So get this written up as a protocol and distribute it worldwide. Just writing this is not enough, you need to follow though and get it directly in the hands of clinicians.
A randomized clinical trial of plasticity-based cognitive training in mild traumatic brain injury
Abstract
Clinical practice guidelines support cognitive rehabilitation for people with a history of mild traumatic brain injury (mTBI) and cognitive impairment, but no class I randomized clinical trials have evaluated the efficacy of self-administered computerized cognitive training. The goal of this study was to evaluate the efficacy of a self-administered computerized plasticity-based cognitive training programmes in primarily military/veteran participants with a history of mTBI and cognitive impairment. A multisite randomized double-blind clinical trial of a behavioural intervention with an active control was conducted from September 2013 to February 2017 including assessments at baseline, post-training, and after a 3-month follow-up period. Participants self-administered cognitive training (experimental and active control) programmes at home, remotely supervised by a healthcare coach, with an intended training schedule of 5 days per week, 1 h per day, for 13 weeks. Participants (149 contacted, 83 intent-to-treat) were confirmed to have a history of mTBI (mean of 7.2 years post-injury) through medical history/clinician interview and persistent cognitive impairment through neuropsychological testing and/or quantitative participant reported measure. The experimental intervention was a brain plasticity-based computerized cognitive training programme targeting speed/accuracy of information processing, and the active control was composed of computer games. The primary cognitive function measure was a composite of nine standardized neuropsychological assessments, and the primary directly observed functional measure a timed instrumental activities of daily living assessment. Secondary outcome measures included participant-reported assessments of cognitive and mental health. The treatment group showed an improvement in the composite cognitive measure significantly larger than that of the active control group at both the post-training [+6.9 points, confidence interval (CI) +1.0 to +12.7, P = 0.025, d = 0.555] and the follow-up visit (+7.4 points, CI +0.6 to +14.3, P = 0.039, d = 0.591). Both large and small cognitive function improvements were seen twice as frequently in the treatment group than in the active control group. No significant between-group effects were seen on other measures, including the directly-observed functional and symptom measures. Statistically equivalent improvements in both groups were seen in depressive and cognitive symptoms.
See Whyte and Turkstra (doi:10.1093/brain/awab210) for a scientific commentary on this article.
Introduction
Mild traumatic brain injury (mTBI, concussion) is the most common type of brain injury in the USA.1 While most individuals recover well after injury, some have persistent physical, mental, and cognitive health complaints, the cause of which is related to a variety of factors.2-4 These post-concussive symptoms5 can have a significant impact on daily functioning and quality of life. Recovery is of particular significance to the military, where the military engagements in Afghanistan and Iraq have led to significant numbers of service members suffering mTBIs. Military veterans are at higher risk for poor recovery than civilians suffering single mTBIs,6–9 likely because of co-occurring psychological trauma and related sequelae.
Current clinical guidelines for post-concussive symptoms in civilian10 and military11 populations recommend non-pharmacological treatments for each of the symptom categories (with certain exceptions, e.g. medication for depression). Treatments for mental and cognitive health issues typically focus on cognitive behavioural therapy, psychoeducation, in-person compensatory/strategy training, and assistive memory aids.12
Improving cognitive function could lead to significantly better outcomes and reduced costs in this population. Cognitive impairment is associated with issues with return to work in mild/moderate TBI.13 An estimate from RAND14 in a study of post-deployment health-related needs in patients with mTBI suggested an annual cost of ∼$25 000 per person/year, with ∼50% of costs derived from lost productivity, which could potentially be helped with effective cognitive remediation.
