Cognitive Enhancement in Healthy Elderly People

Aging is associated with several physiological changes that affect global functioning, daily activity and quality of life. For instance, cognitive functions progressively decline during normal aging, as evidenced by decreased episodic memory and working memory (WM) performance.

The above mentioned cognitive decline reaches medical attention for about 5-25% of the elderly population (over 65 years of age) as they suffer from Mild Cognitive Impairment (MCI). MCI is usually referred to as an intermediate phase between the expected cognitive decline of normal aging and the pathological cognitive decline linked to dementia. Around 46% of people with MCI develop dementia within three years, compared to 3% of the age-matched population. According to Peterson's initial definition (Petersen, 2004), The selected technique to improve cognition as the investigators propose here is transcranial non invasive brain stimulation (TES). The investigators will employ a couple of these techniques of neuromodulation that have proven to influence performance in different cognitive domains. Here the investigators propose to combine the investigators' expertise and to investigate the effects on cognition and health of brain stimulation-based treatment in MCI patients compared to matched healthy controls, combine it with cognitive training and explore the longer term effects of the intervention.

Objectives. The main objective of the proposed research is to explore the potential intervention based on non-invasive brain stimulation and cognitive training to improve cognition in the elderly. In particular the investigators aim to explore:

1. The immediate efficacy of various stimulation protocols with cognitive training on cognitive improvement in the elderly.
2. The long term effect of a selected stimulation protocol on MCI improvement in the elderly.

According to a large controlled study on cognitive stimulation for people with MCI, the treatment proved effective in improving the functioning in several cognitive areas compared to a control group (Ball et al., 2002).The cognitive training in this study included a computerized training, which is more enjoyable and effective than pencil-and paper training due to its immediate feedback and engaging nature. In their systematic review of 26 studies on computerized cognitive training (CCT) for older people with known MCI, Hill et al. (2016) concluded that CCT is an efficient tool for cognitive enhancement in older people with MCI. The overall effect size on cognition score was moderate (Hedges' g=0.35); a large significant effect size on working memory; and there were moderate significant effect sizes for specific cognitive domains, such as verbal memory, non-verbal learning, attention and on psychological functioning measures. In contrast, and consistent with findings of previous CCT meta-analysis (Motter, Pimontel et al., 2016), there were insignificant results regarding executive functions, processing speed and non-verbal memory. The results on dementia patients, as opposed to MCI ones, were less optimistic: there was only a small but statistically significant effect size of the overall efficacy of the CCT on cognition enhancement.

The researchers have previous works that revealed an enhanced training effect when it was combined with non-invasive brain stimulation, for example better cognitive control following training combined with Transcranial direct current stimulation (tDCS) compared to training alone (Ditye et al., 2012).

Transcranial direct current stimulation (tDCS) is a safe, low-cost, non-invasive neurophysiological technique that consists in the application of mild (1-2 milliampere (mA)) electrical current on the scalp (Jacobson et al., 2012).

There is growing evidence that tDCS, combined with cognitive stimulation, improves cognitive functioning among healthy adult subjects. Specifically, tDCS to the prefrontal cortex has been proved effective. Anodal stimulation of the left dorsolateral prefrontal cortex (DLPFC) increases the performance on a working memory task in young healthy adults. In a combined treatment of behavioral training and tDCS stimulation of ten sessions for 10 days, healthy elderly subjects increased working memory skills for up to 28 days (Park et al., 2014).

tDCS has also been proved efficient for people with Alzheimer's Disease (AD) or other types of dementia. In one study, anodal tDCS was applied to both hemispheres of the temporal cortex in 30 minutes sessions for five successive days. Results showed a significant improvement in a visual recognition memory task. tDCS anodal stimulation of the Broca's region within the left inferiorfrontal gyrus (IFG) had some positive effects on verbal fluency among patients with MCI in a double-blind, crossover, sham-controlled stimulation study. Additional brain imaging analysis of these results indicated that there was also a reduction of compensatory upregulated activity within the frontal cortices. Manenti et al. (2016) have used anodal tDCS combined with physical therapies in MCI patients with Parkinson's disease (PD). Following daily administration of 2 mA stimulation for two weeks, subjects have improved their PD Cognitive Rating Scale scores and their verbal fluency test, in comparison with the sham control group.

The efficacy of using tDCS in combination with cognitive training is yet controversial. A study on AD patients which used anodal tDCS to stimulate the left DLPFC in a name-face association learning task, found no additional effect to the tDCS stimulation beyond that of the behavioral training. In contrast to these findings, in a study of healthy subjects, the combination of tDCS stimulation and simultaneous cognitive behavioral training has been proved more effective than tDCS stimulation to the left DLPFC by itself (Martin, Liu, Alonzo et al., 2015).

