electrocardiographic

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(ECG) activity were also recorded using bipolar electrodes. Electrode impedances

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were kept lower than 2 ΚΩs, while the sampling rate was set at 500 Hz. Participants

were instructed to sit in a comfortable armed chair, to close their eyes and to stay
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calm for five minutes.

The electrodes of each hemisphere were re-referenced regarding the earlobe

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signal of the same hemisphere. The electrodes located on the anterior-posterior

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midline were re-referenced by means of the linked earlobe activity. A high-pass filter
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with a cut-off frequency at 1 Hz was used for removing low-frequency signals, while
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a notch filter centered on the 50 Hz eliminated the industrial noise. Both filters were

digital Butterworth filters of 3rd order provided by the Matlab Signal Processing
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Toolbox. The Independent Component Analysis (ICA) algorithm was employed for

the detection of artifactual sources. As artifactual sources were regarded linear drifts,

muscle recordings, high frequency noise, heart modulation or artifacts due to the

participant movements. Then, rejection of short data segments that were contaminated

with noise was done by visual inspection. The aforementioned preprocessing steps

were performed through the EEGLAB graphic user interface (Delorme & Makeig,

2004). Finally, 20 seconds of continuous, high quality, artifact-free data were selected

as an input to the synchronization analysis algorithm.

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2.6 Synchronization analysis

The analysis employed wavelets which are mathematic oscillatory tools ideal

for time-frequency analysis of non-stationary data (Frantzidis et al., 2010). The initial

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step of the wavelet analysis was the selection of the appropriate mother wavelet,

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which determined the basic shape of the wavelet. Then, both time scaling and

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translation took place resulting in the entire wavelet family. The scaling procedure

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was adopted towards the precise representation of frequency varying components,

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while translation captured the time-dependent features. The EEG (20 seconds artifact-

free) continuous data were then divided in windows of 128 milliseconds duration. The
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first 150 windows were further analyzed. Then, the Orthogonal Discrete Wavelet

transform (ODWT) at periodization mode was used for computing the wavelet
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coefficients for each time window through iterative time-frequency decomposition.

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The amplitude of the wavelet coefficients quantified the similarity degree among the

wavelet and the actual signal; while the coefficient’s sign indicated whether the
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correlation was positive or negative (polarity). The discrete version of the wavelet

transform was preferred instead of the continuous one, so as to discard redundant

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information; whereas the orthogonal basis facilitated the perfect reconstruction of the

initial brain data. The decomposition scheme employed recursive low-pass filtering

for extracting the activity of each frequency band with optimal resolution. The above

computations were performed through Matlab functions. The window length was the

minimum one that contained at least one coefficient from each frequency band.
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Figure 1: Visualization of the proposed synchronization analysis framework: Two brain signals from a pair of
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electrodes served as an input (first layer). Then, the Orthogonal Discrete Wavelet Transform was adopted and

a recursive decomposition scheme through low-pass filtering resulted in the extraction of the activity for each
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frequency band with optimal time-frequency resolution (second layer). The wavelet coefficients for each band

were evaluated and the energy of each band was computed (third layer). Then the similarity degree of the

energy distributions among each electrode pair was computed through the relative wavelet entropy, thereby

resulting in the synchronization matrix (fourth layer).

For each time window and for each electrode, the wavelet coefficients were

computed for the five frequency bands according to the decomposition scheme

(Figure 1 – upper panel; right part) through equation (1). Since, there were multiple

wavelet coefficients corresponding to a decomposition level (k=1…K), these wavelet

coefficients were squared and then summed in order to provide the energy of each
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frequency band. In this formula, j=1…5 denoted the decomposition level, Ck were the

wavelet coefficients and Ej were the energy values for each frequency band:

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Ej   Ck 2 ,

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j=1…5 (1)
k 1

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Then, the total energy (Etot) of the EEG signal was computed as the

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summation of the energy values for the five frequency bands:

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Etot= (2)

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Then, the relative energy for each frequency band was computed by simply
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dividing its absolute energy value (Ej) with the entire EEG energy (Etot). The relative

energies represented the total energy contribution of a specific rhythmic activity to the
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whole EEG energy and were positive, non-zero numbers, whereas their summation
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equaled to one (Rosso et al., 2001).

