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6. Cognition Interventions Post Acquired Brain Injury

Abbreviations

ABI Acquired Brain Injury

APT Attention Process Training

CES Cranial Electrotherapy Stimulation

GH Growth Hormone

Met Methionine Allele

PASAT Paced Auditory Serial Addition Task

PDA Personal Digital Assistant

PTA Post Traumatic Amnesia

RCT Randomized Controlled Trial

TBI Traumatic Brain Injury

TPM Time Pressure Management

Val Valine Allele

Key Points


Although attention training programs in general improve attention scores, the level of structure in these programs does not appear to influence the success of the intervention.

Dual-task training has been shown to improve measures of attention to the extent that the ABI population does not significantly differ from healthy controls, however it is undetermined if the strength of these effects compared to non-dual-task training are greater.

Computer-based interventions are no more effective than no intervention in improving measures of attention and concentration post ABI.

Repetitive virtual reality tasks which include repetition are effective in improving attention and concentration in ABI populations.

Goal management training is effective in assisting those who sustain an ABI learning to manage life goals through improved attention.

Therapies which focus on emotional regulation or mindfulness do not appear to be effective at improving attention post ABI.

In order to determine if attentional training is effective in improving attention post-ABI standardized protocols must be developed to allow between study comparisons.

Tasks that involve mathematical skills may be effective at improving attention post-ABI.

Cognitive rehabilitation therapy is not likely to remediate attentional deficits in ABI populations.

Transcranial direct current stimulation may be effective in remediating attentional deficits when combined with computer assisted training in ABI populations.

Donepezil can help improve attention in individuals with ABI.

The effectiveness of methylphenidate treatment to improve cognitive impairment following brain injury is unclear.

Methylphenidate is effective in improving reaction time for working memory.

Response to methylphenidate may depend on genotype.

Bromocriptine might improve executive function, but not memory, attention, or reading ability in patients post TBI.

Cerebrolysin may be beneficial for the improvement of clinical outcome and cognitive functioning following brain injury; however, controlled trials are needed to further evaluate its efficacy.

Rivastigmine may not be effective in treating attention deficits post-ABI.
Pager and voice-organizer programs may improve a patient’s ability to complete tasks post TBI.

Personal digital assistant (PDA) devices are superior to paper-based interventions at improving memory and task completion post TBI; specially when introduced using systematic instructions and in combination with occupational therapy. Patients who have used previous memory aids might benefit from this intervention the most.

Text message prompts sent to a patient’s smartphone, when used alone or in combination with other memory-improvement therapies, likely improve task completion post TBI. However, risk exists of device dependency exists.

A television assisted prompting (TAP) program may be superior to other methods of memory prompting in patients post TBI.

Automated prompting systems, such as Guide (audio-verbal interactive micro-prompting system) and a computerized tracking system, can reduce the amount of prompts needed from support staff to patients to complete tasks post TBI.

Calendars may be effective tools for improving memory and task completion post ABI.

The use of a diary may help to improve memory and task completion post ABI, but more so if diary training is combined with self-instructional training.

Virtual reality programs may enhance the recovery of memory, learning, but there is currently limited evidence supporting the use of virtual reality programs.

Memory-retraining programs appear effective, particularly for functional recovery although performance on specific tests of memory may or may not change.

Specific computer-based softwares seem to be effective for improving memory post-ABI.

Computer-based interventions may be as effective as therapist administered interventions.

Emotional self-regulation therapy may be effective for improving specific elements of memory.

Recall and recognition of words can be enhanced by using a spaced learning condition.

Cranial electrotherapy stimulation is likely not effective at enhancing memory and recall abilities following TBI.

Donepezil likely improves attention and memory following TBI.

There is conflicting evidence that methylphenidate administration post TBI improves attention, memory, concentration and processing speed.

Response to methylphenidate likely varies depending on genotype at the catechol-O-methyltransferase (COMT) gene.

Sertraline has not been shown to improve learning, or memory within the first 12 months post TBI, and may be associated with side effects.

Amantadine might not be effective at improving learning and memory deficits post TBI.

Pramiracetam might improve memory in males post TBI; however, additional studies are required.

Physostigmine likely improves long-term memory in men with TBI.

Bromocriptine may improve dual task performance and motivational deficits but its effect on memory is controversial. More research is needed before the benefits of using bromocriptine to enhance learning and memory deficits are required.

Cerebrolysin may be beneficial for the improvement of clinical outcome and cognitive functioning following brain injury; however, controlled trials are needed to further evaluate its efficacy.

The administration of recombinant human Growth Hormone (rhGH) is likely not different than placebo at improving executive functioning, memory, or learning in patients post TBI; however certain aspects of patient quality of life may be improved.

The administration of recombinant human Growth Hormone (rhGH) might be superior at improving intelligence and cognition in patients with a growth hormone deficiency, versus those who do not, post TBI. Molecular markers of growth however may not be different post treatment between groups.

Rivastigmine may not be effective in treating memory deficits post-ABI.

Targeted hypnosis may improve memory, attention, and cognitive function in patients post TBI or stroke; however, only as long as the intervention is being administered.

Attention improvement interventions may be superior to non-specific cognitive or education programs at improving memory and attention in patients post TBI.

A comprehensive cognitive treatment strategy is likely superior to a computerized training package at improving task initiation and completion in patients post TBI; this intervention may also improve cerebral blood flow.

It is unclear whether virtual-reality training is superior to conventional training at improving cognitive and executive function outcomes post TBI. Conflicting evidence exists, and further studies are required.

Computer or smartphone software programs (BrainHQ, Parrot Software, ProSolv app) may not be superior to common interventions at improving memory, attention, and problem-solving skills in patients post TBI.

Goal management training may superior to motor skills training at improving every day skills (meal preparation), but not intelligence or neuropsychological outcomes in patients post TBI.

It is unclear whether goal oriented interventions delivered in a group setting are more successful than educational interventions at improving cognitive and executive function post ABI. However, no detrimental effects have been found with the intervention.

Emotional regulation interventions delivered in a group setting may improve executive function in patients post TBI; however, it is unclear if it is superior at doing so compared to conventional cognitive remediation.

It is unclear whether cognitive interventions (such as the Metacognitive Strategy
Instruction program) improves language ability, and executive/ cognitive function in patients post TBI.

Remedial occupational therapy is likely superior to adaptive occupational therapy at improving general cognitive functioning in patients post TBI.

Low intensity outpatient cognitive rehabilitation might improve goal attainment and cognitive function in patients post ABI.

Donepezil might improve attention, learning and short-term memory following TBI; however, side effects may incur from its use.

The effectiveness of methylphenidate treatment to improve cognitive impairment following brain injury is unclear. Further studies with larger populations are required.

Sertraline has not been shown to improve cognitive functioning within the first 12 months post TBI, and may be associated with side effects.

Amantadine might not be effective at improving attention and memory deficits post TBI. Its impact on executive functioning should be studied further.

Bromocriptine may improve some executive cognitive functions such as dual task performance and motivational deficits. More research is needed before the benefits of using bromocriptine to enhance cognitive functioning are known.

The administration of recombinant human Growth Hormone (rhGH) is likely not different than placebo at improving executive functioning, memory, or learning in patients post TBI; however certain aspects of patient quality of life may be improved.

The administration of recombinant human Growth Hormone (rhGH) might be superior at improving intelligence and cognition in patients with a growth hormone deficiency, versus those who do not, post TBI. Molecular markers of growth however may not be different post treatment between groups.

Rivastigmine may not be effective in treating memory deficits post-ABI.

Introduction

Cognitive dysfunction is a common symptom of acquired brain injury (ABI) which can negatively affect many areas of cognition such as attention, memory, executive function, learning, and social cognition. Each of these cognitive functions represents a unique area of cognition which allows individuals to execute activities of daily living. Cognitive impairment can be caused not only by the initial trauma, but also by secondary inflammation or insult. Compared to mild traumatic brain injury (TBI), moderate/severe TBI is associated with more severe and persistent cognitive deficits, with about 65% of patients reporting long-term cognitive problems (Rabinowitz & Levin, 2014). The effects of TBI on overall cognitive functioning vary depending on the time post injury (Schretlen & Shapiro, 2003). Even with good medical prognosis, cognitive ability remains one of the best predictors of successful return to work and independent living (Brain Injury Medicine, pp 990). With the diverse nature of the brain there are a multitude of ways that each trauma can impact cognition. As a result, there are a variety of interventions available to clinicians to help rehabilitate cognitive function post ABI. In Ontario, the mean direct per-patient medical costs in the first follow-up year after ABI was $32 132 for TBI and $38 018 for non-traumatic brain injury. (Chen et al., 2012).

