This is a comparative, double-blind, randomized controlled clinical trial for people with Amnestic Mild Cognitive Impairment. The investigators will compare the effects of two non-invasive neuromodulation techniques (Repetitive Transcranial Magnetic Stimulation and Transcranial Direct Current Stimulation) combined with cognitive stimulation. These non-invasive neuromodulating techniques will be applied as a treatment alternative to be able to compare non-invasive techniques with cognitive stimulation CS alone, taking into account clinical and neuropsychological evaluations in addition to: 1) the known clinical risk factors (physical activity, comorbidities treatment, etc.) that allow the investigators to characterize the participants; 2) characterize the participants with genetic biomarkers using the APOE4, CR1, COMT, TREM2 and ABCA7 genotype; 3) document the biological effects related to neurogenesis from olfactory epithelial neural progenitor cells and solubles factors of serum; 4) use hippocampal volume, cortical thickness of the medial temporal cortex and parietal cortex by means of structural magnetic resonance imaging and the default mode network by means of functional magnetic resonance imaging at rest as a biomarker of response to treatment and 5) associate the response to treatment with changes in Motor Evoked Potential (MEP) amplitude and latency in order to generate a response-to-treatment biomarker with neuromodulators in Mild Cognitive Impairment (MCI) and changes in electroencephalogram.
Being vaccinated against the SARS-COV2 virus.
Speak Spanish fluently.
Level of schooling greater than or equal to 6 years.
Amnestic mild cognitive impairment established by clinical examination performed by the treating physician (MoCA score: 19-25 points for probable aMCI) (based on the National Institute on Aging and Alzheimer's Association (NIA/AA) criteria, 2011).
Any neurological disease that raises suspicion of cognitive failure other than Alzheimer's disease, such as Parkinson's, multi-infarct dementia, Huntington's disease, hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, history of trauma craniocerebral with loss of alertness.
Participants with a history of severe psychiatric disorders according to DSM-5 (bipolar disorder, schizophrenia, chronic depression) or with psychotic features, agitation, or behavioral problems in the last three months that could lead to difficulties in meeting the protocol.
History of psychoactive substance abuse and current alcohol consumption with a pattern of abuse or dependence in the last two years.
Participants with alterations in a conventional electroencephalogram (paroxysmal phenomena identified by a neurophysiologist).
Parallel
1. rTMS + CS
DeviceIn the first phase each participant will receive 15 sessions of rTMS and 9 sessions of CS divided in 3 weeks, in the maintenance phase each participant will receive 1 session of rTMS and 1 session of CS per week for 12 weeks. Each session will consist of 10 trains of 10 stimuli, at a 5-Hz frequency and a stimulation intensity of 120% of the resting motor threshold. rTMS will be administered by a MagPro R30 stimulator (MagVenture) and an active/placebo 8-shape coil model MCF-B70. Two surface electrodes will be employed to replicate rTMS skin sensations near the stimulation site. The rTMS condition will be double-blinded through the use of a USB stick. Cognitive stimulation will be a Mexican adaptation of the "Memory Training and Cognitive Stimulation for Mild Cognitive Impairment" from the Center for the Prevention of Cognitive Impairment of the Madrid City Council. In total, each participant will receive 27 sessions of rTMS and 21 sessions of CS.
2. rTMS Sham + CS
DeviceIn the first phase each participant will receive 15 sessions of rTMS Sham and 9 sessions of CS divided in 3 weeks, in the maintenance phase each participant will receive 1 session of Sham rTMS and 1 session of CS per week for 12 weeks. In total, each participant will receive 27 sessions of Sham rTMS and 21 sessions of CS. rTMS will be administered by a MagPro R30 stimulator (MagVenture) and an active/placebo 8-shape coil model MCF-B70. Two surface electrodes will be employed to replicate rTMS skin sensations near the stimulation site. The sham condition will be double-blinded through the use of a USB stick. Cognitive stimulation will be a Mexican adaptation of the "Memory Training and Cognitive Stimulation for Mild Cognitive Impairment" from the Center for the Prevention of Cognitive Impairment of the Madrid City Council. In total, each participant will receive 27 sessions of rTMS and 21 sessions of CS.
3. tDCS + CS
DeviceIn the first phase each participant will receive 15 sessions of tDCS and 9 sessions of CS divided in 3 weeks, in the maintenance phase each participant will receive 1 session of tDCS and 1 session of CS per week for 12 weeks. Each session will consist of the delivery of a weak direct current of 2mA for 30 minutes. tDCS will be administered by the Sooma tDCS stimulator. The tDCS condition will be double-blinded, and a third operator will program the stimulator. Cognitive stimulation will be a Mexican adaptation of the "Memory Training and Cognitive Stimulation for Mild Cognitive Impairment" from the Center for the Prevention of Cognitive Impairment of the Madrid City Council. In total, each participant will receive 27 sessions of tCDS and 21 sessions of CS.
4. tDCS Sham + CS
DeviceIn the first phase each participant will receive 15 sessions of tDCS Sham and 9 sessions of CS divided in 3 weeks, in the maintenance phase each participant will receive 1 session of Sham tDCS and 1 session of CS per week for 12 weeks. tDCS will be administered by the Sooma tDCS stimulator. The sham condition will be double-blinded, and a third operator will program the stimulator. Cognitive stimulation will be a Mexican adaptation of the "Memory Training and Cognitive Stimulation for Mild Cognitive Impairment" from the Center for the Prevention of Cognitive Impairment of the Madrid City Council. In total, each participant will receive 27 sessions of Sham tDCS and 21 sessions of CS.
Changes in orientation
Measured by the Barcelona Test. Score ranges from 10 or less to 95. Direct scores are converted to percentile. Higher scores mean better outcomes.
Changes in language
Measured by the WAIS-IV vocabulary test. Score ranges from 1 to 19. Direct scores are converted to standardized scores. Higher scores mean better outcomes.
Changes in language
Measured by the Barcelona Test. Score ranges from 10 or less to 95. Direct scores are converted to percentile. Higher scores mean better outcomes.
Changes in verbal memory
Measured by the Barcelona Test. Score ranges from 10 or less to 95. Direct scores are converted to percentile. Higher scores mean better outcomes.
Changes in Apathy symptoms
Measured by Apathy Evaluation Scale (self-report, informant report and clinician report). Score ranges from 18 to 72. Higher scores mean worse outcomes.
Changes in Depression
Measured by Yesavage Geriatric Depression Scale. Score ranges from 0 to 30. Higher scores mean worse outcomes.
Changes in behavioral and psychological symptoms
Measured by Cummings Neuropsychiatric Inventory. Score ranges for frequency are 1 to 4, severity score ranges from 1 to 3 and distress score ranges from 0 to 4. Higher scores mean worse outcomes.
Changes in electroencephalogram
Measured in each frequency band (delta, theta, alfa beta y gamma) before and after the intervention with the small-worldness measure, which will be obtained in order to observe the global optimization in the transmission of brain information. Likewise, will be complemented with an analysis of the clustering coefficient, local efficiency and global efficiency, calculating these measures in the F3 and F4 regions. To find changes in the small-worldness after the intervention.
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