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Finally, the similarity between the energy distributions among electrodes was
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computed and was regarded to reflect the synchronization degree in terms of

generalized rhythmic activity co-operation. The synchronization metric was computed

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as follows: each electrode activity was compared with each other using electrode

pairs. So, in each time window, there existed N × N electrode comparisons, where N

denoted the number of electrodes (N=57 in this case). The comparison was performed

using the notion of relative wavelet entropy (RWE), whereas pj and qj were the energy

distributions of the electrode pairs that were compared:

RWE= pj × ln (pj / qj) (3)

The aforementioned computations resulted in a synchronization matrix (Figure

1 – fourth layer) and were repeated for each time window. Then, average values of the
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matrix were computed for each participant. The larger the value (red color) of a

matrix element, the less synchronization among the corresponding electrode pair; a

zero value (blue diagonal line) was obtained when comparing an electrode with itself.

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The present study employed the family of bi-orthogonal wavelets of fifth order since

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this was a suitable choice when dealing with EEG/ERP data as indicated by Frantzidis

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et al. (2010).

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2.7 Neurophysiological Evaluation of the LLM Intervention

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The aforementioned analysis was performed twice for each participant: prior

to the training and after the training. To express synchronization increases as a result
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of the intervention, the synchronization matrix of each participant at post condition

was subtracted from the baseline condition (pre condition).

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2. 8 Feature Selection Procedure

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Since the total number of likely synchronization features was extremely large
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(57 * 57 = 3249 electrode pairs), a feature selection procedure was essential to take

place prior to any statistical analysis. To this extent, a two-fold procedure was
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followed. The initial step involved a pre-selection of the electrode pairs in accordance

to brain interactions relevant to aging. More specifically, we included electrode pairs

reflecting long distant synchronizations (e.g. prefrontal – (parieto)-occipital

synchronization) (Babiloni et al., 2004; Babiloni et al., 2009), associated with markers

of executive functioning (Daffner et al., 2003), as well as, indices of compensatory

mechanisms either on anterior (Sankari et al., 2011) or posterior regions (Knyazeva et

al., 2013). Then, as a second step, a threshold parameter regarding synchronization

increase was defined. The threshold value was set arbitrarily at a particularly high

value in order to avoid false positives. More specifically, the average synchronization
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matrices were computed for both the LLM (N1=53) and the ACTIVE control group

(N2=50) and for each experimental phase (baseline, post-training). Then, a threshold

value corresponding to synchronization increase ≥10% was set to these average

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matrices. This process essentially selected only 12 electrode pairs (out of the possible

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(57 × 57)-57 = 3192) corresponding to less than 0.4 % of the available (likely)

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features. So, this resulted in the following electrode pairs which were then further

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analyzed:

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Table 2: List of selected features used for the neurophysiological evaluation of the LLM training

Electrode Pair Involved areas

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Fp2 – Oz Right Prefrontal – Occipital midline

FC2 – CP3 Right Frontocentral – Left Centroparietal

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Oz – Fp2 Occipital midline – Right prefrontal

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Pz – FCz Parietal midline – Frontocentral Midline

CP3 – FC2 Left Centroparietal - Right Frontocentral

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CP3 – CP1 Connection among left centroparietal areas

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CP3 – P6 Left Centroparietal – Left Parietal

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Afz – Fp2 Anteriofrontal midline – Right Prefrontal

FC6 – P4 Right Frontocentral – Right Parietal

CP3 - POz Left Centroparietal – Parietooccipital midline

CP3 – Oz Left Centroparietal – Occipital midline

POz – CP3 Parietooccipital midline - Left Centroparietal

2.9 Data-mining framework

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The classification of the neurophysiological data was performed using the

Mahalanobis distance (Md) based classifier, which was simple, robust and offered a

quantifiable way of measuring the individual impact of the intervention. The Md

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classifier received as an input vector μ which denoted the mean values (centroids) of

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the neurophysiological features estimated for the training group (μtr) and the control

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group (μctrl). The neurophysiological data of each individual participant form a

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feature vector χ that was compared with the centroids of the two groups according to

the following formula:

Md = ((χ-μ) × S-1 × (χ-μ)Τ )1/2 NU (4),

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where S-1 matrix was the inverse of the covariance matrix either for the feature data of

the training or for the control group. So, the above formula computed the distance of
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each individual feature vector from the mean value of the training or the control data.

Therefore, it could provide an estimation of whether the mean training

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neurophysiological effects were obvious in an individual participant or not.