The broadest categories of cognitive interventions can be classified as pharmacological and non-pharmacological. Pharmacological interventions use medication in an attempt to remediate cognitive deficits. These types of medications usually moderate neurotransmitters in the brain which regulate cognitive functions. By influencing the concentration and absorption of either excitatory or inhibitory neurotransmitters these medications are able to affect memory, attention, and social behaviours (Brain Injury Medicine, pp 1205). Non-pharmacological interventions span a broader spectrum and can include anything from physical exercise to memory programs with assistive technology. However, there are multiple challenges when evaluating the effectiveness of cognitive interventions. First, there is no consensus regarding a definition of attention; currently, it is used as a general construct. Attention can be further broken down into sub types (sustained, divided, focused, selective, vigilance, speed of information processing), however this is not always reflected in the literature. Second, researchers and clinicians may use different measures when reporting outcomes, making comparisons between interventions difficult. Third, a study may use the same outcome measures repeatedly, thereby confounding practice and treatment effects (e.g., Paced Auditory Serial Attention Task (PASAT)). Finally, studies may not consider or account for the rate of spontaneous recovery following brain injury (i.e., would participants naturally show recovery of function in the absence of treatment?). For these reasons, assessing the efficacy of interventions for cognitive rehabilitation is more challenging compared to other modules due to the heterogeneous presentation and assessment of cognitive deficits..

This module reviews the available evidence related to interventions for cognitive rehabilitation following ABI. Studies that specifically deal with cognitive-communication deficits are discussed in module 7.

6.2 Remediation of Attention, Concentration, and Information Processing Speed

Although there is no specific agreement on the definition of attention, it is usually measured using externally directed tests, such as instructing participants to focus their attention on a sequence of stimuli or attenuating to a particular stimulus.

In general, TBI populations demonstrate significant deficits compared to control populations. Dymowski et al. (2015) showed that mild to severe TBI participants performed significantly worse on speed of information processing tasks compared to a healthy control group.
Dockree et al. (2006) and Hasegawa and Hoshiyama (2009) found that TBI patients made significantly more errors than their non-TBI counterparts on dual task experiments for sustained attention. However, a case series by Foley et al. (2010) found that level of injury severity as measured by the Glasgow Coma Scale or PTA did not play a role in who performed poorly on the dual task assignment given to participants. They found that only 27% of TBI study participants performed below the cut-off for normal performance.

Two studies assessing the reaction times of individuals demonstrated that those with a TBI were found to have slower reaction times than individuals who had not sustained a TBI (Azouvi et al., 2004; Stuss et al., 1989). Results of the visual analogue scale also indicated that mental effort was higher for those with a TBI than for the controls. The results of this study confirmed what previous studies had found: those with a TBI have greater difficulty when dealing with two simultaneous tasks (Azouvi et al., 2004).

In order to better understand the mechanism by which cognitive interventions can improve attention, concentration, and information processing, there needs to be a consensus as to the definition of specific cognitive processes, such as attention.

6.2.1 Non-Pharmacological Interventions

6.2.1.1 Drill & Practice

Key Points

Although attention training programs in general improve attention scores, the level of structure in these programs does not appear to influence the success of the intervention.

The following studies examined the influence of “drill & practice” exercises (either computerized and/or paper-and-pencil) on attentional functioning. Drill and practice training aims to improve attention through repetitive training of specific tasks involving attention.

Discussion

Park et al. (1999) examined whether “attention processing training (APT)” had a beneficial effect on attention measures (PASAT, Consonant Trigrams) in a severe TBI group (tested pre and post training approximately 7 months apart). They compared their results to a “convenience” sample of controls, given the same measures one week apart without training. Results suggested that APT did not have a significantly beneficial effect as performance improved on all measures across both groups (indicating practice effects and possibly spontaneous recovery). Similarly, two trials did not find significant differences between groups for attentional, functional, and/or cognitive skills assessed (Lindelov et al., 2016; Novack et al., 1996). Novack et al. (1996) compared focused hierarchical attentional learning with an unstructured non-sequential, non-hierarchical intervention, while Lindelov et al. (2016) compared N-back training with visual search training. Overall there is weak evidence in support of training programs as an effective rehabilitation intervention for attention.

Conclusions

There is level 2 evidence that training programs designed to improve attention in general may be effective compared to unstructured stimulation in ABI populations.

There is level 3 evidence that attention processing training may improve attention compared to visual search training in ABI populations.

6.2.1.2 Dual-Task Training

Key Points

Dual-task training has been shown to improve measures of attention to the extent that the ABI population does not significantly differ from healthy controls, however it is undetermined if the strength of these effects compared to non-dual-task training are greater.

The following studies examined the effect of “dual-task” training on speed of processing. Dual-task training involves dividing attention between two stimuli in order to complete two tasks concurrently and successfully, such as walking while speaking.

Discussion

One RCT with a TBI population showed that attention and information processing outcomes could be improved within the dual task paradigm (Couillet et al., 2010; Sacco et al., 2016). Couillet et al. (2010) found that dual-task training significantly improved attentional behaviour and reaction time compared to a non-specific cognitive program.

Conclusions

There is level 2 evidence that dual task training may be effective in improving attention task performance in ABI populations compared to non-specific training.

6.2.1.3 Computer-Based Interventions

Key Points

Computer-based interventions are no more effective than no intervention in improving measures of attention and concentration post ABI.

Repetitive virtual reality tasks which include repetition are effective in improving attention and concentration in ABI populations.

An increase in available technology has allowed for the development for more computer-based interventions designed to improve attention, concentration, and information processing. Common treatment modalities include computer cognitive training programs and virtual reality sessions. Virtual reality is discussed in further detail in 6.3.1.1.3 where its effects on learning and memory are presented.

Discussion

Chen et al. (1997) studied the effect of computer assisted cognitive rehabilitation versus traditional therapy methods. While measures of attention significantly improved in both groups after treatment, no significant differences were observed between groups (Chen et al., 1997). Other studies with brand name computer-assisted cognitive rehabilitation showed less favourable results. A small pre-post study of Luminosity showed improvements in attention for a minority of participants, however this improvement did not significantly differ from those who received Attention Process Training-3 (Zickefoose et al., 2013). Parrot software showed mixed results with a pilot study reporting significant attention improvement post-intervention (Li et al., 2013), but a subsequent study reported no significant changes on measures related to attention (Li et al., 2015). BrainHQ did not significantly improve attention outcomes over time or compared to no intervention (O’Neil-Pirozzi & Hsu, 2016). The lack of evidence supporting the efficacy of computer-based cognitive rehabilitation may be due to different programs and strategies used to train participants. An RCT by Dirette et al. (1999) found no significant differences in improvements between participants taught specific compensatory strategies and those that simply completed the computer tasks without instruction of compensatory strategies. However, both groups significantly improved over time, with those that used the compensatory strategies (whether taught or spontaneously acquired) performing better than those that did not (Dirette et al., 1999).

Repetition of tasks in virtual reality improved performance, both in terms of speed and accuracy (Dvorkin et al., 2013; Gerber et al., 2014). Gentle nudges corrected behaviour better than break-through or no feedback (Dvorkin et al., 2013). However, repetition of the Stroop test in different virtual reality environments showed limited improvement in performance on those specific tests (Dahdah et al., 2017). A virtual reality exercise program demonstrated significant benefits in reaction times but not attention after intervention; more high quality research is needed to confirm the efficacy of virtual reality exercise (Grealy et al., 1999).

Conclusions

There is level 2 evidence that neither general nor name brand computer-based rehabilitation intervention may improve attention outcomes compared to usual care in ABI populations.

There is level 4 evidence that attention performance can be improved in ABI populations through repetition of tasks, either through computer-based or virtual reality environments.

6.2.1.4 Attention Training Programs

Key Points

Goal management training is effective in assisting those who sustain an ABI learning to manage life goals through improved attention.

Therapies which focus on emotional regulation or mindfulness do not appear to be effective at improving attention post ABI.

In order to determine if attentional training is effective in improving attention post-ABI standardized protocols must be developed to allow between study comparisons.

Tasks that involve mathematical skills may be effective at improving attention post-ABI.

Cognitive rehabilitation therapy is not likely to remediate attentional deficits in ABI populations.

With regards to cognitive rehabilitation, much of therapy is patient goal directed with both long and short term goals often identified (Carswell et al., 2004). The ability to manage goals is often emphasized as a component of brain injury community reintegration programs and is integral in the completion of instrumental activities of daily living. The execution of these goals relies on an individual having the ability to maintain attention on a given task.

Cicerone et al. (2005) recommended strategy training for persons with TBI for improving deficits of attention. It should be noted, however, that there was insufficient evidence to distinguish the effectiveness of specific attention training during acute stage rehabilitation from improvements made from spontaneous recovery or from more general cognitive interventions (Cicerone et al., 2005).

Discussion

Levine et al. (2000) completed an RCT comparing a group of patients taking goal management training strategies to a control group who were exposed to only motor skills training. The treatment group improved on paper and pencil everyday tasks as well as meal preparation, which the authors used as an example of a task heavily reliant on self-regulation.

