Along with changes in emotional regulation, impairments in attention, memory, and executive function dominate the clinical profile of PPCS (8). However, a variety of symptoms can exist following concussion. The most common symptoms are a disruption of consciousness and a brief period of posttraumatic amnesia. The individual may also report feeling as though he or she is “in a fog.” Somatic symptoms, such as headache, fatigue, and balance problems, are also very common. During the acute stages following concussion, a patient may demonstrate disturbances in memory and concentration and feel “slowed down” (9).

It has been hypothesized that PPCS is caused by microstructural damage to the brain due to shearing injury, which is not detectable with conventional imaging techniques and may be responsible for functional deficits (10, 11). The brain regions affected by a concussion seem to especially involve the mesial regions and deeper regions including the hippocampus and corpus callosum. This “preference” would justify the deficits found in post-concussion patients who have memory complaints. Another area that is frequently involved is the prefrontal cortex, which would explain the executive function deficits that can persist even 3 months after the trauma (12, 13).

Cognitive dysfunction is characterized by impairments in attention, concentration, memory, and/or executive function. Patients may have difficulties following instructions and performing tasks or jobs that would have been routine before the trauma (14).

The rapid resolution of symptoms after MTBI raises questions of whether patients can directly benefit from neuropsychological interventions. However, PCS can undoubtedly persist in some cases. Addressing such cases through research in neuropsychology and neuroscience would help to improve our understanding of the progression and etiology of PCS, as well as produce new interventions to help patients who do not improve as expected (15).

Neuropsychological assessment provides diagnostic information about the nature and extent of cognitive dysfunction in neurological conditions, including MTBI. The National Institute of Mental Health and Neurosciences suggests that some neuropsychological batteries have adequate sensitivity and ecological validity to assess the cognitive deficits associated with MTBI (16).

Recent reports have documented the therapeutic potential of non-invasive neuromodulation techniques for cognitive enhancement (17–23). The main techniques used for this purpose are repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS).

Transcranial direct current stimulation is a non-invasive neuromodulatory technique that is inexpensive, is easy to use, and applicable to the modification of cerebral excitability. This technique delivers weak polarizing direct current to the cortex via two electrodes placed on the scalp. One electrode is an active electrode that is placed over the targeted cortical region, whereas the second electrode is a reference electrode that is typically placed over the contralateral supraorbital area or a non-cephalic region (24). Several studies have demonstrated that a single session of rTMS or tDCS can improve performance on computerized neuropsychological tests that measure cognitive functions, such as working memory, verbal fluency, reaction time, cognitive interference, and sustained attention in patients with TBI (23, 25–28). These stimulation techniques appear to modulate not only “cold” (non-emotional) cognitive functions but also cognitive processes that involve decision-making, attention, and working memory, as shown in studies of patients with depression (29) and eating disorders (30, 31).

Most studies show that anodal instead of cathodal tDCS is better to enhance cognitive function (32–44). Repetitive anodal tDCS (A-tDCS) applied to the dorsolateral prefrontal cortex (DLPFC) was reported to enhance cognition (37–39), reduce depression (40), and suppress food craving (41). Some studies showed short-term facilitation effects on visual recognition memory and memory peformance after prefrontal and temporal A-tDCS applied 30 min at 2 mA, in patients with Alzheimer disease (42–44). Moreover, A-tDCS over the DLPFC may also improve working memory in patients with Alzheimer disease (42). Another recent study showed that applying tDCS to the left temporal lobe effectively improved auditory memory of patients with poststroke cognitive impairment (45). To date, no study evaluated the effects of A-tDCS over left temporal lobe on cognitive function in patients with TBI.

Considering the possible cognitive effects of tDCS and the clinical importance of TBI, the purpose of this study is to investigate the early effects of tDCS in patients diagnosed with PPCS exhibiting cognitive deficits in long-term episodic memory, working memory, and executive function. tDCS was chosen instead of rTMS for several reasons, including that tDCS is more suitable for conducting neuropsychological tests (rTMS causes noise and slight discomfort at the stimulation site, which could interfere with patient performance on the tests), that blinding to tDCS is more reliable considering the study design, and that rTMS is expensive. Furthermore, there is a lower risk of seizures related to tDCS than to rTMS, which is contraindicated for patients with an elevated risk of seizures (46).

The purpose of this study is to determine the early effects of a single session tDCS in patients with MTBI and PPCS with cognitive deficits in long-term episodic memory and executive function (inhibitory control).

The primary hypothesis is that there will be evidence of improvement of patient’s episodic memory and executive function measured by neuropsychological test after the stimulation over the left DLPFC (L-DLPFC) in comparison to the other two types of stimulation [sham stimulation and stimulation over the left temporal cortex (L-TC)].

This is a randomized, sham-controlled, crossover trial. All patients will be selected from the outpatient services at the Neurotrauma Clinic of the Hospital das Clínicas of the University of São Paulo Medical School (HCFMUSP). The recruitment period will be from February 2016 to April 2018.

This trial will follow the main Consolidated Standards of Reporting Trials guidelines.