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3. Results

3.1 Statistical Analysis

The mean difference in synchronization (mean synchronizationpre-intervention

minus mean synchronizationpost-intervention) for each electrode pair was computed for

each participant and submitted to a one-way MANOVA in order to investigate

whether EEG synchronization increase differs as a function of the intervention (LLM

versus AC). Results showed that the mean synchronization increase was significantly

larger for the participants of the LLM intervention compared to the AC [F (1, 107) =

3.566, p < .0005, Wilk's λ = 0.308, η2 = .308] (see Table 3). Further one-way
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ANOVAs for each electrode pair using the Bonferroni correction for multiple

comparisons (corrected alpha level= 0.004), showed a significant main effect of

intervention for four of the pairs (see Figure 2).

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Table 3: Means, standard deviations and statistical significance of the candidate features (electrode pairs) that
differed as a function of intervention. The first four rows of Table 3 depict the directed electrode pairs that

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reached statistical significance after the Bonferroni correction (p-value < 0.004), while the remaining ones
contain the electrode pairs with 0.05≥p-value≥0.004.

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Electrode pairs Mean Values p-value

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LLM Active

FC2 – CP3 0.064 ± 0.11 -0.024 ± 0.12 .00001**

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CP3 – FC2 0.060 ± 0.12 -0.030 ± 0.12 .00001**

Afz – Fp2 0.057 ± 0.14 -0.040 ± 0.16 .001**

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FC6 – P4 0.058 ± 0.11 -0.015 ± 0.11 .001**

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Pz – FC2 0.059 ± 0.15 -0.005 ± 0.11 .011

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CP3 – P6 0.067 ± 0.13 0.010 ± 0.11 .016

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CP3 – CP1 0.062 ± 0.13 0.002 ± 0.14 .022

Oz – Fp2 0.061 ± 0.15 -0.080 ± 0.18 .032

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Fp2 – Oz 0.065 ± 0.14 -0.001 ± 0.18 .035

*Larger relative wavelet entropy value denotes less synchronization of the

electrode pair. Therefore, decreased value in the formula (mean
synchronizationpre-intervention minus mean synchronizationpost-intervention) indicates
that relative wavelet entropy value was higher during baseline and
synchronization increased after training
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Figure 2: Visualization of the average values for each statistically significant feature, computed for both the

LLM (blue bar) and the Active Control (AC) training group (red bar).
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3.2 From electrode pairs to Regions of Interest (ROIs)

The aforementioned methodological analysis involved a feature selection

procedure in order to detect electrode pairs that exceeded a synchronization increase

over a user-defined threshold. Then, these pairs were statistically analyzed. However,

such a procedure may increase the risk of false positive results. Aiming to investigate

whether the LLM training resulted in more generalized synchronization increases the

analysis was extended by defining regions of interest instead of selecting single

electrode pairs. Therefore, the following areas were defined (see Fig 3).
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 Right Hemisphere Region –RG1 (FC2, Af4, Fp2, F2, F4, F6, F8, C2, C4, C6,

T8, FC4, FC6, FT8)

 Left Hemisphere Region – RG2 (CP3, CP1, CP5, TP7, P7, P5, P3, P1, PO3,

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O1, C1, C3, C5, T7)

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 Right Anterior & Anterior Midline Area - RG3 (Fpz, Afz, Fz, Fp2, Af4, F2,

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F4, F6, F8)

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 Right Frontocentral & Right Parietal Region – RG4 (FC2, FC4, FC6, FT8, C2,

C4, C6, T8, CP2, CP4, CP6, TP8, P2, P4, P6, P8)

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Figure 3 Definition of regions of interest by extending the electrode pairs identified previously. The left part
defines a right anterior and a left posterior region in order to investigate inter-region synchronization increases
at both directions. The right part defines two regions (another right anterior and a right centroparietal one) for
investigating intra-region synchronization increases.