A recent RCT (Dundon et al., 2015) examined the effect of adaptive training on dichotic listening tasks and attention, interestingly the adaptive training group had significantly higher scores on the listening task compared to non-adaptive training group, however, the non-adaptive training group surpassed the adaptive training group in test of everyday attention scores.

Emotional regulation was also examined as a potential intervention for the remediation of attention post-ABI (Cantor et al., 2014). However, this treatment was not seen to be effective in the recovery of attention, other significant effects on executive functioning from this study are discussed further in section 6.4.1.1. Another study which focused specifically on mindfulness (McHugh and Wood, 2013) found that mindful focused training significantly improved participant’s ability to correctly select stimuli compared to controls.

Fasotti et al. (2000) assessed the effectiveness of time pressure management (TPM) training compared to concentration training in patients with slowed processing speed as a result of traumatic brain injury. Though both groups showed improvements on information intake task performance, no significant differences between groups were observed even though specific time pressure management strategies were learned by the experimental group (Fasotti et al., 2000).

Taking focused training a step further, many studies examined the effects goal training or cognitive training (Boman et al., 2004; Chen et al., 2012; Laatsch et al., 1999; Novakovic-Agopian et al., 2011; Sohlberg et al., 2000). Physiologically cognitive rehabilitation therapy resulted in an increase in cerebral blood flow during treatment in the experimental group (Laatsch et al., 1999), as well as the experimental group reporting greater improvements in productivity. Levine et al. (2000) completed an RCT comparing a group of patients taking goal management training strategies, to a control group who were exposed to only motor skills training. The treatment group improved on paper and pencil everyday tasks as well as meal preparation, which the authors used as an example of a task heavily reliant on self-regulation. A pre-post study (Boman et al., 2004) found that cognitive training for three weeks significantly improved attention task scores compared to pre-test scores. One study did demonstrate that cognitive training (although beneficial) may not be more beneficial than other interventions such as educational training with respect to processing speed (Chen et al., 2011). In this study both groups significantly improved in attention directed goal completion. Another study comparing the effects of attentional training with another intervention (in this case physical exercise), found that there was no significant difference between groups post-intervention, but there was a within subjects effect such that both groups reported significantly less cognitive failures (McMillan et al., 2002). Novakovic-Agonian et al. (2011), found similar results in an RCT crossover where participants were assigned to received goal-training followed by education or the reverse. The goal training first group saw a significant improvement in sustained attention compared to the education-first group, additionally the goal training first group maintained their gains over 10 weeks. When it comes to attention process training, that was also shown to have greater results in attention remediation compared to education (Sohlberg er al., 2000). One study examined the effects of a memory training program on attention, to positive results. Hellgren et al. (2015), found that a memory training program was successful in improving attentional scores on the Paced-Auditory Serial Attention Test, as well as further enhancing memory in general which is discussed later on in the chapter.

The inconsistencies between studies may be due to a lack of standardized goal management training or attention process training protocols. The lack of a consensus on the definition of certain cognitive processes appears to be reflected in the interventions used to attempt to rehabilitate these deficits. Unfortunately, this decreases the ability to compare studies on a more specific level, however, general conclusions can still be made that specific training programs which intend to increase attentional capacity are effective, to what extent they are more beneficial than other training programs needs to be addressed in the future through comparative methodologies. Only one study (Serino et al., 2007) described the specific task which was successful in improving attention. This cognitive task involved mental addition in combination with two other standardized tasks and was an effective strategy for improving attention.

Conclusions

There is level 2 evidence that adaptive training is no more effective than non-adaptive training in remediating attention in ABI populations.

There is level 1b evidence that emotional regulation therapy is not effective in treating attentional disorders compared to waitlist controls in ABI populations.

There is level 2 evidence that mindfulness training compared to no intervention may improve an individual’s ability to correctly reject inappropriate stimuli post ABI.

There is level 2 evidence to suggest goal management training, when compared to education, may be effective at improving attention in post-ABI individuals.

There is level 2 evidence that goal management training is more effective in remediating task completion times than motor skill training, however is not more effective in treating attention deficits, in post-ABI individuals.

There is conflicting (level 2) evidence that attentional control or processing training may not significantly improve attention in post-ABI individuals compared to control training.

There is level 4 evidence that summation tasks may be effective at improving attention in individuals post ABI.

There is level 4 evidence that a working memory training program may remediate attention in post-ABI individuals.

There is level 4 evidence that cognitive rehabilitation therapy may not be effective for improving attention post-ABI.

6.2.1.5 Transcranial Direct Current Stimulation

Key Points

Transcranial direct current stimulation may be effective in remediating attentional deficits when combined with computer assisted training in ABI populations.

Transcranial Direct Current Stimulation (tDCS) is a technique that painlessly delivers electrical currents to specific regions of the brain. These electrical currents modulate neuronal activity through electrodes placed over the head at different regions. To our knowledge only one recent study has examined the effects of tDCS on cognitive functioning post-ABI.

Discussion

Only one RCT to our knowledge has examined the effects of transcranial direct current stimulation (tDCS) on attention in a post-ABI population. Sacco et al. (2016) found that the addition of transcranial direct current stimulation to computer-assisted training was superior to sham stimulation for improving divided attention. However more high level studies are needed in order to fully examine the potential benefits of adding tDCS to standard attentional therapies.

Conclusions

There is level 2 evidence that transcranial direct current stimulation compared to sham stimulation may improve divided attention in individuals post ABI.

6.2.2 Pharmacological Interventions

6.2.2.1 Donepezil

Key Points

Donepezil can help improve attention in individuals with ABI.

Originally developed for improving cognitive function and memory in people with Alzheimer’s disease, donepezil is an acetylcholinesterase inhibitor (Cacabelos, 2007). Donepezil has been found to be effective at delaying cognitive impairment in people with Alzheimer’s disease (Takeda et al., 2006). Since evidence suggests that cholinergic dysfunction may contribute to persistent cognitive deficits for people after traumatic brain injury, improvements in attention, memory, and other aspects of cognition related to the acetylcholine system are expected when cholinergic function is reduced (Arciniegas, 2003).

Discussion

Khateb et al. (2005) found only modest improvement on the various neuropsychological tests used to measure attention. In an RCT, Zhang et al. (2004) demonstrated that donepezil was associated with significantly more improvement in tasks of sustained attention compared to placebo. These improvements were sustained even after the washout period, resulting in non-significant differences between groups after crossover.

Conclusions

There is level 1b evidence that donepezil may improve attention compared to placebo post ABI.

6.2.2.2 Methylphenidate

Key Points

The effectiveness of methylphenidate treatment to improve cognitive impairment following brain injury is unclear.

Methylphenidate is effective in improving reaction time for working memory.

Response to methylphenidate may depend on genotype.

Methylphenidate is a stimulant whose exact mechanism is unknown (Napolitano et al., 2005). One theory is that methylphenidate acts on the presynaptic nerve to prevent the reabsorption of serotonin and norepinephrine, thereby increasing their concentrations within the synaptic cleft. This in turn leads to increased neurotransmission of serotonin and norepinephrine (Kim et al., 2006). In healthy individuals, methylphenidate has been found to improve memory but not other cognitive functions such as attention, mood, or executive function (Repantis et al., 2010). Methylphenidate is extensively used as a treatment for attention deficit disorder, as well as narcolepsy (Glenn, 1998). No serious side effects have been observed in clinical trials, though there is a lack of evidence for long term safety (Godfrey, 2009).

Discussion

In an RCT, Whyte et al. (2004) indicated that speed of processing, attentiveness during individual work tasks and caregiver ratings of attention were all significantly improved with methylphenidate treatment. No treatment related improvement was seen in divided or sustained attention, or in susceptibility to distraction. Similarly, Plenger et al. (1996) and Pavlovskaysa (2007) found that methylphenidate significantly improved attention and concentration, and visuo-spatial attention, respectively

Speech et al. (1993) conducted a double blind placebo controlled trial evaluating the effects of methylphenidate following closed head injury. In contrast to the results noted by Whyte et al. (2004) and Plenger et al. (1996), methylphenidate did not demonstrate significant differences compared to placebo on measures of attention, information processing speed, or learning. Kim et al. (2006) examined the effects of a single-dose treatment of methylphenidate and, although a trend was found in favour of improved working and visuospatial memory for the treatment group, these results did not reach significance. Recently, Kim et al. (2012) found that reaction time improved significantly while on the methylphenidate. This is in line with Willmott and Ponsford (2009) who found that administering methylphenidate to a group of patients during inpatient rehabilitation, did significantly improve the speed of information processing. Conflicting results continue to be reported, as two high-quality RCTs reached different conclusions regarding methylphenidate use. While Dymowski et al. (2017) noted no improvements in any measures of attention and mental processing, Zhang and Wang (2017) noted improvements in reaction time, arithmetic tests, and even mental health outcomes after intervention by methylphenidate.

