INTRODUCTION:

Mild cognitive impairment (MCI) is a critical transitional stage in dementia related disorders. Dorsolateral prefrontal cortex (DLPFC), and the lateral parietal (LPC) cortex are subjected to neuropathological changes in MCI. Parietal memory network (PMN) integrity alterations and default mode network (DMN) alterations also occur in MCI. Transcranial direct current stimulation (tDCS) is a promising neuroprotective tool that modulates functional connectivity and might be useful to interfere with cognitive decline in relation to amnestic MCI (aMCI) and Parkinson's disease-MCI (PD-MCI) when applied to DLPFC and LPC.

METHODS:

This is a multicenter, randomized, and controlled study evaluating the effectiveness of anodal tDCS (atDCS ) applied bilaterally to the DLPFC/F3-F4 and LPC/ P3-P4 for 5 sessions with a total of 10 sessions in 14 days. The stimulation will be delivered with a 2 mA current frequency and will last 20 minutes a day for 5 days a week. The study consists of anodal, and sham control groups with a total of 120 participants with DLPFC and LPC anodal groups including 40 participants each and sham including 40 participants which are all between 45-80 years of age.

At baseline and as an outcome measure, neurocognitive evaluation will be conducted using various tests standardized to use in the Turkish population. Functional magnetic resonance (fMRI) will be used to detect possible PMN and DMN alterations and hippocampal connectivity, and electroencephalogram (EEG) will be used to assess possible electrophysiological alterations that may happen as a result of atDCS. Baseline evaluation will be done before atDCS sessions and it will be repeated at the end of 14 days and 90 days.

DISCUSSION:

This study aims to explore the effectiveness of atDCS in PD-MCI, aMCI and to contribute to the literature in the field.

Study Design This is a multi-center, randomized, controlled study registered and carried out at Medipol University Hospital and Alaaddin Keykubat University Training and Research Hospital. The objective of the study is to evaluate the effectiveness of atDCS stimulation over DLPFC and LPC on cognitive skills of patients with PD-MCI and aMCI.

The patients will be randomized to 2mA tDCS over DLPFC and over LPC, or Sham control. tDCS stimulation will last for 20 minutes a day for 5 consecutive days, a total of 10 sessions in 14 days. The outcome of the simulations will be evaluated by various neurocognitive tests at the baseline, at the end of 14 days and then, 90 days.

Brain connectivity will be analyzed by resting state-functional magnetic resonance imaging (fMRI) and neuronal activity will be analyzed by electroencephalography (EEG) at the baseline, at the end of 14 days and 90 days..

This study aims to give important translational messages in the field of clinical neuroscience by exploring the pro-cognitive effects of tDCS application including its optimal application methods. In this framework, the restorative benefits of tDCS can be critical to understand the cause-effect relationship between certain neural circuits and behavioral outcomes, which might be important in understanding the pathophysiology of MCI and PD. From another point of view, our findings might be valuable in terms of prolonged life-expectancy and the maintenance of preserved cognitive skills in the elderly.

Although tDCS is still in a premature stage, it has certain advantages in terms of portability, cost-effectiveness and user-friendly application compared to other non- invasive stimulation applications. This study will contribute to the growing literature in terms of its optimal application methods, side-effects and long-term (90 days) neurobehavioral results.

Inclusion Criteria:

1. Providing an informed consent;
2. Literate and between 45-80 years of age;
3. 60 females and 60 males;
4. Diagnosed with PD based on criteria suggested by UK Parkinson's Disease Society, Brain Bank and PD-MCI in accordance with the diagnostic criteria suggestions by Litvan;
5. Diagnosed with aMCI based on diagnosis criteria (CDR>0.5) suggested by Petersen;
6. On a stable pharmacological treatment minimum for one month with no washout period.

Exclusion Criteria:

• Illiterate or education level less than primary school
• Having an existing and/or prior neurological disease; psychiatric disease or head trauma; and/or irreversible hearing or sight problems or other medical illness (e.g. diabetes mellitus, hypertension);
• Exhibiting signs of dementia for PD group ;
• Having medical issues that prevent undergoing fMRI or for tDCS application.

The distribution of the sham or real stimulators will be based on the random allocation which makes it impossible to identify the sham or real stimulation for the participants and the test instructors. This double-blind masking procedure will be applied all throughout the study steps in line with the reference study. The randomization data will be confidential and will not be accessible except for the medical emergencies. After the above-mentioned blinding process has been ended, the participants will be managed as off-study.