However, the strength of evidence for cognitive remediation in mTBI guidelines is typically described as low, due to the small number of trials conducted with strong designs (e.g. adequate statistical power, randomization, and active control groups). These guidelines, as well as a recent meta-analysis15 and systematic review16 show only seven randomized controlled trials (RCTs) of cognitive remediation conducted primarily with patients with mTBI; including five trials with in-person compensatory interventions,17–21 a single trial with a mix of manualized and computerized interventions,22 and a single trial with a virtual reality intervention.23 A recent review of computerized cognitive training programmes for adults with TBI found no RCTs meeting the American Academy of Neurology standards for a class I efficacy trial.24
Computerized cognitive training programmes could offer benefits to people with a history of mTBI and cognitive impairment. First, appropriately designed programmes can intensively and adaptively engage neural systems involved in sensory and cognitive processing, with the goal of engaging brain plasticity to renormalize brain and cognitive function. This approach is distinct from compensatory strategy coaching. Second, such programmes offer the opportunity for in-home self-administered training, which could complement in-clinic programmes.21,22,25 Third, remote clinical oversight for patients located far from clinical centres can provide a means for continued intervention to maintain gains as well as an avenue for clinicians to monitor performance post-discharge.
One specific restorative approach has been derived from brain plasticity experiments in animal and human models showing that it is possible to reorganize neural systems using intensive adaptive training programmes. For example, in an animal model a training programme required rats to detect a tone of a specific frequency in a sequence of tones of various frequencies.26 As performance improved, the sequence was made faster and the tones made more similar, requiring faster and more accurate information processing on the part of the rat auditory system to detect the target tone among the sequence of distractors. Behavioural task performance improved over the 4-week training period, as did (in a related way) neurophysiological measures of speed and accuracy in primary auditory cortex (e.g. tuning curve bandwidth, pulsed noise training following rate), as well as cellular (e.g. parvalbumin-labelled inhibitory cortical neurons) and molecular (e.g. myelin) markers of brain health.
In parallel, it has been argued that a key contributor to poor cognitive function is an underlying deficit in the speed and accuracy of neural information processing coupled with relatively weakened neuromodulatory control over learning.27,28 In ageing, this viewpoint is referred to as the information degradation hypothesis,29 and it has been argued that these same principles apply to cognitive impairment following mTBI.30
In combination, the observations that (i) appropriate training programmes improve the speed and accuracy of neural information processing in animal models; and (ii) the speed and accuracy of neural information processing contributes to cognitive impairment in various neurological conditions suggest that training programmes appropriate for humans may improve cognitive function. Such programmes offer the potential to improve cognitive function by improving the quality of information available from neural systems involved in early sensory/perceptual processing for use by neural systems involved in cognitive function.
Based on this view, cognitive training exercises have been developed on these principles (BrainHQ, Posit Science). These exercises have been shown to improve both cognitive function and functional performance in normally ageing populations with mild levels of cognitive impairment similar to post-concussive symptoms,31,32 and show promise in several clinical populations.33–35 Studies employing a single exercise of this type (referred to as ‘speed training’) in a single sensory modality (the visual domain) showed within-domain improvement in visual cognitive and functional measures, but did not show improvement in other cognitive function measures.36,37 Studies involving multiple exercises of this type, including purely auditory31 as well as auditory, visual, and multimodal exercises38 that have shown improvements in multiple measures of cognitive function (including composite measures), suggesting that programmes composed of multiple exercises, which may improve speed and accuracy of information processing across multiple neural systems, may drive larger effects on overall cognitive function and broader functional benefits than individual exercises alone. Several studies have documented a relationship between neural target engagement by the training (assessed by improvements in a psychophysical measure of processing speed) and change in cognitive function.39,40 Additional brain imaging studies have shown that the training alters early sensory processing (measured with EEG) in a way correlated with changes in cognitive function41 and functional connectivity across cortical networks involved in cognitive function (measured with functional MRI).42
These results from related conditions, as well as pilot studies in TBI,43,44 led us to conduct the current BRAVE trial as a multisite, randomized, active-controlled trial of a brain plasticity-based cognitive training programme (BrainHQ, Posit Science) in people with a history of mTBI with cognitive impairment. Based on the putative mechanism of action (improving the speed and accuracy of information processing in the auditory and visual systems with multiple cognitive training exercises in the auditory, visual, and multi-modal domains) and based on results from trials in normal ageing, we hypothesized that the intervention would improve cognitive function across a broad range of measures, including working memory, recall, and executive function; as well as a speed-based directly observed functional measure and participant self-report measures of symptoms.
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