In a recent RCT conducted by Willmott et al. (2013), the authors hypothesized that an individuals’ response to methylphenidate depends on their genotype. More specifically, that individuals possessing the methionine (Met) allele at the catechol-O-methyltransferase (COMT) gene would confer greater response to methylphenidate compared to those with the valine (Val) allele. While both Met/Met and Val/Val carriers performed more poorly in various attentional tasks compared to healthy controls, Met/Met carriers did show greater improvements in strategic control in attention than Val/Val carriers. As well, the authors were able to identify one significant drug and genetic interaction between Met/Met carriers and performance on the Symbol Digit Modalities Test (SDMT). These findings suggest Met/Met carriers may in fact be more responsive to methylphenidate than individuals with the Val genotype. However, further studies are needed to draw firm conclusions.

Conclusions

There is conflicting level 1b evidence regarding the effectiveness of methylphenidate following brain injury for the improvement of attention and concentration in individuals post ABI.

There is level 1a evidence that methylphenidate improves reaction time of working memory compared to placebo in individuals post ABI.

6.2.2.3 Bromocriptine

Key Points

Bromocriptine might improve executive function, but not memory, attention, or reading ability in patients post TBI.

Bromocriptine is a dopaminergic agonist which exerts its effects primarily through the binding of D2 receptors (Whyte et al., 2008). It has been suggested that dopamine is an important neurotransmitter for prefrontal function (McDowell et al., 1998). In a study looking at the effects of bromocriptine on rats, Kline et al. (2002) noted that the animals showed improvement in working memory and spatial learning; however, this improvement was not seen in motor abilities. Two studies have been identified investigating the use of bromocriptine as an adequate treatment for the recovery of cognitive impairments following brain injury.

Discussion

The question of whether bromocriptine improves cognitive function in patients with ABI was explored in two RCTs (McDowell et al., 1998; Whyte et al., 2008). In an earlier investigation, low-dose bromocriptine (2.5 mg daily) improved functioning on tests of executive control including a dual task, Trail Making Test, the Stroop test, the Wisconsin Card Sorting Test and the controlled oral word association test (McDowell et al., 1998). However, bromocriptine did not significantly influence working memory tasks. Further, a study by Whyte et al. (2008) found that bromocriptine had little effect on attention. It was noted that several participants did experience moderate to severe drug effects and withdrew or were withdrawn from the study.

Although McDowell et al. (1998) demonstrated some benefits following administration of bromocriptine, there was only a single administration of bromocriptine and the dose was considerably lower than that given by Whyte et al. (2008). Spontaneous recovery may have been a factor leading to the improved abilities in individuals receiving a single dose (2.5 mg daily) of the medication; however, study results did not answer this question. Results from Whyte et al. (2008) noted that the placebo group demonstrated better (although not significant) trends in improvement on the various tasks administered.

Conclusions

There is level 1b evidence that bromocriptine compared to placebo does not improve performance on attention tasks in patients post TBI.

There is level 2 evidence that bromocriptine improves attention, compared to placebo post ABI.

6.2.2.4 Cerebrolysin

Key Points

Cerebrolysin may be beneficial for the improvement of clinical outcome and cognitive functioning following brain injury; however, controlled trials are needed to further evaluate its efficacy.

As explained by Alvarez et al. (2003), “Cerebrolysin (EBEWE Pharma, Unterach, Austria) is a peptide preparation obtained by standardized enzymatic breakdown of purified brain proteins, and comprises 25% low-molecular weight peptides and free amino acids” (pg. 272). Cerebrolysin has been demonstrated to have neuroprotective and neurotrophic effects, and has been linked to increased cognitive performance in an elderly population.

Discussion

In an open-label trial of 20 patients with TBI Alvarez et al. (2003) found that cerebrolysin was associated with improved brain bioelectrical activity, as evidenced by a significant increase in fast beta frequencies. A brief neuropsychological battery (Syndrome Kurztest) consisting of nine subtests was administered to evaluate memory and attentional functions in patients undergoing treatment with cerebrolysin. There was an overall significant improvement in performance post treatment, suggesting patients experienced cognitive benefits from cerebrolysin treatment. Improvements were also seen in terms of neurological recovery, as measured by the Glasgow Outcome Scale (Alvarez et al., 2003). Together these findings suggest that cerebroylsin may represent an effective neuroprotective therapy with tangible cognitive benefits for individuals living with an ABI. However, controlled trials are necessary to further explore the efficacy of this drug.

Conclusions

There is level 4 evidence that cerebrolysin may improve attention scores post ABI.

6.2.2.5 Acetylcholinesterase Inhibitors

Key Points

Rivastigmine may not be effective in treating attention deficits post-ABI.

Acetylcholinesterase inhibitors prevent the enzyme acetylcholinesterase from breaking down acetylcholine. This increases the concentration of acetylcholine in synapses. Acetylcholine has been most strongly linked with the hippocampus and memory deficits, however it is also implicated in attentional processing.

Discussion

In two studies rivastigmine was administered to patients who had sustained a moderate to severe TBI (Silver et al., 2006; Silver et al., 2009). Results from both studies indicate that rivastigmine improved cognitive function and memory impairment, although results were not significant. In Silver’s (2009) follow-up open-label cohort study to their original RCT, participants (n=98) showed significant improvement on the CANTAB RVIP A’, the HVLT and the trail A and B scales at the end of 38 week study period; however when further sub-analysis was performed depending on what group the patient previously belonged to, , those in the ex-rivastigmine group to those in the ex-placebo group, the improvements were not significant.

Conclusions

There is level 1b evidence that Rivastigmine compared to placebo may not be effective for improving concentration or attention in individuals post

6.2.2.6 Growth Hormone (GH) Replacement Therapy

6.3 Remediation of Learning and Memory Deficits

Memory impairment is one of the most common symptoms following brain injury and it is estimated that time and cost of care would be reduced if effective treatments were found to improve memory (Walker et al., 1991). When evaluating intervention strategies to improve memory performance following brain injury, the literature indicates that there are two main approaches to rehabilitation: restoration/retraining of memory, and compensation of deficits. Compensation includes “training strategies or techniques that aim to circumvent any difficulty that arises as a result of the memory impairment.” (McLean et al., 1991). Compensatory techniques include internal aids, which are “mnemonic strategies that restructure information that is to be learned.” (McLean et al., 1991). (McLean et al., 1991)(McLean et al., 1991)(McLean et al., 1991)(McLean et al., 1991)(McLean et al., 1991)(McLean et al., 1991)(McLean et al., 1991)(McLean et al., 1991)(McLean et al., 1991)(McLean et al., 1991)On the other hand, various interventions have focused on the remediation of memory deficits in individuals with TBI, ranging from interventions that include assistive technology to visual imagery. Several studies were identified examining interventions to improve learning and memory following ABI. Studies were categorized into the following groupings: assistive technology (external aids, computer assisted training and virtual reality and cognitive functioning), internal strategies used during learning to enhance recall, memory interventions and cranial electrotherapy stimulation and memory.

Cicerone et al. (2000) reviewed 42 studies examining the effectiveness of various interventions to improve memory impairment following stroke and TBI. In 2005 and again in 2011, Cicerone and colleagues updated their original review (2005; 2011). It should be noted that studies were not included in our review if the population did not comprise of more than 50% brain-injured patients, or if the sample size (n) was less than 3. As well only those studies dealing with moderate-to-severe brain-injured individuals were included in this review.

Cappa and colleagues (2005) reviewed various strategies used to improve memory deficits without the use of electronic devices, external aids were judged to be “possibly effective.” Specific learning strategies (e.g. errorless learning) were found to be “probably effective” depending upon the task used, the type of memory involved and the severity of impairment.

6.3.1 Non-Pharmacological Interventions

6.3.1.1 Assistive Devices

Assistive devices for aiding learning and memory can include anything from physical or external devices to internal memory strategies. The following section discusses a variety of aids which can be used to support individuals with memory or learning deficits as a result of an ABI.

6.3.1.1.1 External Technology Aids

Key Points

Pager and voice-organizer programs may improve a patient’s ability to complete tasks post TBI.

Personal digital assistant (PDA) devices are superior to paper-based interventions at improving memory and task completion post TBI; specially when introduced using systematic instructions and in combination with occupational therapy. Patients who have used previous memory aids might benefit from this intervention the most.

Text message prompts sent to a patient’s smartphone, when used alone or in combination with other memory-improvement therapies, likely improve task completion post TBI. However, risk exists of device dependency exists.

A television assisted prompting (TAP) program may be superior to other methods of memory prompting in patients post TBI.

Automated prompting systems, such as Guide (audio-verbal interactive micro-prompting system) and a computerized tracking system, can reduce the amount of prompts needed from support staff to patients to complete tasks post TBI.