Thirty patients with a history of MTBI who are least 18 years of age will be recruited through our outpatient services at the Neurotrauma Clinic. In our institution, all patients sustaining MTBI at the emergency department are advised to come to our outpatient clinic if they have persistent symptoms. Participants must be diagnosed with clinically defined PPCS based upon established criteria for the presence and frequency of three or more current PCS-like symptoms. Those symptoms will be assessed using the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) (47). The inclusion criteria are as follows: (1) a history of MTBI on hospital admission, (2) age between 18 and 60 years, (3) current subjective complaints related to memory and executive function, (4) able to sign an informed consent form, and (5) consent to participate in the study. The exclusion criteria are as follows: (1) outside the age limits, (2) no specific complaints related to memory or executive function, (3) severe symptoms of major depression (Beck Inventory >35), (4) drug addiction, (5) uncontrolled epilepsy, (6) presence of a metallic prosthesis implant, (7) presence of a cochlear implant, (8) intracranial hemorrhage other than subarachnoid hemorrhage on admission CT scan, or (9) unable to sign an informed consent form.

All patients will be informed about tDCS and the experimental protocol, which has been approved by the Ethics Committee of our hospital.

First the patients will be evaluated by a senior licensed neurosurgeon in the outpatient clinic. Those who present with PCS for a minimum of 3 months will be diagnosed with PPCS. The diagnosis of PPCS will be established using the RPQ (42). Patients will then be referred for a neuropsychological evaluation. Individuals with cognitive impairment related to episodic memory, working memory, and/or executive function will be eligible for the study.

The study will consist of three phases: (1) a baseline neuropsychological assessment before starting the stimulation sessions; (2) a single tDCS session (L-DLPFC, L-TC, or Sham stimulation) once a week for three consecutive weeks. Figure 1 show the fluxogram of the study.

All the subjects will receive all types of stimulation (L-DLPFC, L-TC, or Sham). The interval between each session will be 7 days to avoid carry-over effects. Because this is a crossover study, all participants will receive all proposed stimulation sessions. A computerized neuropsychological test will be performed before and immediately after each stimulation session.

After each session, patients will be questioned about adverse events. If a major adverse event occurs, the patient will receive medical assistance and further examination and investigation will be provided as needed.

To obtain the necessary data to perform this clinical trial and to analyze the results, the following instruments will be used.

Randomization will be done via a computer-produced randomized controlled table. All the 20 patients will be randomized into the three types of stimulation: frontal stimulation, temporal stimulation, and sham stimulation. The neuropsychologists and the patients will be blinded for the type of stimulation performed in each session.

Data will be stored in a database developed with the Research Electronic Data Capture system (56), which is hosted on the server of the University of São Paulo. This software developed at Vanderbilt University (TN, USA) is fully web-based and enables electronic data collection, management, and also study process management, while meeting the criteria set by the international policies on data privacy and security in the health sector (57).

Most studies which aimed to assess the effects of non-invasive neurostimulation on cognitive function in TBI were case reports or small open labels studies. Moreover, there have been no previous studies comparing the cognitive effects of tDCS stimulation in patients with PPCS. Considering that there were no prior data on the effects of A-tDCS on patients with PPCS using our primary outcome measure, a formal sample size calculation was not possible; thus, we estimated that enrolling 30 patients would be a reasonable approach for an exploratory trial.

All analysis will be performed using Statistical Package for Social Sciences software version 23.0 for Windows (Prentice Hall, Chicago, IL, USA). A significance level of p < 0.05 will be considered for all tests. The quantitative variables will be described using the mean and SDs for normally distributed data or median with inter-quartile range for non-parametric data. The qualitative variables will be presented as absolute and relative frequencies. The five neuropsychological assessments will be summed and averaged to create a composite score. Cohen’s d will be calculated to compare the changes in the neuropsychological scores between the groups. An analysis of variance will be used to test whether there is an overall effect of any type of active stimulation on each outcome measure. When appropriate, we will perform post hoc paired comparisons using Bonferroni correction for multiple comparisons.

Considering the study’s context and design, there will be minimal risk to patients. Non-invasive neuromodulation techniques follow the ethical criteria for studies involving human participants by respecting the principles of autonomy, beneficence, non-maleficence, and proportionality to ensure that the subject will not be harmed if he/she participates in the study.

Transcranial direct current stimulation can be considered a safe intervention for several reasons: (A) the electric current applied is very low (1–2 mA over an area of 25–35 cm²), (B) there is no direct contact between the electrodes and the brain, and (C) the electrodes are embedded in a saline solution, minimizing tissue resistance and avoiding overheating (58–60).

The most common adverse effects observed in safety studies were tingling sensations, itching, mild transient redness of the skin and discomfort on the site of stimulation, moderate fatigue, difficulty concentrating, nausea, and headache. However, these effects were short-lived and were presented at the same frequency between the experimental and placebo groups (60). Patients will be queried after each tDCS session as to whether they experienced adverse effects and how these effects were related to the tDCS treatment. Stimulation sessions have been established by Dr. André Russowski Brunoni, Assistant Professor in the Division of Psychiatry of HC-FMUSP, who will provide any assistance if necessary.

Several advantages of tDCS have been highlighted in clinical practice. These advantages include few side effects that are usually benign, high tolerability, and good potential for efficacy. Notably, it has been emphasized that this technique “has been used in several clinical trials in the last decade and to date, no serious adverse effect has been reported” (58).