tDCS as Adjunctive Therapy to Cognitive Stimulation in Medical Students With Depression

Major depressive disorder (MDD) is a major public health problem, it negatively affects cognition and cognitive deficits affect information processing speed, attention, memory, executive function and working memory. In addition, cognitive deficits associated with MDD do not resolve after successful treatment of depressive symptoms. In one study, 94% of individuals with MDD and cognitive deficits at the start of treatment retained these deficits one year later, despite achieving clinical remission. Long-term maintenance of antidepressants does not prevent cognition decline, despite maintaining recovery from depression. Cognitive stimulation, has shown the potential to produce broad benefits primarily in working memory. The anodal tDCS increases task-related CPFdl activation. Furthermore, anodal tDCS on CPFdl has been shown to facilitate working memory processes, making tDCS a promising tool for the amelioration of depression-induced working memory impairment in a population with a high prevalence of depression and/or stress, such as medical school students.

Research question: Is Cognitive Stimulation (CS) + active tDCS in CPFdl more effective compared to sham CS+ tDCS in improving on working memory test scores, cognitive functioning, P300 cognitive evoked potentials and academic performance in medical students with depressive symptomatology? Aims: To evaluate the effect of active CE + tDCS in CPFdl to improve scores on tests of working memory, cognitive functioning, P300 cognitive evoked potentials and academic performance in medical students with depressive symptomatology vs sham CE + tDCS.

Materials and Methods: This is a single-blind, comparative (cognitive stimulation + active tDCS vs cognitive stimulation + simulated tDCS), randomized, longitudinal and prolective clinical trial. Analysis: A descriptive analysis of demographic and clinical characteristics will be performed with frequencies and percentages for categorical variables and with means and standard deviations for dimensional variables. Mean comparison tests (t-tests), analysis of variance (ANOVA) and correlation tests. Significance level p≤0.05.

Cognitive training has demonstrated the potential to produce broad benefits in functional cognitive. As a fundamental and essential cognitive skill and essential, working memory supports complex thinking, but has limited capacity. Therefore, working memory training interventions have become popular as a means of potentially improve cognitive skills related to working memory for those who need it (Au et al.,2016) Transcranial direct current stimulation is one of the most widely studied techniques in neuromodulation non-invasive neuromodulation. With a very good safety profile and low cost, it has been widely used to modulate cognition and behavior in both experimental and clinical settings A growing body of literature, including randomized controlled trials, reports the clinical benefits of tDCS for many clinical benefits of tDCS for many psychiatric symptoms, such as depression, anxiety, psychosis, addiction, and cognitive function. tDCS has considerable potential as a treatment because of its relative cost, portability, safety, and ease of use compared with other neuromodulation methods. Early studies evaluated the effects of tDCS on the motor cortex; although more recent research has also focused on its effects on the dorsolateral prefrontal cortex (DLPFC), particularly for treating psychiatric disorders and modulating cognitive performance.

Side effects, such as itching, burning sensation or headache are common, but generally mild and without long-term impact.

Therefore, tDCS compares favorably with other therapeutic approaches such as antidepressants or transcranial magnetic simulation (TMS).

Transcranial direct current stimulation (tDCS), which has shown potential to modulate cortical excitability and cortical activity of the brain, by transmitting a weak electrical current to the brain, has been found as a possible way to improve working memory, sustained attention, motor learning, multitasking. Therefore, cognitive enhancement through tDCS has attracted increased attention over the last decade. A considerable number of single-session studies using tDCS have studies using tDCS have revealed potential benefits for improving participants' performance on working memory tasks. In a particularly anodal tDCS (a-tDCS) applied to the left dorsolateral prefrontal cortex, increased accuracy of response of the working memory task performed at the same time as the stimulation. However, no significant effect appeared when they applied anodal stimulation to the primary motor cortex and cathodal stimulation to the primary motor cortex and cathodal stimulation on the left CPFdl. These findings indicate that the potentiating effect of tDCS on working memory recall depends on the polarity of stimulation and is specific to the site of stimulation . Many subsequent studies compared factors such as electrode placement electrode placement, current density, and duration of stimulation that may affect the efficacy of tDCS and found that anodal stimulation of the left prefrontal tended to improve MT performance. Neuroimaging studies utilizing EEG and functional near-infrared spectroscopy (fNIRS) have provided evidence that tDCS may alter brain activities. In addition to studies related to working memory, tDCS has also shown potential to mitigate decreased vigilance and improve multitasking performance.