External aids, of which there are active or high tech (computers, personal digital assistants (PDAs), and mobile phones) devices and passive or low tech/no tech (calendars, diaries, lists, timetables and dictaphones) devices, have been shown to assist memory (McDonald et al., 2011). As active aids become more readily available, there is a greater need to study their effectiveness in helping those with an ABI deal with prospective memory impairments. Included here are studies which examined how external aids, both active and passive, could be used to enhance memory following brain injury.

Cicerone et al. (2000) recommended that the use of memory notebooks or other external aids “may be considered for persons with moderate to severe memory impairments after TBI (and) should directly apply to functional activities, rather than as an attempt to improve memory function per se.”

Discussion

Many studies have been conducted looking at the effectiveness of various active reminders used for those with memory impairment. Wilson et al. (1997) found that a portable paging system, NeuroPage, could reduce everyday memory problems and improve task completion. A crossover RCT also demonstrated that the pager system significantly increased participants’ ability to carry out daily tasks, and successful task achievement was more efficient after the pager intervention was introduced (Wilson et al., 2005; Wilson et al., 2001). However, the need for a centralized system to send reminders reduces the feasibility of pagers since many people may be able to achieve the same results using other electronic reminder systems.

Voice organizers have also been shown to improve goal execution. In a study by Kim et al. (2000), 12 TBI patients were given palmtop computers programmed with scheduling software capable of generating audible reminder cues. Patient feedback suggested that the use of the palmtop computer was beneficial for their rehabilitation, and over half of the patients continued to use the device even after the conclusion of the study. In addition, one case series (van den Broek et al., 2000) and one RCT (Hart et al., 2002) found that voice organizers helped to improve recall of previously identified goals.

With advances in technology, more sophisticated organizers integrating these tools into personal digital assistants (PDAs) have also been studied. Patients accustomed to using memory aids were more likely to make use of computerized organizers (Wright et al., 2001b). Dowds et al. (2011) found that two different PDAs improved task completion rates compared to a paper-based schedule book, while Lannin et al. (2014) found that the use of a PDA in addition to conventional occupational therapy significantly reduced memory failures and forgetting. However, the variety of available electronic organizers and learning curve for use prevent clear conclusions across studies. An RCT by Powell et al. (2012) demonstrated the importance of systematic instruction, as they compared direct instructions to conventional, trial and error patient learning on a PDA. Those receiving systematic instruction were superior in the number and speed of correct PDA tasks compared to conventional trial and error learning group. No differences were found between groups based on PDA input (physical vs touch-screen keyboard), provided the three core memory aides of appointment diary, notebook, and to-do list were maintained (Wright et al., 2001a).

Smartphones represent a relatively new area of accessible technology and provide the user with many benefits. Smartphones are already designed to send notifications about their use, as well as multiple companies design apps for each phone brand interface allowing individuals to keep their current devices and still access helpful applications. The most common advantages to smartphones are reminders/alarms and ability to combine a calendar, tasks list, contacts, mail, and phone on one device. Disadvantages included the reduction of battery life and risk of dependency on the assistive device, however these are minor inconveniences in comparison to the reported improvement in memory in some patients (Evald, 2015).The increasing availability of smartphones also creates the ability to enhance current therapies with text messages. A case series by Fish et al. (2007) demonstrated that participants could be trained to associate a text message with stopping and thinking about what needed to be done, with participants more likely to remember the instruction to call the investigators when texted the message “STOP”. Gracey et al. (2017) also found that goal management training could be supplemented with text messages for improving achievement of everyday intentions, with individuals who received text prompt more likely to succeed in their goals compared to those not receiving prompts. This effect was not observable once the texts had stopped to both groups.

External memory aids can also be incorporated into an individual’s home or work environment. Lemoncello et al. (2011) developed a television assisted prompting (TAP) system that provided reminders of events to be completed through the television screen. This crossover RCT found that compared to traditional methods (paper planner, cell phones or computers), participants using the TAP system completed significantly more tasks (Lemoncello et al., 2011).

These external aids can also be adapted for use in an inpatient settings. O’Neill et al. (2017) developed an audio-verbal interactive micro-prompting system, Guide, designed to emulate the verbal prompts and questions provided by caregivers or support workers. The number of support workers prompts needed during their morning routine was reduced, even though there were no significant differences between groups in terms of the number of errors and satisfaction scores (O’Neill et al., 2017). An acute rehabilitation unit also showed efficacy for a computerized tracking system designed to locate patients and send reminders when patients moved in the wrong direction for appointments (Burke et al., 2001). By reducing the number of staff prompts needed, these systems can increase patient independence and help free up support personnel for other tasks.

Conclusions

There is level 4 evidence that the NeuroPage system may increase a patient’s ability and efficiency to complete tasks post TBI.

There is level 4 evidence that voice organizer programs are effective at improving recall of goals, and are found to be effective by patients post TBI.

There is level 2 evidence that personal digital assistants (PDAs) are superior to a paper-based schedule book at improving task completion rates post TBI.

There is level 1b evidence that the use of a personal digital assistant (PDA) in combination with conventional occupational therapy is superior to occupational therapy alone at improving memory in patients post TBI.

There is level 1b evidence that use of a personal digital assistant (PDA) after receiving systematic instructions is superior to PDA trial and error learning at improving the number and speed of correct tasks post TBI.

There is level 4 evidence that conventional or touch-screen personal digital assistant (PDA) use are similar at improving memory post TBI.

There is level 1b evidence that reminder text messages sent to patients through their smartphones, whether alone or in combination with goal management training, may improve goal completion post TBI.

There is level 2 evidence that a television assisted prompting (TAP) system is superior to traditional methods of memory prompting (paper planners, cell phones, computers) at improving the amount of completed tasks post TBI.

There is level 1b evidence that the audio-verbal interactive micro-prompting system, Guide, can reduce the amount of support-staff prompts needed for the patient to complete a task post TBI.

There is level 4 evidence that a computerized tracking system that sends reminders to patients when they are moving in the wrong direction reduces the amount of support-staff prompts needed for patients to complete a task post TBI.

6.3.1.1.2 External Passive Techology or Non-Technology Aids

Key Points

Calendars may be effective tools for improving memory and task completion post ABI.

The use of a diary may help to improve memory and task completion post ABI, but more so if diary training is combined with self-instructional training.

A specific intervention for improving general cognitive functioning is computer-assisted training. The use of computer-assisted cognitive retraining has multiple potential benefits within the rehabilitation setting following brain injury. Computer retraining allows for flexibility in retraining procedures, increased individuality of therapy programs, and also decreases the amount of direct time a therapist is with the patient. It also has the potential of continuing cognitive retraining within the community setting. Furthermore, as presented at the NIH Consensus Development Panel (1999) computer-assisted strategies are used to improve neuropsychological processes, including attention, memory and executive skills.

In recent years, clinicians have recommended the use of computers as an efficacious tool in cognitive rehabilitation. A systematic review identified 23 studies that demonstrated computerized cognitive interventions were effective for improvement of attention and executive functions (Bogdanova et al., 2016).

Discussion

Multiple RCTs have examined the use of calendars and calendar tools on learning and memory (Bergquist et al., 2009; McDonald et al., 2011; Ownsworth & McFarland, 1999; Watanabe et al., 1998). In one RCT by McDonald et al. (2011), the use of a Google calendar was compared to the use of diary tracking. It was found that although both groups achieved a fair amount of desired tasks, those using the Google calendar had a significant increase in task completion through the use of automated reminders and messages. A second RCT also compare the use of a calendar to diary use (Bergquist et al., 2009). However, in this instance no significant between group differences were found. In another RCT (Ownsworth & McFarland, 1999) diary use was examined alone as well as with the combination of self-instructional training. On self-reported memory scales, all subjects reported improvements in memory, as well as a significant increases in the degree of memory strategies used regardless of diary training. There were no significant differences between groups on memory performance however (Ownsworth & McFarland, 1999). Lastly, Watanabe et al. (1998), found no significant effects of calendar use on a test of orientation, compared to no calendar use.

Conclusions

There is conflicting (level 2) evidence regarding whether or not the use of a calendar, compared to diary training, is effective for improving memory post ABI.

There is level 2 evidence that the presence of a calendar may not improve orientation post ABI.

There is level 2 evidence that diary training in combination with self-instructional training may be more effective than diary training alone at improving memory and task completion post ABI.

6.3.1.1.3 Virtual Reality

Key Points

Virtual reality programs may enhance the recovery of memory, learning, but there is currently limited evidence supporting the use of virtual reality programs.

Virtual reality (VR) allows individuals to interact with and experience a virtual environment in three-dimensions, realistically simulating different situations/environments/tasks through immersive (head-mounted display) or non-immersive (computer monitor or projector screen) multimedia (Sisto et al., 2002). VR systems are constantly evolving, providing a safe and motivating environment for practicing real life scenarios (Shin & Kim, 2015). A systematic review by Shin and Kim (2015) found that VR may be an effective cognitive therapy, though the limited low quality evidence has prevented strong conclusions.