These regions were then considered as regions of interest (ROIs). The

formation of ROIs was based on a priori information (for a justification see the

Discussion Section). Aiming, to avoid any methodological limitations, a bootstrap-

randomization technique for selecting the electrode pairs was followed. More

specifically, the available electrode pairs for each ROI were input into a random

number generator which in turn outputs choices of electrode pairs to be used for
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unbiased estimations of synchronization alterations between the two phases of the

experiment. So, a fixed number of electrode pairs were randomly selected for each

participant and for each experimental phase (pre & post condition), in accordance

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with usual bootstrap technique practice. Then, the synchronization analysis

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framework was applied for each selected pair. The synchronization among two ROIs

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was computed as the average value among all the selected electrode pairs. Therefore,

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we avoided multiple testing of electrode pairs and estimated a single mean

synchronization value. This, region-based synchronization estimation was performed

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in the following four cases: two inter-region estimations (RG1-RG2, RG2-RG1) and
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two intra-region synchronization computations (RG3 and RG4), thereby resulting in

four ROI-based synchronization values. Finally, these four synchronization features

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were averaged, and a single, generalized synchronization value was computed for
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each participant and for each phase. This approach was adopted in order to avoid

multiple computations over single electrode pairs that strictly define an interaction
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usually affected by volume conduction and poor spatial resolution. Thus, instead of
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computing synchronization of electrode pairs, this was done for specific ROIs. These
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ROIs covered a much broader area (an entire anterior/posterior region of a specific

hemisphere). Therefore, the effects of volume conduction were greatly attenuated,

while there was no need for accurate spatial resolution. The ROI synchronization

degree was computed as an average value of a great number of randomly selected

electrode pairs, which was hypothesized to provide a better estimate of the

synchronization among entire regions and reduced the number of false positives. The

whole process is visualized in Figure 4.

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Figure 4 Flowchart demonstration of the computational framework proposed for estimating the
synchronization degree among Regions of Interest (ROIs). Selection of ROIs was performed using a priori
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knowledge and already existing aging models. Electrode pairs were randomly selected (bootstrap technique)
and the synchronization degree among two ROIs is estimated (average synchronization among randomly
selected electrode pairs). An overall synchronization value for each participant and for each experimental
phase was estimated for the ROIs under investigation.
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The mean synchronization increase (pre-post) of the LLM group was .02836 ±
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.07791 (standard mean error = .01055); whereas the mean synchronization increase

for the ACTIVE control group was -.02061 ± .01055 (standard mean error = .01070).
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We conducted an Independent Samples t-test and found significant differences

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between the groups (t=3.254, df=101, p=0.002).

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3.3 Classification Results

To estimate whether the beneficial overall effect of the intervention was

indeed observed in the majority of the participants in the LLM group, we estimated

the mean value of the synchronization increase/decrease regarding the four (4)

electrode pairs for both the LLM (Figure 2; blue bar) and for the ACTIVE participants

(Figure 2; red bar). Then, we computed the Mahalanobis distance of each feature

instance from the two centroids.

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Then, each feature instance was classified by comparing its distance from both

centroids (corresponding to each group's overall mean). The classification was

performed through the Md classifier. According to this metric 43/53 participants of

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the training group demonstrated synchronization increases that were closest to the

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mean neurophysiological pattern of the LLM group. Regarding the AC group, the

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classification performance reached 72%, whereas the overall performance was

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76.57%.

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4. Discussion

In this piece of work, a novel approach was employed to investigate brain changes
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associated with a combined cognitive/physical intervention in a group of old adults.

We measured synchronization at rest (eyes closed) and employed an evaluation

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framework based on the notion of relative wavelet entropy (RWE). In agreement with

our hypotheses we found a significant increase in synchronization in four directed

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electrode pairs (FC2-CP3, CP3-FC2, Afz-Fp2, and FC6-P4) and the corresponding
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ROIs in the LLM group relative to an active control group. Using a data-mining
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technique we found that the majority of the participants (81%) in the LLM group

showed this pattern of improvement. Thus, we can conclude that this is a robust

finding.

4.1 Synchronization as a valid measure of intervention effects in old adults.

The present study proposes a novel neurophysiological measure for

quantifying the benefits of cognitive and physical training for promoting healthy

aging. Given that intervention programs are performed in day care centers and small

clinics, there is need for an examination that would be relatively low-cost, non-

invasive, easily performed and with no risk. Although the EEG is a suitable technique
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since it fulfills all the above criteria, it is rarely used in clinical practice. One of the

main reasons for the relatively low acceptance among clinicians was the vulnerability

of brain signals to noise contamination and muscle/motion artifacts, which prevented

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the extraction of reliable neurophysiological features. Nowadays, these

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methodological limitations have been greatly overcome by technological advances

