Computerised Working Memory Training in Acquired Brain Injury

Working memory is a limited capacity cognitive system in which information is held temporarily in order to make it available for processing. The amount of information that can be held in mind varies considerably from person to person and changes across the lifespan.

Working memory is frequently affected following brain injury. As working memory is important for cognitive skills such as problem solving, planning and active listening, a deficit in working memory can lead to difficulties with many everyday activities that are necessary for work, study and general functioning. Impaired working memory may consequently have a significant impact on a person's quality of life and ability to participate in previous social roles, with potential for effects on mood and emotional wellbeing.

Evidence shows that non-invasive transcranial direct current brain stimulation (tDCS) can be used in combination with computerized memory training (CT) over multiple days, to enhance working memory in healthy and clinical populations. In patients with an acquired brain injury (ABI), cognitive training or brain stimulation have been used alone to improve attention or memory-related impairment, but the effect of the concurrent used of the two interventions over multiple days is yet to be investigated.

With this research the investigators propose to investigate the effect of the combined use of tDCS and CT to improve memory performance in patients with acquired brain injury. The investigators propose to use a multi-day cognitive training regime to exercise working memory, while stimulating the brain with low intensity direct currents. Success will be measured as improvement in performance in several cognitive domain, before and after training.

Participants will be recruited through Northampton Healthcare NHS Foundation Trust Acquired Brain Injury clinics. They will complete 5 weeks of training at home. During the first two weeks they will be visited in their home by a researcher who will administered the current stimulation together with the working memory training program. The remaining 3 weeks the patient will complete the training program at home, while receiving a motivational / catch up call every week. Weekends will be exempt from testing. The working memory training software program is accessed via a password-protected website on a secure server at Dalhousie University. Training data will be saved on the Dalhousie University server and will be downloaded in Birmingham for data analyses.

RECRUITMENT As the aim of this research is to improve spatial working memory, only participants with a working memory impairment will be included in the study. To identify a working memory impairment, cognitive tests from the Wechsler Adult Intelligence Test (WAIS-IV) and the Wechsler Memory Scale (WMS-IV), will be administered in paper and pencil versions or using iPads. These tests are administered to every patient, as part of the routine care protocol.

The investigators will consider the following scores:

* A Full-Scale Intelligent Quotient (FSIQ) obtained from the WAIS-IV higher than 70: this score identifies patients able to follow instructions. The FSIQ will also be used as a covariate in the analysis to control for low average overall ability rather than a specific working memory issue.
* A Working Memory Index (WMI), obtained as a combination of the digit span score and the arithmetic score in the WAIS-IV, smaller than 85: this score identifies a general working memory impairment;
* A Visual Working Memory Index (VWMI), obtained as a combination of the symbol span and the spatial addition score in the WMS-IV, smaller than 85: this score identifies impairment specific to spatial working memory.

These tests are co-normed on a large sample (mean = 100; SD = 15). In order to be included in the study, a patient should have a FSIQ \>70 and either a WMI or a SWMI or both \< 85. This means that the investigators use a criterion score of one standard deviation below the mean. This score doesn't reflect significant impairment, but it allows us to identify patients with an impairment significant enough to potentially improve with training. See below for a detailed description of the cognitive tasks used. Participants who don't present a working memory impairment, as defined above, will be excluded from further participation. Patients identified as potential participants in the study will be approached with a letter.

SCREENING PROCEDURE:

Following the informed consent procedure, each participant will be randomly assigned to one of the two training conditions (active or sham stimulation) and interviewed with a Screening Questionnaire, which includes questions about demographic information and health history that will evaluate the inclusion/exclusion criteria. The investigators will also ask about current medications and information about time since injury, handedness and colour blindness will be recorded. At this point, participants who don't meet the eligibility criteria will be excluded from further participation. Finally, participants will be made aware of possible side effects of brain stimulation and they will ask to confirm their willingness to participate in the study.

TESTING AND TRAINING:

The protocol is detailed in the protocol flowchart (Annexe 5). After the consent and screening procedures, eligible participants will begin the administration of the baseline measures (T0), and outcome measures (T1). The baseline measures involve completing a series of questionnaires (see below for a list and a brief explanation of each questionnaire), since these variables may impact performance on the tasks. The baseline data will be included in our data analyses as potential modifiers of performance. In total, the investigators expect the entirety of the first in-lab session (informed consent, screening, and baseline measures (T0)) to take about 1 hour. In addition, participants will be asked to refrain from excessive alcohol or coffee drinking during the intervention and to maintain good sleeping habits, where possible. On the following day participants will perform a series of pre-training outcome tasks (see above) to measure their working memory capacity baseline (T1) and to assess, during and at the end of the training intervention, the efficacy of the training and the stimulation regime. Participants will then be offered a break before familiarizing them with the stimulation procedure (sham or active according to the group they belong to) and the training game. The trainer will answer any questions about the study. This second session will last for about 1 h. On T1, the cognitive screening measures (WAIS-IV and WMS-IV) will not be repeated, as already administered as part of the routine care.