Discussion

Virtual Reality training can used to improve learning and memory deficits. . The repetition of tasks in VR with feedback can improve performance on that specific activity. Gerber et al. (2014) found that VR repetition of tasks (clearing a workbench, spelling words from a set of tiles, preparing a sandwich, and tool use) reduced the time needed to complete each activity. Another pre-post study where participants moved the handle of a robot towards virtual targets found that performance on the second day of testing was improved compared to the first day in terms of the number of targets acquired (Dvorkin et al., 2013). Dahdah et al. (2017) also found that multiple Stroop tasks in VR environments resulted in improved performance on parts of those tasks. Haptic feedback using a gentle pulse of force or no haptic feedback were associated with better performance than break-through feedback similar to popping a balloon (Dvorkin et al., 2013). (Dahdah et al., 2017)Sorita et al. (2013) found that practicing a route-learning task in a real urban environment or in a virtual stimulation of that environment showed similar improvements in route recall, suggesting that VR training improvements in functional tasks may be due to repetition and not the presented medium.

In terms of cognitive functioning, two RCTs found that training in a virtual environment did not show significantly more improvement than general cognitive re-training or psychoeducation groups on executive functioning outcomes (Jacoby et al., 2013; Man et al., 2013). One RCT focusing on vocational problem-solving skills (Man et al., 2013)identified significant improvements in both VR intervention and conventional psychoeducation control groups, but no differences between groups for cognitive or vocational outcomes except on WCST % errors and % conceptual level response (Man et al., 2013).

Yip and Man (2013) found that a non-immersive prospective memory VR training program significantly improved some memory outcomes compared to a control with regular activities, suggesting larger scale trials may be needed to fully assess the effect. Virtual reality in combination with exercise has also been found to improve performance on learning and memory tasks (Grealy et al., 1999). (Man et al., 2013)

Conclusions

There is level 4 evidence that virtual reality (VR) training may improve learning performance post ABI, although the effect may not be different from non-VR training.

There is level 2 evidence that virtual reality training alone may be promising for improving memory outcomes, and has a positive impact on visual and verbal learning when in combination with exercise.

6.3.1.2 Internal Memory Strategies

Key Points

Internal strategies appear to be an effective aid in improving recall performance post ABI.

The following studies examined how different cognitive strategies could be used to enhance learning and memory following an ABI.

Discussion

In a recent study Potvin et al. (2011) assigned 30 patients with moderate to severe TBI to either an experimental group (n=10) or a control group (n=20). Both groups were matched based on age and education. All participants were initially assessed using the Test Ecologique de Memoire Prospective. Those in the experimental group participated in ten prospective memory training sessions. Each session lasted 90 minutes. The PM program was divided into 5 phases: understanding PM functioning; training to visualize simple images; learning visual imagery techniques; applying visual imagery in PM; and applying visual imagery in everyday situation. The scores on the Test Ecologique de Memoire Prospective, following treatment, improved for those in the experimental group. Study authors also noted that those in the experimental group reported fewer symptoms of depression than the control group.

Twum and Parente (1994) randomly assigned 60 patients with a TBI into one of 4 groups (one control and three mnemonic strategy groups) counterbalanced. The researches demonstrated improved performance for subjects who were taught a strategy (either verbal labeling or visual imagery) while learning paired-associations. Treatment groups showed greater efficiency in learning and greater delayed recall information.

Thoene and Glisky (1995) using a case series design also showed enhanced performance following the use of a mnemonic strategy (verbal elaboration and visual imagery) compared to vanishing cues and/or video presentation during paired associations.

Goldstein et al. (1996) evaluated a visual-imagery technique “Ridicuously Imaged Story” technique in training severely brain injured individuals to learn and recall lengthy word lists. Participants were asked to read a story where 20 words are presented in bold-face and subjects were instructed to remember the bold-face words for later recall. If subjects could not recall all the words they were provided with (1) the part of the story in which the word appeared and if that didn’t aid recall, they were then provided with (2) a category cue for the word. It should be noted that in both studies reviewed, a number of their subject pool (N=10) came from a previous study (Goldstein et al., 1988). Goldstein et al. (1996) evaluated whether there were differences between a computerized and non-computerized version of “Ridicuously Imaged Story” and another visual imagery technique (Pictorial Imagery). Results indicated that although the computerized versions resulted in a slightly better performance on learning trials, the difference was non-significant.

By using the various visual imagery techniques to aid learning and recall, researchers have demonstrated that increasing the saliency of features encoded, results in an increase in the amount recalled. Milder et al. (1998) examined performance on a name learning task by increasing the meaningfulness of people’s names with various strategies (e.g. when learning a new name-face association try to think of an occupation or object with the same name or a famous person with a similar name etc). When subjects (13 severely TBI versus 13 matched controls) were tested on 3 different memory tasks, results indicated a significant difference following training, more so for the control group than the TBI group. Also, learning procedures were more effective on one task (where subjects were required to learn the name-occupation-and town) compared to the other two tasks (famous-faces or name learning).

In a 4 year follow up study, to one conducted by Berg and colleagues, Milder et al. (1995) found the effects at 4 months were no longer evident at 4 years (all groups were equivalent). In the original study, Berg et al. (1991) demonstrated that severely brain injured patients demonstrated improved effects on objective measures of memory at 4 months following training in a strategy-use group compared to a pseudo-treatment and a no treatment control group. In the strategy group, individuals were taught general cognitive principles of memory functioning and aids (i.e., internal and external strategies were taught and practiced). In contrast, the pseudo-treatment group practiced memory games and tasks with no explanation.

How individuals learn (i.e., encode) information will determine to a large extent what is later recalled. Twum and Parente (1994) demonstrated that if an active strategy (either verbal labeling for visual information or visual imagery for verbal information) is taught to individuals while learning the paired associations, learning and recall is enhanced (i.e., fewer trials needed to reach criterion during learning and improved recall following a delay). Tailby and Haslam (2003) also examined how learning can improve or limit later recall of information. They had 24 ABI subjects matched on basis of age, gender, premorbid and current intellectual status divided into 3 groups based on performance of verbal memory (mild, moderate & severe). Each group (n=8) was randomly assigned to one of 3 learning conditions: errorless learning, self-generated; errorless learning, experimenter generated; and errorful learning. Results showed that regardless of severity level, subject recalled more information in the errorless learning conditions (with self-generated superior to experimenter generated) than in the errorful learning condition.

Constantinidou and Neils (1995) examined the effects of stimulus modality on verbal learning of patients with moderate-to-severe closed head injury and a matched control group. Results indicated that when information is presented visually (with and/or without auditory presentation of names) more information is learned than when information is presented within the auditory modality alone. As expected, patients learn new information at a significantly slower rate compared to controls.

It is generally thought that while patients are experiencing post-traumatic amnesia (PTA), they are not able to learn and retain new information, and as a result, cognitive rehabilitation is usually postponed until PTA has resolved. This tends to be true if using tasks of explicit or declarative learning and recall. Two studies were reviewed that reported that PTA patients were capable of learning and retaining new information when task demands were dependent on implicit/procedural learning. Glisky and Delaney (1996) evaluated implicit memory (priming using a stem completion task) and the use of vanishing cues when learning semantic information in a small number of patients with a TBI (n=8 & 4) who were still experiencing PTA and a matched control group. Findings revealed that learning and recall of information (once PTA has resolved) had occurred, albeit at reduced levels compared to controls. Ewert et al. (1989) also demonstrated procedural learning and retention in a group of 16 severely closed head injured participants and matched controls.

Conclusions

There is level 2 evidence that internal strategies may be an effective aid in improving recall performance compared to X post ABI.

6.3.1.3 Learning and Memory Training Programs

Key Points

Memory-retraining programs appear effective, particularly for functional recovery although performance on specific tests of memory may or may not change.

Specific computer-based softwares seem to be effective for improving memory post-ABI.

Computer-based interventions may be as effective as therapist administered interventions.

Emotional self-regulation therapy may be effective for improving specific elements of memory.

Recall and recognition of words can be enhanced by using a spaced learning condition.

Following an ABI or TBI one of the most persistent problems are memory deficits. Although the literature examining the efficacy of memory programs is limited, there is some support for training that stresses external memory strategies. Again the support for these programs is limited as many individuals post injury neglect their devices or simply stop using them (O’Neil-Pirozzi et al., 2010). Internal memory strategies have also been used with limited success.

Discussion

A group out of Denmark investigated the effects of hypnosis, as delivered in a targetter or non targeted manner, on memory, attention, and cognitive function in a mixed TBI and stroke population (Lindelov et al. 2017). The researchers showed that working memory, attention, and cognitive function could be transiently increased during targeted hypnosis, however the benefits of the treatment were not sustained when the treatment was discontinued. This last finding calls into question the practicality of the intervention, as it may not be feasible to deliver targeted hypnosis to patients post brain injury on a continual basis.