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allowing simultaneous recordings from dense electrode arrays and facilitating the

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acquisition of high quality data through the usage of active electrodes. Artifact

rejection techniques (ICA algorithm) and modern filtering ways (discrete wavelet

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decomposition) when combined with elaborate algorithms result in precise and robust
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neurophysiological markers that provide insights about the degree of cognitive

deficits.
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Furthermore, studies suggest that measuring brain activity at rest, and not in
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relation to an event, may be more useful when studying aging populations. The

pioneering work of Biswal and collaborators demonstrated that functional cooperation

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among motor-related brain regions was preserved in resting state condition (Biswal et

al., 1995). This finding indicates that intrinsic activity (resting state) may reflect a
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state of brain’s functional organization. Functional connectivity during resting state

was employed as a powerful tool for linking brain function with the underlying

structural properties and small-world topology (Bullmore and Sporns, 2009).

Structural brain networks, being deterministic in nature, facilitate the occurrence and

dynamical formation of functional co-operations. These interactions are not

completely random signal alterations, but form the brain’s intrinsic dynamic

properties that continually evolve towards the formation of optimal functional

network configurations (Deco et al., 2011). The importance of the continuous

evolution of functional resting state networks for cognitive function has been
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demonstrated in developmental studies with children (McIntosh et al., 2008) as well

as elderly populations (Garrett et al., 2010). According to these studies brain

variability is correlated with the efficiency of brain and consequently cognitive

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functioning, and it is also negatively correlated with age (that is the elderly people

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show decreased variability). Therefore, we propose that synchronization at rest may

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be a useful and valid index of brain and cognitive function in old adults, and may,

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therefore, be a good outcome measure for assessing the effect of interventions.

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On the backbone of the neurophysiological evaluation framework employed

herein was relative wavelet entropy, used as synchronization metric. RWE was
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derived as a robust way of quantifying the dynamic cooperation among short EEG

signals (Rosso et al., 2001). This time-evolving entropy notion is based on the
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orthogonal discrete wavelet transform (ODWT) and was used for its attractive
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mathematical properties in comparison to other synchronization measurements. More

specifically, it is a parameter-free methodology that only requires the input of the

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time-series data of each electrode pair. This makes it an ideal methodology for

biological data since it does not require the unrealistic assumption of time-series
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stationarity (Blanco et al., 1995). The mathematical principle of stationarity assumes

that the signal’s mean value and variance remain constant over time. This limitation

was overcome thanks to the localization characteristics of the wavelets. The adoption

of the ODWT facilitates the optimal time-frequency resolution for each frequency

band and time scale.

The proposed synchronization analysis was initially based on estimating the

synchronization degree among electrode pairs. The feature selection procedure

resulted in four electrode pairs. Two of them were defined by a right frontocentral

(FC2) and a left centroparietal (CP3) electrode, thereby implying an inter-hemispheric

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co-operation. The third pair involved the electrode placed on an anteriofrontal midline

position (Afz) and the right prefrontal electrode (Fp2), whereas the latter pair

involved electrodes located on the right hemisphere (FC6-P4). However, analysis of

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single electrode-pairs faces a statistical limitation of producing a high number of false

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positives. A partial solution to that problem may be the definition of an extremely

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high threshold of synchronization increase (greater than 10% in comparison with the

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baseline recordings). Even in that case, analysis of single EEG electrodes cannot be

directly linked to specific cortical areas due to the poor spatial capacity of EEG

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analysis and the problem of volume conduction. Therefore, findings of
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synchronization increases on a few and specific electrode pairs would be of limited

value. Aiming to investigate whether the LLM intervention induced synchronization

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increases among broader brain areas we extended the synchronization analysis by

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defining ROIs. These ROIs were located on the entire right anteriocentral (RG1), left

centroposterior (RG2), right anterior (RG3) and right posterior (RG4) areas. The
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definition of these ROIs was based on previous neuroscientific findings which

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demonstrate the preferential vulnerability of prefrontal cortex (Salat et al., 2004;

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Peelle et al., 2013), the age-related decline of the right hemisphere proposed by the

Right hemi-aging model (Albert & Moss, 1988; Dolcos et al., 2002) and the anterior-

posterior functional disconnection due to pathological aging (Babiloni et al., 2004;

Delbeuck et al., 2003; Babiloni et al., 2009). According to the Right hemi-aging

model, the right-hemisphere and especially its posterior part is more vulnerable to

age-related decline in comparison with the left hemisphere (Albert & Moss, 1988).