In a recent study (André et al., 2016), four sessions of anodal tDCS stimulation over the left DLPFC, in combination with different cognitive tasks, were applied to 21 patients with mild vascular dementia. There was a significant improvement up to two weeks later in visual short term memory (in a pictures naming task), verbal working memory (2-back task) and executive control (go/no go task) in the anodal stimulation group, Yet, there are still some considerable limitations to the research on tDCS effects on cognition and to its clinical applications. For instance, choosing the target area or network is, of course, critical. Various target areas have been used in different studies: frontal lobe, especially the DLPFC and the IFG, are natural candidates. Few studies have targeted the inferior parietal lobe, which might require further research.

To overcome some of the problems the investigators will test another brain stimulation technique, transcranial alternating current stimulation (tACS) where promising previous results suggest that tACS over prefrontal areas might be a better tool to improve cognitive functions in the elderly. tACS, a specific subtype of Non-invasive Brain Stimulation methods (NIBS), is based on the application of low-intensity electrical currents oscillating sinusoidally at a predetermined frequency (Antal et al., 2008). TACS-mediated physiological and behavioral changes seems to be frequency-dependent, thus, tACS could interact with the on-going brain activity through cortical oscillatory entrainment.

Since episodic memory decline is one of the most important markers of MCI, the investigators will test brain stimulation protocols that were found to affect different types of memory performance. Possible effects of transcranially applied oscillating currents on memory functions have been investigated on humans by using transcranial Slow Oscillation Stimulation (SO-tDCS; i.e., anodal transcranial direct current stimulation oscillating at 0.75 Hz in a trapezoid waveform-fashion, applied bi-frontally) in combination with on-line EEG recording during slow wave sleep (Marshall et al., 2006). Ripple-range oscillations in the hippocampus have also been associated with declarative memory consolidation. The co-PI, Prof. Antal reported that bilateral 140 Hz tACS over both DLPFC during encoding may have a positive effect on the consolidation of declarative material (Ambrus et al., 2015). Novel cross-frequency protocols (theta-gamma coupling) of tACS affected spatial working memory performance in humans: enhancement of working memory performance and increase of global neocortical connectivity were observed when bursts of high gamma oscillations (80-100 Hz) coincided with the peaks of the theta waves, whereas superimposition on the trough of the theta wave and low gamma frequency protocols were ineffective.

In sum, evidence from recent studies portray a promising picture of this new line of research, suggesting that non-invasive brain stimulation techniques, in general, and tDCS and tACS, in particular, may be used to ameliorate cognitive dysfunction in patients in pre-dementia. Though prospects seem promising, the mixed results and inconclusive findings of several studies call for cautious. Hopefully, the proposed research will narrow the gap between theoretical knowledge and the clinical applicability of the findings for the sake of a treatment that can truly affect many people's lives.

The current approach is to employ cognitive enhancement tools aiming to develop effective protocols that will preserve (and ultimately improve) cognitive abilities in MCI and healthy elderly. The main method are non-invasive brain stimulation tools, tDCS and tACS, combined with computer-based cognitive training in a multiple session design.

Patient Registries:

Each subject is met by the experimenters (PhD students) for 16 individual meetings. The baseline measurements and cognitive evaluation that is manually conducted by the experimenters is inserted and saved in local Excel files. The subjects' performance in the computerized games (the cognitive training) is automatically saved on the lab's computer.

Quality assurance: the completeness and accuracy of the training log files is checked after every session.

Standard Operating Procedures - a paper file is prepared for each subject to keep background and contact details, printed records of the subjects' performance in the memory evaluation tests (at baseline, immediately after completing the intervention, and 3 months after completing the intervention).

Sample size assessment: The sample size was a priori calculated using More Power software (Campbell \& Thompson, 2012) based on the effect size reported for memory enhancement by transcranial electrical stimulation by Jacobson et al. (2012) (d = 0.49). This established that with a α = 0.05, power = 0.95, 60 participants are necessary to detect a moderate-large effect.

Statistical analysis plan: data will be analyzed with IBM Statistical Package for Windows, version 23 (IBM Corp., Armonk, N.Y., USA). The main analysis is a mixed design analysis that compares the experimental conditions (between subject factors) regarding their effect on memory performance in 2 episodic memory tests and 3 time points (within subjects variables). The cognitive status at baseline will serve as a covariate (the baseline scores). In addition, the investigators plan hierarchical regression to check how ongoing scores in the cognitive training predict episodic memory score at the end of the intervention.