Chiaravalloti et al. (2016) compared the efficacy of the modified Short Memory Technique to conventional therapy for the improvement of memory post TBI. Amongst the memory assessments quantified, significant improvements were seen only in two specific categories; the Memory Assessment Scale- Prose Memory (MAS-PM) and “hidden belonging task” of the Rivermead Behavioural Memory Test (RBMT). A follow-up study further recognized the lack of improvement in the treatment group compared to controls in terms of memory capacity, however they did note that working memory capacity and long-term memory retainment were positively correlated with each other.

Further, similar results were found in an RCT by Novakovic-Agopian et al. (2011), where a goals training group showed significant improvement on attention and execute function assessments compared to the educational group. Despite switching interventions at the 5 week mark to the educational intervention, the goal training group continued to improve significantly.

In another RCT, 45 individuals were randomly assigned into one of 4 treatment groups (Shum et al., 2011). The treatment groups consisted of 4 different intervention programs: self-awareness plus compensatory prospective memory training; self-awareness training plus active control; active control plus compensatory prospective memory training and active control only. Pre intervention scores on the CAMPROMPT did not reveal any significant differences between any of the groups. Those assigned to the compensatory prospective memory training groups showed greater changes in strategies used to improve memory. Compensatory prospective memory training included use of a diary or organizational devices, and group members were encouraged to use written reminders, appointments and note taking. Although at total of 45 participants started the study, only 36 completed it.

In an RCT conducted by Vas et al. (2011), 28 individuals who had sustained a TBI and were at least 2 years post injury, were assigned to one of two groups: the strategic memory and reasoning training group or the Brain Health Workshop group. Each groups received 15 hours of training over an eight week period. Those in the strategic memory and reasoning training group were given information about brain injuries, were asked to read pieces of literature on brain injury and were given homework assignments to be completed for the next meeting. The strategic memory and reasoning training sessions were built around three strategies: strategic attention, integration (combining important facts to form higher order abstracted meaning) and innovation (derive multiple abstract interpretations). Those in the brain health workshop group participated in information sessions. Sessions for the brain health workshop groups included an introduction to brain anatomy, functions of the brain, neuroplasticity, and the effects of lifestyle on the brain (diets, exercises and cognitive changes following a TBI). Study results indicate that those assigned to the strategic memory and reasoning training group showed significant improvement on gist reasoning and measures of executive function.

Further lending support for attention training post TBI, one RCT showed that attention and information processing outcomes could be improved with dual-task training (Couillet et al., 2010; Sacco et al., 2016). Specifically, the group found that dual-task training significantly improved attentional behaviour and reaction time compared to a non-specific cognitive program.

An RCT conducted by Dou et al. (2006), found there were no significant differences in memory and cognitive improvements between participants receiving computer-administered or therapist-administered memory training, though both groups showed significant improvements compared to the control group that received no training

Thickpenny and Barker-Collo (2007) randomly assigned 14 individuals to either the treatment or control groups. Those in the treatment group participated in a memory rehabilitation program. The memory groups consisted of eight learning modules each 60 minutes long. They ran twice a week for 4 weeks. Memory improvement and difficulties were evaluated. Overall a reduction in memory impairment was noted at the end of the 4 weeks of intervention and again at the one month follow-up time period.

Further support for emotional oriented intervention can be found in an earlier study by Rath et al. (2003). The group completed an RCT comparing two cognitive rehabilitation therapies: conventional (cognitive remediation and psychosocial components) versus an innovative rehabilitation approach focusing on emotional self regulation and clear thinking. Outcomes were measured across multiple domains of cognition including attention, memory, reasoning, psychosocial functioning, and problem solving measures. Significant changes comparing baseline to post intervention outcomes were seen for each group, however, the improvements were different for the interventions. No between-group comparisons were made.

With respect to attention process training, it was shown that individuals receiving attention remediation significantly improved in memory and attention measurements compared to controls- whoTBI education alone (Sohlberg er al., 2000).

). Similarly, two trials did not find significant differences between groups for attentional, functional, and/or cognitive skills assessed (Lindelov et al., 2016; Novack et al., 1996). Novack et al. (1996) compared focused hierarchical attentional learning with an unstructured non-sequential, non-hierarchical intervention, while Lindelov et al. (2016) compared N-back training with visual search training. Overall there is weak evidence in support of training programs as an effective rehabilitation intervention for attention.

Recently, BrainHQ, a commercially available online computerized cognitive exercise program, did not significantly improve attention outcomes over time or compared to no intervention (O’Neil-Pirozzi & Hsu, 2016)
Gabbatore et al. (2015) implemented a cognitive group rehabilitation program for patients post TBI, and discovered that compared to before the intervention, patient’s recall (IDR), attention (WCST), and communication skills (ABaCo) all significantly improved.

Hellgren et al. (2015), found that a memory training program was successful in improving attentional scores on the Paced-Auditory Serial Attention Test, as well as further enhancing memory in general which is discussed later on in the chapter.

The Parrot Software is another computer-based cognitive retraining program, and was investigated by a pre-post study assessing the efficacy of using eight modules focussed on attention and memory (Li et al., 2015; Li et al., 2013). While significant post-treatment improvements in attention and memory on the Cognistat assessment were found in a pilot study (Li et al., 2013), a subsequent study did not find significant improvements on the attention and memory subscales of the Montreal Cognitive Assessment (MoCA) or a medication-box sorting task despite significantly improved overall MoCA scores (Li et al., 2015).

In a recent prospective cohort study, Johansson and Tornmalm (2012) looked at the benefits of a working memory program on 18 individuals who had sustained either a TBI or had had a stroke resulting in moderate to severe cognitive deficits. The working memory training program used the Cogmed QM (computerized training software) coaching, education and peer support to help improve the daily functioning of participants. Results show the Cogmed QM program helped to improve working memory and these benefits were seen at the 6th month follow up.

. Only one study (Serino et al., 2007) described the specific task which was successful in improving attention. This cognitive task involved mental addition in combination with two other standardized tasks and was an effective strategy for improving attention.

Boman et al. (2004) in a study of 10 individuals with mild or moderate TBI, after completing 1 hour of an individual cognitive training 3 times a week for 3 weeks, significant improvement was noted on the attention processing training test in sustained attention (p<0.05), selective attention (p<0.05), and alternating attention (p<0.01) pre to post training and at 3 month follow-up. Scores on the Rivermead Behavioural Memory Test were also seen to have significantly increased at the 3 month follow-up compared to pre test scores (p<0.05). Changes on the Claeson-Dahl Memory test did not increase pre to post to 3 month follow-up.

Quemada et al. (2003) examined memory rehabilitation following severe TBI in 12 individuals (no controls). The program ran for 6 months (50 minute sessions 5 days a week for 5 months and then 3 days a week for one month) and followed a specified format utilizing behavioural compensation techniques, mnemonic strategies, and environmental adaptations, external and internal aides. Results indicated little improvement in standard measures of memory functioning, although patients and family members report meaningful functional gains (self-report and observed behaviour in everyday functioning).

The findings of the previous experiment agree with the findings of the study by Laatsch et al. (1999), where cognitive rehabilitation therapy was found to increase productivity and everyday functioning. This older study also had the benefit of reporting SPECT imaging results, which revealed increases in cerebral blood flow during the intervention.

Parente et al. (1999) also studied retraining of working memory post traumatic brain injury. Although working memory would at first glance appear to be a primarily memory related brain function, the authors describe the concept of working memory as involving three main elements. These elements are the articulatory loop which hold verbal information, the visuospatial sketchpad which stores and interprets visual information and the executive system which organizes, prioritizes and allocates information processing resources. In this pilot study, 10 subjects were assigned to the intervention group who completed tasks to enhance working memory functioning between testing sessions. The testing sessions were only one hour apart. A control group matched for age, gender and injury type completed the same testing without training. The results showed a significant improvement for the letter number sequencing task for the intervention group, however there was no difference between groups on digit span task performance.

Finally, Chen et al. (1997) studied the effect of computer assisted cognitive rehabilitation versus traditional therapy methods. While measures of attention significantly improved in both groups after treatment, no significant differences were observed between groups (Chen et al., 1997). Cumulatively, by observing studies from across a period of nearly 20 years, the literature reveals little support for the use of computer software programs for the improvement of executive function post TBI.

Conclusions

There is level 1b evidence that hypnosis compared to no treatment may not be effective at improving memory in individuals post ABI.

There is level 1b evidence that the Short Memory Technique may not be more effective than standard memory therapy at improving memory in individuals post ABI.

There is level 2 evidence that participation in a goals training program, followed by an educational program, may be more effective for improving memory in individuals post ABI compared to receiving the treatment conditions in reverse order.