More recent studies demonstrated structural changes due to aging, which were more

prominent on the prefrontal cortex (Salat et al., 2004). The current piece of work

investigated whether LLM training could prevent alterations (i.e. physiological

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decline) in these right-hemisphere regions. The intra-region neurophysiological

synchronization through the notion of RWE was employed as a metric. The study

results imply that LLM training may strengthen these vulnerable regions. Previous

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research efforts attempting to shed light into the neurodegenerative phenomena have

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demonstrated the functional disorganization of the mature brain (Delbeuck et al.,

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2003). These phenomena affect mainly long-distant areas (Babiloni et al., 2004;

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Babiloni et al., 2009). Aiming to also investigate whether LLM training would be

effective in senior citizens at high risk (preclinical phase) or already suffering from

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dementia, we computed directional synchronization among a right anterior (RG1) and
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a left posterior (RG2) region. The aforementioned results demonstrated statistically

significant synchronization increases among these regions for the LLM participants
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when compared to ACTIVE controls.

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The time duration of the proposed analysis may seem a bit short for analyzing

functional patterns obtained from a large number of electrode pairs. However, it has
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been previously demonstrated that twenty seconds of data are sufficient for resting-

state analysis with eyes closed in the elderly, while longer epochs did not provide
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significant improvement regarding reliability of EEG features (Gudmundsson, et al,

2007; Hsu et al., 2012). Moreover, the proposed methodology is particularly suitable

for short data segments since the existence of at least one wavelet coefficient for each

frequency band adds to the model’s stability. Apart from its robustness, the proposed

methodology is computationally fast and noise-resistant due to the iterative, multi-

resolution decomposition scheme. Therefore, it may be a suitable tool for computing

dynamically evolved frequency EEG patterns over short time segments.

4.2 The effectiveness of a combined cognitive/physical intervention on brain

functioning.
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The neurophysiological evaluation approach proposed in the present study greatly

favors holistic approaches aiming to measure both the brain and cognitive function of

senior citizens. The present study showed an increase in synchronization, in the LLM

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relative to the AC group, in a network involving four pair electrodes (FC2 - CP3, CP3

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- FC2 and FC6 - P4) and the corresponding ROIs. However, EEG signals may be

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influenced by volume conduction. Therefore, interpretation of EEG functional

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connectivity in the source domain should be avoided, or be supported by

neuroimaging studies (Berger & Posner, 2000; Corbetta & Shulman, 2002; Garavan et

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al., 2000; Reuter-Lorenz et al., 2000). The finding of increased synchronization in
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prefrontal brain areas after a combined cognitive and physical training (LLM) have

important clinical implications, as these areas seem to be the most susceptible to the
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aging process (Head et al., 2004; Marshall et al., 2011; Raz et al., 2005; Resnick et al.,
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2003). Thus, the present results suggest that the LLM intervention may be effective in

promoting healthy aging.

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Synchronization increases, as a function of the LLM training, mainly involved

long-distant (inter-lobe) synchronization patterns. This finding, validated by three

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different reference methodologies (see Appendix), fits well with the hypothesis that

AD can be characterized as a disconnection syndrome, which reflects a loss of inter-

lobe connectivity (Damoiseaux et al., 2012; Delbeuck et al., 2003; Sanz-Arigita et al.,

2010). In addition, it has been suggested that long-range disconnection can be

counteracted by the enhancement of co-operation among close brain areas especially

within the parietal cortex (intra-parietal connectivity) (Jacobs et al., 2012). Thus, one

outstanding question for future research in neuropsychological interventions is

whether they should be targeted at increasing long- or short-distant connectivity.

Selection of the appropriate approach would depend on parameters such as intensity

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and duration of the intervention, the baseline cognitive level of the sample,

socialization level, depression vulnerability, etc. More specifically, selection of an

intensive and cognitive demanding intervention approach aiming to induce long-

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distance structural and functional connectivity may be more suitable to be applied on

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cognitively healthy and highly-functioning elderly participants (Smith et al., 2009).