On the first training day after the T1 session, depending on the group, participants will receive active or sham brain stimulation (see below for stimulation parameters). At the same time, both groups will complete one session of the NIGMA game, e.g., one session of their training routine (20 minutes). Before each training session, participants will also be asked to answer short questions (level of alertness, engagement, etc.). Once the training session and the stimulation are completed, the participant will fill in a feedback form on the experienced side effects of brain stimulation, if any.

Participants will complete 10 additional consecutive training sessions (2 weeks, excluding weekends). Each session should take about 45 minutes (\~10 minutes setting up of tDCS and \~20 minutes of N-IGMA training). This phase will be completed at home, with the researcher visiting the participant at a convenient time.

When the first training phase is complete, the participant will undergo time 2 (T2) assessment. Like before, this involves completing a series of computerised cognitive tasks to measures training gains and transfer (see "outcome measures" section, including also WAIS-IV and WMS-IV).

Participants will then start the second training phase, involving 3 weeks of training only (no brain stimulation). During this phase, patients will stay at home and access the training program via internet. Manualised phone calls will be used to educate the patients about attention and how they could apply the training to their daily life, to promote generalisation. When the second training phase is completed, participants will undergo time 3 (T3) assessment, during which they will repeat the same series of computerised cognitive tasks as in T2.

A last follow-up assessment, identical to the one at T2, and T3, will be carried out at T4, a month after the completion of the intervention, to assess maintenance of working memory improvements and transfer.

BRAIN STIMULATION PROTOCOL The brain stimulation targets the right dorsolateral prefrontal cortex (DLPFC). A bipolar setup will be used. The bipolar setup includes two Ag/AgCl electrodes filled with conductive EEG gel and placed on F4 (active electrode) and Fp1(return electrode). Reference electrodes will be attached to the earlobe and impedances will be measured throughout the stimulation. If impedances exceed 20kOhm at any time, the stimulation will automatically stop and will not resume until impedances are restored. The investigators will use a total current intensity of 2mA for 20 minutes, preceded by 30 seconds ramping up and followed by 30 seconds ramping down (total stimulation time = 21s). With these parameters and Ag/AgCl electrodes (area 3.14 cm2) a current density of approximately 0.6 mA/cm\^2 is obtained, slightly higher than the one obtained with larger electrodes, but still well below the threshold for tissue damage (Antal et al., 2017; Bikson et al., 2016; Liebetanz et al., 2009)). During sham stimulation the investigators will use the same setup as in the active condition but after ramping up, the current will be brought back to zero and the process repeated 30 seconds before the end of the 21 minutes time interval (total sham stimulation time = 21s).

DATA ANALYSIS The investigators will analyse the data using parametric statistics if appropriate. These will include mixed and repeated measures ANOVAs, with factors such as group and test variables. Significant main effects and interactions (p \< .05) will be followed by post-hoc tests corrected for multiple comparisons. Dependent variables on the computerized tasks will include mean reaction time (RT) and accuracy (% correct).

Eligibility Criteria:
Inclusion Criteria:

1. Referred to the service
2. Are between 18 and 69 years of age
3. Have capacity and able to provide informed consent
4. Normal or corrected-to-normal vision and hearing
5. Having a working memory impairment (see screening procedure below)
6. At least three months between the injury and the starting of the study
7. Has a computer or has access to a computer

Exclusion Criteria:

1. Pre-injury psychiatric or neurological disease by self-report (e.g., anxiety disorder, ADHD, Parkinson's disease, etc.)
2. History of diagnosed severe depression (diagnosed pre-injury)
3. History of epilepsy (diagnosed pre-injury)
4. Family history of epilepsy
5. Have had fainting spells or syncope in the last three years pre-injury
6. Have significant hearing loss, vision or motor impairment that would prevent them from performing the task
7. Known to be pregnant
8. Assuming medication affecting cortical excitability or recreational drugs
9. Metal (except titanium) or electronic implants in the brain /skull (e.g., splinters, fragments, clips, cochlear implant, deep brain stimulation, medication pump...)
10. Metal (except titanium) or any electronic device at other sites in the participant's body, such as cardiac pacemaker or traumatic metallic residual fragments
11. Have skin problems such as dermatitis, psoriasis or eczema under the stimulation sites
12. Have had brain stimulation in the past six months
13. Have undergone transcranial electric or magnetic stimulation in the past (more than 6 months) which resulted in adverse effects
14. Skull fractures, significant skull defects, skull plates or large vessels occlusions in the site of electrode placement
15. having had a seizure at the time of accident or between the injury and starting of the therapy.