The goal of this clinical trial is to test a home-delivered intervention that combines Non-Invasive Brain Stimulation techniques (transcranial direct and alternating current stimulation -tDCS and tACS-) and Online Cognitive Training (OCT) to treat depressive symptomatology and cognitive decline associated with breast cancer. The main questions aims to be answered are:

• To analyze the efficacy and feasibility of the intervention to treat depressive symptomatology.
• To analyze the efficacy and feasibility of the intervention to treat cognitive decline.
• To evaluate the medium and long-term effects (1, 3 and 6 months) of intervention.

An OCT program and a portable wireless tDCS/tACS system will be used to perform the intervention at home. Patients will be divided into four treatment groups, depending on whether they will receive the OCT applied independently or combined with tDCS/tACS active or sham.

In addition, saliva samples will be collected to identify bomarkers predictive of treatment efficacy.

This study is aimed at analyzing the feasibility and therapeutic efficacy of a home-based treatment using tDCS/tACS and an OCT program to treat depressive symptomatology (primary outcome variable) associated with breast cancer.The effect of the intervention on the patients' cognitive functioning (secondary outcome variable) will be also studied. In addition, saliva biomarkers and other clinical variables will be analyzed to determine whether they are related to the response to treatment. Finally, the impact of the intervention on the burden of the relatives/caregivers will be studied.

Oncology Units of the Galician Health Service will be contacted for recruitment. Oncologists will review whether patients meet the inclusion criteria and none of the exclusion criteria. If so, patients will be given an information flyer and will contact the research team to receive more information and, if they wish, to participate in the study. If patients are interested in participating, researchers will contact them to confirm the inclusion/exclusion criteria and participants will be invited to the first face-to-face session. In this session, informed consent will be signed, pre-treatment neuropsychological assessment will be performed, medical data will be reviewed, and a saliva sample will be collected. After collecting this data, the first treatment session will take place in the presence of the researcher. The type of treatment each patient will receive (OCT, tDCS active+ OCT, tACS active+ OCT or sham neurostimulation+ OCT. ) will be chosen randomly, using a randomization list.

After that, each patient will undergo 14 sessions, daily, at home. The tES devices (Soterix Medical Inc) have been designed for home use and allow the application of the stimulation by the patient himself, while being monitored by the researcher. The OCT will be delivered through NeuronUp2GO platform.Possible adverse effects associated with neurostimulation (which are mild and transitory) and other variables that may affect its efficacy (medication diary, caffeine intake...) will be monitored daily.

Finally, a post-treatment assessment will be carried out 15 days after the start of treatment and a follow-up assessment will be carried out 1, 3 and 6 months after the end of treatment. The 15-day and 1 month assessments will be the same as the pre-treatment (questionnaries and neuropsychological test). The follow-ups at 3 and 6 months will be done online, by filling in questionnaires.

Both the treatment administration and analysis of the results will be blinded.

First, descriptive analyses will be performed on the sociodemographic and clinical data. To evaluate the efficacy of the treatments on depressive symptomatology and cognitive function, linear mixed models will be carried out. The dependent variable will be the test score, and treatment group, time (pre, post, follow-ups) and group*time interaction as fixed factors, and participants as random effects.

The possible modulating effect of sociodemograpchic and clinical variables on treatment efficacy will be analyzed. Also, for the clinical validation of the treatments, the analysis of the Minimal Clinically Important Difference (MCID) at short (15 days), medium (1 month) and long term (3 and 6 months) will be included. The difference between the pre- and post-treatment assessment in the primary and secondary variable scores should be equal to or greater than 30%.

Proteomic analysis will be performed at the Fundación Biomédica Galicia Sur. The following analysis will be performed: determination of total protein, mass spectrometry and electrophoretic separation of the samples by SDS-PAGE and identification of the bands of interest by Shotgun. The whole sample will be analyzed in liquid mass spectrometer (LC-MS/MS). Linear or logistic regression analysis will be performed to determine the predictive power of the saliva biomarkerson treatment efficacy.

Since the present research involves adult humans, it will be conducted under applicable international, EU and national laws and regulations (The Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects; The International Conference on Harmonisation (ICH)/Good Clinical Practice (GCP) Guidelines; the Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine; and the UNESCO Universal Declaration on Bioethics and Human Rights (2005). Permission has been obtained from the local IRB committee (CEIm de Galicia) to conduct the study.

In terms of data protection, this study complies with the directives of the General Data Protection Regulation (GDPR), approved by the European Commission on April 27, 2016 (EU 2016/679) and with the Organic Law 3/2018, of December 5, 2018, on the Protection of Personal Data and guarantees of digital rights. The storage and treatment of the samples will be carried out in accordance with the Biomedical Research Law 14/2007 and RD 1716/201.

Patients' clinical data will be collected in the study-specific data collection notebook using REDCap (Research Electronic Data Capture), a secure web-based application for building and managing online surveys and databases. Data collection will be pseudo-anonymous, protecting the identity of the participant. Only the principal investigator of the entity responsible for data collection (USC) will know the pseudonymization codes. The research team will have access to all coded data collected for the study.

Inclusion Criteria:

• Diagnosis of breast cancer in early stages (life expectancy greater than 12 months).
• Patients who are receiving or have finished (maximum 6 months prior to participation in the participating in the study) some type of oncological treatment (Chemotherapy, Radiotherapy, Immunotherapy, Hormonal Therapy).
• Patients whose mother tongue is Galician or Spanish.
• Ability to give informed consent.
• Present depressive symptomatology: score of 4 or higher in the BDI-FS.
• Ability to use WhastApp
• Have access to some technology (desktop computer, laptop or tablet) and the Internet (Firefox or Chrome browsers).

Exclusion Criteria:

• Pregnant or breastfeeding women.
• Patients with metastasis.
• Patients with a mental health disorder (major depressive disorder, bipolar,anxious, psychotic...) diagnosed by a psychiatrist prior to the oncological process.
• Patients with a history of cognitive impairment or dementia prior to the oncologic process.

oncological process.

• Patients with a history of neurosurgery, cortical lesions or neurological alterations prior to the oncological process.
• Patients with history or current consumption of non-prescribed drugs.
• Patients with the following medication regimen: mood stabilizers, antipsychotics, anticonvulsants, l-dopa, rivastigmine, dextromethorphan, flunarizine, sulpiride, use of benzodiazepines (excluding long half-life benzodiazepines (Bromazepam, Diazepam) on a continuous/habitual basis,Alprazolam >1mg per day, Lorazepam >2mg per day).
• Patients taking antidepressant medication should have a stable regimen ( same medication at the same dose for a minimum of four weeks prior to entering the study.The regimen with antidepressant drugs or drugs used as treatment to improve cognition should be kept stable during the entire participation (until the follow-up evaluation has been performed).
• Patients unable to complete a neuropsychological examination.
• Patients who are participating in a research study/clinical trial with drugs.
• Patients who present any condition contraindicated to undergo tES (intracranial ferromagnetic devices or implanted stimulators; history of active epilepsy; history of neurosurgery, traumatic brain injury with loss of brainwith loss of consciousness and/or cortical lesion) (Antal et al., 2017)

In this study, a double-blind design will be used, since the device used for the tDCS/tACS intervention allows for total blinding. The patient and the researchers involved in treatment will be blinded to the group of treatment (except for the OCT group). Evaluation and data analysis will be blinded to group assignment until the participant has completed the study. Only the members of the research team in charge of generating the randomization list will have access to the patient's intervention status.