A 39-year-old right-handed (dominant hand), Caucasian female was referred to our memory clinic 3 years after a bicycle accident, which resulted in a left temporo-parietal epidural hematoma and scattered right temporal lobe contusions that required surgical evacuation and intensive care unit monitoring. Retrospectively, post-traumatic amnesia was unclear and loss of consciousness was prolonged. This would be most appropriately graded as severe TBI although we do not have information on her initial Glasgow Coma Scale and length of hospitalization. Brain MRI acquired within a few months of treatment initiation showed encephalomalacia involving the right frontal and temporal lobes (Figure 1A). Even though there was no evident encephalomalacia near the previous left epidural hematoma, there was visibly reduced volume in the left parietal region suggesting prior injury. She had significant functional recovery and regained her independence in daily functioning. Modified Rankin Scale was 2 at post-TBI baseline. Prior to the injury, she was a high functioning executive with 18 years of education. She was not able to resume her prior job as a manager due to persistent cognitive complaints and frequent episodes of dizziness. She was taking levetiracetam 500 mg twice daily due to a post-TBI seizure immediately after the accident and she had been seizure free since then. She had a history of migraine but did not have any pre-morbid developmental delay or learning disabilities. Of note, during the study she was on a stable dose of off-label use of ropinirole 0.75 mg twice daily for at least 3-4 months to treat her verbal retrieval deficits, with reported mild improvement. Use of dopaminergic agents for improving verbal fluency has been reported in the literature with mixed results [see review by for its potential mechanisms], as we have observed in our clinical practice with often variable success among different individuals.
The patient reported stable, persistent cognitive symptoms for at least the past 2 years, including difficulties with concentration to complete a task, word finding, naming objects, understanding what she has read, difficulties in remembering names and trouble recognizing people's faces, organizing ideas and shifting attention. She denied any such issues prior to the accident.
The patient was recruited as part of an open-label group study using HD-tDCS targeting the pre-SMA for cognitive deficits in patients with chronic TBI. Both safety and feasibility were evaluated in this study. HD-tDCS (with a similar 4 x 1 montage) has been tested extensively in healthy subjects, with side effects reported to be minimal even at a current significantly higher than ours. However, there is lack of large-scale studies that systematically examine safety in neurologic patients, other than case reports and case series. We are not aware of studies reporting major safety concerns for HD-tDCS application in neurologic patients that precluded our study protocol. We strictly followed exclusion criteria for tDCS protocols [e.g., presence of electronic implants or any extracranial or intracranial foreign objects ] and closely executed safety protocol including having a trained physician on site, and closely monitoring the patient's symptoms during and after HD-tDCS sessions. Informed consent was obtained in accordance with the protocols approved by the Institutional Review Board of the University of Texas at Dallas and the University of Texas Southwestern Medical Center.
The HD-tDCS montage targeting the pre-SMA consisted of Fz for the central anodal electrode and FPz, Cz, F7, and F8 for the return (cathodal) electrodes (i.e., five circular Ag/AgCl electrodes 1 cm radius with conductive gel). A battery-driven, wireless multichannel transcranial current source generated the stimulation current (Neuroelectrics Starstim ). This montage has been reported in previous studies and was designed to target the dorsomedial prefrontal cortex, with the electric field most concentrated in the pre-SMA/dACC based on electric field simulation (Figures 1B-F; including pre-SMA and part of the dorsal Anterior Cingulate Cortex, dACC). At each session, active HD-tDCS was ramped up over 60 s until it reached 1 mA, maintained at 1 mA for 20 min, and then ramped down to 0 mA over 60 s. This current was selected based on a prior study that showed good tolerability in healthy adults. HD-tDCS was administered across 10 sessions over 2 weeks, each constituting 20 min of stimulation while the patient sat quietly or engaged in casual conversation with the experimenter. We assessed the patient's pain and comfort level during and after each session. The patient only experienced minimal tingling sensation near the electrodes in the beginning of each session, and did not report discomfort or any other side effects.