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The goal of this training would be to minimize the possibility of dementia onset. On

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the other hand, it may be more realistic for patients already suffering from cognitive

impairment to be assigned to a training program targeting the development of

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functional compensatory mechanisms in order to counteract brain degeneration.
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Therefore, the goal of these training programs would be to delay the onset of the

clinical symptoms of dementia. Multi-dimensional evaluation frameworks could

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encompass the aforementioned parameters and define the optimal therapeutic strategy
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at a personalized level. Then, neurophysiological evaluation would be adopted to the

intervention parameters and to the participant herself/himself. The ultimate goal of an

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evaluation framework would be to provide a holistic evidence of training induced

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brain alterations by linking improvements in functional synchronization with both

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enhanced cognition and structural connectivity. These benefits should be sustainable

over a long time period and demonstrated by follow up examinations.

The combination of the RWE synchronization metric with the Mahalanobis distance

classifier provides a way of estimating the agreement between improvement at the

individual level and the overall group. The study proposes a pattern recognition

technique, which essentially acts as a marker capable of identifying and quantifying

whether and how each senior citizen benefited from the program by comparing her/his

own pattern of synchronization increases with the mean pattern of the training group.

The employment of the proposed approach revealed that 81% of the participants in
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the intervention group showed similar improvements after training to the overall

group improvement. This suggests that our findings are rather robust. Still 10 out of

53 participants did not seem to show an improvement in synchronization with the

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cognitive/physical intervention. As one cannot be certain about the factors that may

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account for these individual differences, further studies are needed to investigate what

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specific factors (e.g., personality, education, gender, intervention duration and dose

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etc) may modulate the effect of such interventions.

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4.3 Conclusions

To sum up, the current piece of work presents a novel approach to evaluate brain
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functional outcomes of aging-related interventions in general and the LLM training in

specific. By using quantitative electroencephalography it was possible to demonstrate

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that the LLM intervention (combined cognitive and physical training) was effective in
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increasing synchronization at rest when compared to an active control group. In

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support of our initial hypothesis, we specifically found that synchronization across the
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two hemispheres was increased for the LLM group after the intervention. Future

research may address the clinical relevance of this finding, since disturbance of long
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range connections among distant brain regions (anterior-posterior) is one of the main

characteristics of pathological aging. It is believed that the present work may trigger

further research aiming at the production of novel quantifiable ways towards the

evaluation of non-pharmaceutical interventions to promote healthy aging (Bamidis et

al, 2014).

Appendix – Methodology verification employing various re-reference

approaches
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To ensure that our main finding was not an artifact of the reference method employed,

we re-analysed the data (randomly selecting some 35 LLM participants and 34

ACTIVE controls) by employing (i) common average, (ii) linked earlobes reference

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(A1+A2)/2 and (iii) the reference already used in our study.

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We performed independent samples t-test for each reference methodology and for

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each electrode pair as suggested by one reviewer. The results are demonstrated in the

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following table:

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Table A1: Demonstration of the statistical significance of the four electrode pairs for each re-reference
approach
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Electrode Study Approach Common Average Linked Earlobes
Pairs
t value p value t value p value t value p value

FC2 – CP3 -2.672 .009 -2.459 .017 -2.384 .020

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CP3 – FC2 -3.217 .002 -2.743 .008 -2.608 .011

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Afz – Fp2 -2.054 .044 -2.226 .029 -2.254 .027

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FC6 – P4 -2.444 .017 -2.206 .031 -2.339 .022

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All four electrode pairs demonstrated statistically significant results. Moreover,

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distant electrode pairs (FC2-CP3 & CP3-FC2) yielded the most significant results

regardless of the re-reference methodology.

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Acknowledgements

This research was partially funded by the European CIP-ICT-PSP.2008.1.4 Long

Lasting memories (LLM) project (Project No. 238904)

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(www.longlastingmemories.eu).

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The authors would like to thank: A. Semertzidou, M. Karagianni, S. Fasnaki for

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neurophysiological data acquisition, A. Billis for technical assistance and software

development, E. Grigoriadou and A. Kyrillidou for neuropsychological assessments,

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and V. Zilidou and E. Romanopoulou for pilot executions with seniors.
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http://www.longlastingmemories.eu/, last access on 06/05/2013.

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Highlights

 Neurophysiological evaluation of interventions for healthy aging

 Comparison with an active control group performing cognitive stimulation
 Combination of synchronization analysis with data mining classification

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 Robust, cheap and easily applicable to day care centers

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 Results were in line with existing neuroscience findings

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