In the United States, annually over 20,000 adults receive inpatient rehabilitation for moderate-to-severe traumatic brain injury (TBI) (1). Studies show that only 26.1% of individuals with a moderate-to-severe TBI reach a disability free global level of functioning at 5-year post-injury. With regards to cognitive function, 49.1% of patients with TBI are not fully independent after 5 years (1).
In the acute stage of TBI, the primary injury refers to lesions related to the trauma mechanism (2–4). Among focal insults, contusion is the commonest, and most often located in the frontal and temporal lobes where the fragile brain tissue comes in contact with irregular bony protuberances of the anterior and middle cranial fossa (2, 4, 5). The secondary injury occurs up to several weeks after the primary injury and can result from excitotoxicity, cerebral edema, ischemia, and neuro-inflammation (4, 6). Then, functional cell plasticity and remyelination prevail within the first three months after insult. Therefore, we can expect the greatest recovery in the subacute phase (4, 6). In the acute stage of TBI, impaired consciousness and post-traumatic amnesia are mostly seen, whereas attentional deficits, memory impairments, communication disorders, altered processing speed and executive dysfunction are noted in the subacute period (5).
Attention is a complex mental activity that refers to how individuals receive and process internal and external stimuli (7). Sustained attention is the capacity to maintain a constant focus on a continuous and repetitive activity; divided attention is the ability to pay attention and to process information coming from two or more sources; and selective attention is the faculty to maintain focus on one trigger or idea for a short moment without being distracted by environmental or competitive stimuli (8, 9). Those disturbances in the attentional processes have a direct negative effect on functional recovery and on return to complex activities after TBI (5). Thus, attentional impairments represent an important target in the rehabilitation intervention in subacute phases of TBI. Traditional attention remediation programs consisting of a battery of pen and paper tasks, informatics software and coping strategies have shown their usefulness, but the evidences supporting specific intervention strategies remains limited (10).
1.1 Transcranial Neurostimulation
To influence neuronal plasticity, non-invasive brain neurostimulation (NIBS) uses an extrinsic-induced electrical stimulus to modulate neuronal excitability, synaptic strength and dendritic connections. Long-term potentiation (LTP) increases synaptic transmission between two neurons by modulating GABAergic and glutamatergic synapses, while long-term depression (LTD) decreases it and reduces glutamate excitotoxicity and GABA-mediated inhibition (4, 11, 12). The two most studied modalities are transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS). tDCS allows a weak direct current to flow from the anode to the cathode placed on the scalp to modify the resting membrane potential and modulate the activity level of spontaneous excitatory neurons. Anodal tDCS increases the excitability of the cortex, and cathodal stimulation decreases it. rTMS generates a magnetic field that induces an electric current to neural tissue. High-frequency stimulation facilitates neuronal efficiency, while low-frequency rTMS reduces it (3, 12). Depending on the frequency of stimulation (rTMS) or the polarity of the direct current (tDCS), these techniques can induce LTP-like or LTD-like effects that last beyond the stimulation time frame (3, 4, 11, 12).
For this research project, tDCS was determined a better option than rTMS. First, its convenience such as portability allows a better adherence to treatment. Furthermore, the current produced by tDCS being less focal than the rTMS, is of interest given the diffuse nature of the TBI. Lastly, tDCS has not been reported to induce seizures and thus appears to be a safer choice (3, 13, 14).
1.2 Neurostimulation and Cognitive Impairment
To date, studies have mainly explored the use of neurostimulation to improve psychiatric disorders, stroke rehabilitation and healthy subjects (3, 12, 13). Among those, Dubreuil-Vall et al. concluded that stimulating the left dorsolateral prefrontal cortex (DLPFC) leads to a significant improvement in reaction time (15), and Jones et al. demonstrated a significant improvement on the working memory task with stimulation of the right frontoparietal area (16).
Research on patients with TBI was published later on because NIBS and especially rTMS are regarded as relative contraindications given that TBI increases neuronal excitability and seizure risk (13). Post-traumatic epilepsy has an incidence of about 5% in patients with closed head injuries and 50% in those with a penetrating injury (3). Seizures are the most concerning adverse events in the therapeutic application of NIBS. If compensatory safety steps are taken, experts agree that the expected benefit justifies the increased risk (3, 13). In fact, literature reports only two incidences of seizures in patients with TBI, both in rTMS and none in tDCS (13).
Two systematic reviews highlight the use of NIBS for improvement of motor function, memory, tinnitus, alteration of consciousness and depression (11, 13). The most recent concluded that tDCS is a safe and non-invasive neuromodulatory technique that may be best combined with other therapeutics to improve cognitive and motor outcomes (11). Out of the 14 studies reviewed, 7 used tDCS to improve responsiveness in patients with disorders of consciousness, 6 in cognition and one in motor outcomes. They underline the challenge in clinical trials due to the heterogeneous procedures in rehabilitation and the difficulty to target a cognitive function as it do not correspond to delineated network as compared to motor function (11).
Only eight papers were published on the impact of NIBS on attention after TBI with abnormal structural imaging in human subjects (7, 17–23). Four research teams used rTMS (17–19, 23), and four used tDCS (7, 20–22). Five of the protocols targeted targeted the DLPFC (7, 20–23), four of which chose the left side (7, 21–23). Because of the studies’ low statistical power, wide variability in type of attention evaluated, study design, lack of consistency between attention type and the tests chosen to assess it, it was difficult to draw a conclusion on NIBS’ effectiveness. Nonetheless, the majority of results were promising and exhibit a positive trend, except for one pilot study (21), and one randomized double-blind trial (23) which failed to show significant differences between the groups. Four studies showed an improvement in some form of attention (17–20), two studies showed an improvement in reaction time (7, 20), one study reported gains in activities of daily living (18), and three studies revealed favorable visible changes in brain imaging (MRI, fMRI, SPECT scans) (17, 18, 20). Ulam’s study is the only one with all 26 patients studied in the subacute phase (the first 6 months following trauma). It showed significant EEG changes after 10 consecutive sessions of tDCS compared to the sham group, suggesting improved regulation of cortical excitability that correlate with improved performance on neuropsychological tests (22). A study by Kang et al., which also included subacute patients with TBI, demonstrated that a single session of anodal tDCS applied to the left DLPFC improved attention compared to the sham stimulation, suggesting its potential role in improving attention (7). This finding is consistent with literature reporting the crucial role that DLPFC plays on attention (5, 20, 22).
In accordance with theory and previous studies, we hypothesized that anodal tDCS applied on the left DLPFC has the potential to enhance attention in patients with mild complicated to severe TBI. Although TBI causes multiple cognitive impairments, we targeted specifically the attentional deficit, because of its impact on rehabilitation.
The primary objective of this pilot study was to evaluate the feasibility of implementing an intervention protocol consisting of nine sessions of tDCS to improve attention disorders in patients with mild complicated to severe subacute TBI hospitalized in a rehabilitation facility. Our secondary objective was to extract preliminary data and observational information on participant responses to treatment on selective attention.