The overall study protocol is demonstrated in Figure 2A. We administered verbal fluency (phonemic and category) before and after each single HD-tDCS session in order to monitor instantaneous and cumulative change over time. Both phonemic and category fluency tasks reflect aspects of lexico-semantic processing and executive function. In addition, a comprehensive battery of neuropsychological measures was performed at baseline as well as immediately, 6 weeks, and 14 weeks after completion of the 10 HD-tDCS treatment sessions. For cognitive outcome measures, we evaluated verbal retrieval function (phonemic fluency using FAS and category fluency using animal category, Boston naming test), executive functions (Trails Making B, Delis-Kaplan Executive Function Systems color-word interference), speed of processing (Trails Making A) and facial recognition (the Benton face test) (see references in Table 1). Electrophysiological measures (to be described in detail later) were also recorded at baseline, immediately, and at 6 weeks after completion of the 10 HD-tDCS sessions. We used different parallel versions as were available for HVLT-R and Digit Span for testing. Given limited versions available for any other tests, we did not use multiple versions.
After each session, we observed immediate improvements in verbal fluency (Figure 2B), but these changes did not persist until the next session.
As shown in Table 1, at baseline, the patient exhibited impaired performance (<1 standard deviation from the average) in verbal retrieval (phonemic and category fluency, Boston naming test). She also demonstrated impaired executive functions (Trails Making B, color-word interference), speed of processing (Trails Making A) and facial recognition (the Benton face test) on neuropsychological measures (Figure 2C). Otherwise, she had near average performance in working memory, visuo-spatial and verbal learning functions (Table 1). Improvement in performance was found in tasks at which the patient was most impaired, most evident in verbal retrieval and executive function tests, including trails B, confrontational naming, phonemic and category fluency (Table 1, Figure 2C). These positive therapeutic effects persisted for at least 14 weeks after HD-tDCS was completed. In inhibition and inhibition/switch parts of the color-word interference test, we found incremental improvements over time, indicating delayed effects.
In order to investigate underlying neural changes in response to HD-tDCS intervention, we recorded EEG and evaluated N2/P3 event-related potentials (ERPs) components at baseline, immediately and at 6 weeks after completion of HD-tDCS treatment. EEG was recorded during two Go/NoGo tasks, including 2 different levels of perceptual and semantic complexity [applied extensively in a series of prior studies where more detailed description can be found, e.g., in ]. The N2 and P3 components during the response inhibition (Go/NoGo) paradigm are in general thought to represent correlates of cognitive control and response selection/inhibition. While we recorded absent and markedly diminished N2/P3 components prior to HD-tDCS, we found restoration and normalization of the typical N2/P3 ERP components after completion of treatment (Figure 3), which persisted until 6 weeks after intervention, with overall increased amplitude and decreased latency in both N2 and P3 components. Behavioral performance improved significantly as well, with Go reaction time reduced from 635 ms at baseline to 447 and 327 ms immediately and at 6 weeks post intervention, respectively, in the more perceptually driven task (Figure 3, Task 1), and improved from 662 ms at baseline to 559 and 494 ms immediately and 6 weeks post intervention, respectively, in the more semantically driven task (Figure 3, Task 2). Accuracy remained relatively stable above 90% except for the baseline Go accuracy that was 77 % but improved to above 95% for all subsequent testing.
The patient reported significant and progressive improvement in her daily function during and after HD-tDCS. Before treatment she had dizziness that could be triggered by rapid head and eye movements. Her dizziness improved such that she started reading books, doing grocery shopping and watching her daughter's football practices. Second, she had trouble organizing and following her schedule and constantly relied on her notes and calendar. She noticed that after HD-tDCS she was able to follow plans by memory, and was less dependent on notes. Third, before she began this treatment regimen she experienced mental fatigue quite easily after limited duration of cognitive activity. After HD-tDCS, she had more energy and could carry out more daily tasks that she had not been able to prior to treatment.