Based on the assumption that tDCS has the potential to modulate neuronal excitability and synaptic plasticity, several studies have explored the effect of tDCS on training cognitive training in the last 3 years. One study in a non-human primate model found that tDCS, together with multi-session learning, facilitated associative learning and altered functional connectivity when analyzing behavioral outcomes and local field potential. In a study of three-session working memory training, implemented in healthy adults, the advantage of working memory training combined with a working memory training combined with a-tDCS was not only present immediately following training, but also in the follow-up session up to 9 months after training. The benefits related to A-tDCS remained stable even up to one year after the original intervention, in a study of working memory training paired with 7-day tDCS in healthy young adults. Improved cortical efficiency and connectivity was also demonstrated in a study that found a significant improvement in cortical working memory through working memory training paired to -tDCS in healthy young adults.

A recent study in monkeys provided evidence that single-neuron activation rates and network interactions could be be modulated by polarity, and a dose of tDCS and a higher intensity of a-tDCS induced higher activation rates of regularly firing neurons. Although some reviews questioned the efficacy of tDCS, these recently published studies provide further evidence that working memory training combined with tDCS working memory training combined with tDCS can enhance cognition.

Patients with depression exhibit cognitive deficits in several domains (i.e., psychomotor speed, executive functions, memory, and attention), factors such as severity of depression are associated with greater cognitive deficits and lower remission rates, even after antidepressant treatment. These issues highlight the importance of investigating cognitive deficits in major depressive disorder.

However, only a few studies have investigated the brain mechanism underlying the effects of tDCS on cognition effects of tDCS on cognitive processing, with P300. Thus, the present project contributes in to propose a new treatment alternative for cognitive symptoms in MDD, to assist the pharmacological treatment, in addition to an early detection in terms of prevention of cognitive deterioration, providing new cognitive impairment, providing new tools for the diagnostic approach and management of this entity.

HYPOTHESIS Personalized cognitive stimulation in conjunction with transcranial direct current stimulation tDCS will be more effective compared to personalized cognitive stimulation + tDCS-placebo or sham in improving scores on neuropsychological neuropsychological test scores on the cognitive variables to be studied, cognitive potentials P300 and academic performance in UNAM medical students with depressive symptoms at 15 treatment sessions (acute phase) and at 15 sessions of treatment (acute phase) and at 4 weeks of maintenance.

After cognitive stimulation and tDCS, it is expected that in the experimental group the amplitude will be greater in the P300 component since the P300 component ncreased mastery of attention and working memory processes.

Eligibility Criteria:
Inclusion Criteria:

1. Age18 - 30 years old.
2. Vaccinated against SARS-COV2 virus.
3. Students of the Faculty of Medicine of the UNAM.
4. Fluent in Spanish.
5. Adequate visual and auditory acuity to be able to perform neuropsychological tests and perform cognitive stimulation.
6. Depressive symptoms with working memory impairment (diagnosed by applying a specific neuropsychological battery).
7. That they are not under antidepressant pharmacological treatment prior to admission to the research.
8. Good general health without medical illnesses (systemic arterial hypertension, diabetes mellitus, dyslipidemias, infections, thyroid disease, vitamin deficiencies) that do not interfere with the study.
9. Willingness to participate in a scheduled 8-week study and able to attend scheduled evaluations.

Exclusion Criteria:

1. Any neurological disease that allows suspicion of cognitive failure other than depression, such as Parkinson's disease, multiple infarct dementia, Huntington's disease, hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, history of head injury with loss of alertness.
2. Participants with history with severe psychiatric disorders according to DSM-5 (bipolar disorder, schizophrenia, chronic depression) or psychotic features, agitation or behavioral problems in the last three months that could lead to difficulties in complying with the protocol.
3. History of psychoactive substance abuse and current alcohol use with pattern of abuse or dependence in the past two years.
4. Participants with alterations in a conventional electroencephalogram (paroxysmal phenomena identified by a neurophysiologist).
5. Participants with pacemakers, intracranial metal objects or history of brain surgery, aneurysm clips, artificial heart valves, ear implants, metal fragments or foreign objects in the eyes, skin or body.