There is level 1b evidence that compensatory memory strategies, self-awareness training, and participation in memory group sessions may be effective for improving memory in individuals post ABI compared to no treatment.

There is level 2 evidence that Strategic Memory and Reasoning Training (SMART) may improve learning and working memory compared to no memory training in individuals post ABI.

There is level 2 evidence that dual-task training may be effective for improving memory in individuals post ABI when presented before the control condition, compared to the reverse.

There is level 2 evidence that both computer-administered and therapist-administered memory training may be more effective than no treatment for improving memory in ABI participants. However, no treatment appears to be better than the other.

There is level 2 evidence that both cognitive remediation and emotional self-regulation may be effective at improving different elements of memory in individuals post ABI.

There is level 1b evidence that attention processing training compared to supportive listening may improve memory in individuals post ABI.

There is level 2 evidence that BrainHQ is not an effective program for improving memory and learning compared to no intervention in individuals post ABI.

There is level 4 evidence that using mental representations and role-playing may not be effective at improving memory in individuals post ABI.

There is level 4 evidence that Cogmed training software may improve working memory performance and occupational performance in individuals post ABI.

There is conflicting (level 4) evidence regarding whether or not Parrot software is effective at improving memory and learning in individuals post ABI.

There is level 4 evidence that mental addition tasks may improve working memory in individuals post ABI.

There is level 4 evidence that the Wilson’s Structured Behavioral Memory Program is not effective for improving memory post ABI.

6.3.1.4 Cranial Electrotherapy Stimulation

Key Points

Cranial electrotherapy stimulation is likely not effective at enhancing memory and recall abilities following TBI.

Cranial electrotherapy stimulation (CES) is the application of less than 1 mA of electric current to the cranium. This intervention has been used to treat a variety of disorders, including withdrawal of patients with substance abuse (Michals et al., 1993). The effect of CES for the improvement of memory following brain injury was investigated.

Discussion

Michals et al. (1993) studied cranial electrotherapy stimulation and its effect on post-traumatic memory impairment in clinical care patients with a closed head injury. Patients received CES or sham CES treatments for 40 minutes daily over a period of four weeks. The group receiving CES treatment did not improve in their memory performance, nor did their immediate or delayed recall improve. Further, with retesting, both the CES and the sham CES group showed a similarly significant trend with no group performing any better than the other. These results suggest that CES stimulation in brain-injured patients does not improve memory functioning.

Conclusions

There is level 1b evidence that cranial electrotherapy stimulation may not improve memory and recall compared to sham stimulation post TBI.

6.3.2 Pharmacological Interventions

6.3.2.1 Donepezil

Key Points

Donepezil likely improves attention and memory following TBI.

The effectiveness of donepezil, a cholinesterase inhibitor, in improving cognitive and memory functions following brain injury has been assessed. Cognitive impairments negatively impact patient autonomy, affecting one’s ability to return to work or school, and live alone (Masanic et al., 2001). When tested in individuals diagnosed with Alzheimer’s disease, donepezil has been found to be useful in treating memory problems (Morey et al., 2003; Walker et al., 2004). The impact of Donepezil impact on cognitive function and memory in a TBI population is explored in the table below.

Discussion

In an RCT, Zhang et al. (2004) demonstrated that donepezil was associated with improvements in tasks of sustained attention and short-term memory, and that these improvements were sustained even after the treatment had finished. Benefits associated with donepezil were also documented in an open-label study by Masanic et al. (2001) who found that the treatment tended to improve both short- and long-term memory of patients living with TBI. Improvements in memory were also reported by Morey et al. (2003) in their retrospective study who demonstrated that donepezil led to significant benefits in visual memory function.

The most recent study, a pre-post by Khateb et al. (2005), found only modest improvement on the various neuropsychological tests used to measure executive function, attention, and learning and memory. Of note results from the learning phase of the Rey Auditory Verbal Memory Test (RAVMT) showed significant improvement (p<0.050). The Donepezil intervention also demonstrated improvement in executive function, as the results from the Stroop-colour naming test showed significant improvements (p<0.030). On the test for Attentional Performance a significant change was noted on the divided attention (errors) subsection of the test. Overall, donepezil was found to be effective in improving learning, memory, divided attention, and executive function. However, possible benefits of donepezil administration must be balanced against the observed side effects in 27% of the population. Further randomized control trials are required to better explore the efficacy of donepezil post TBI.

Conclusions

There is level 1b evidence that donepezil improves short-term memory compared to X post ABI.

There is level 4 evidence that donepezil may be effective in improving short-term, long-term, verbal, and visual memory post ABI.

6.3.2.10 Acetylcholinesterase Inhibitors

Key Points

Rivastigmine may not be effective in treating memory deficits post-ABI.

Acetylcholinesterase inhibitors prevent the enzyme acetylcholinesterase from breaking down acetylcholine. This increases the concentration of acetylcholine in synapses. Acetylcholine has been most strongly linked with the hippocampus and memory deficits, however it is also implicated in attentional processing.

Discussion

In two studies rivastigmine was administered to patients who had sustained a moderate to severe TBI (Silver et al., 2006; Silver et al., 2009). Results from both studies indicate that rivastigmine improved cognitive function and memory impairment, although results were not significant. In Silver’s (2009) follow-up open-label cohort study to their original RCT, participants (n=98) showed significant improvement on the CANTAB RVIP A’, the HVLT and the trail A and B scales at the end of 38 week study period; however when further sub-analysis was performed depending on what group the patient previously belonged to, those in the ex-rivastigmine group to those in the ex-placebo group, the improvements were not significant.

Conclusions

There is level 1b evidence that rivastigmine may be effective in improving memory in ABI populations.

6.3.2.2 Methylphenidate

Key Points

There is conflicting evidence that methylphenidate administration post TBI improves attention, memory, concentration and processing speed.

Response to methylphenidate likely varies depending on genotype at the catechol-O-methyltransferase (COMT) gene.

Methylphenidate is a stimulant whose exact mechanism of action in the CNS (?) is unknown (Napolitano et al., 2005). One theory is that methylphenidate acts on the presynaptic nerve to prevent the reabsorption of serotonin and norepinephrine, thereby increasing neurotransmitter concentrations within the synaptic cleft and leading to increased neurotransmission (Kim et al., 2006). In the past, methylphenidate has been extensively used as a treatment for attention deficit disorder, as well as narcolepsy (Glenn, 1998). A total of six RCTs examined the efficacy of methylphenidate as a treatment for the recovery of cognitive deficits post ABI.

Discussion

Dymowski et al. (2017) investigated the effects of short-term, 7 wk, methylphenidate administration (0.6 mg/kg/d) in patients post TBI compared to a placebo (control). After analysis, it was concluded that there was no significant improvement, or difference between groups for various measures and tests of attention. More than 2 decades earlier, Speech et al. (1993) conducted a double blind placebo controlled trial evaluating the effects of methylphenidate (0.3 mg/kg, 2 ×/d, for 1 wk,) following closed head injury. Both studies arrived at similar conclusions, as the treatment and placebo group did not vary in any measurements of memory, intelligence, or attention. Conversely, Plenger et al. (1996) found methylphenidate administration (30 mg/kg, 2 x/d, 30 d) significantly improved attention and concentration when compared to a placebo. The conflicting literature on the effect of methylphenidate on attention and concentration makes it difficult to draw a conclusion; especially due to the high methodological quality of all studies involved. However, the positive results seen by Plenger’s group may be due to the use of much higher doses of methylphenidate (30 mg/kg/d vs. 0.6 mg/kg/d for the other studies). Although side effects were unreported, the literature suggest that high doses can lead to acute methylphenidate intoxication; a state comparable to acute amphetamine intoxication, which may cause psychological distress in patients. As a result, the group who most recently published on the topic were likely deterred from increasing the dose past a safely accepted value.

In the first of two studies by Willmott, they and Ponsford (2009) found that administering methylphenidate (0.3 mg/kg, 2x/d, 6 wk) during inpatient rehabilitation significantly improved the patient’s speed of information processing and attention post TBI. In the more recent RCT (Willmott et al. 2013), the authors hypothesized that an individuals’ response to methylphenidate depends on their genotype. More specifically, that individuals possessing the methionine (Met) allele at the catechol-O-methyltransferase (COMT) gene would confer greater response to methylphenidate compared to those with the valine (Val) allele. While both Met/Met and Val/Val carriers performed more poorly in various attentional tasks compared to healthy controls, Met/Met carriers did show greater improvements in strategic control in attention than Val/Val carriers. As well, the authors were able to identify one significant drug and genetic interaction between Met/Met carriers and performance on the Symbol Digit Modalities Test (SDMT). These findings suggest Met/Met carriers may in fact be more responsive to methylphenidate than individuals with the Val genotype. However, further studies are needed to draw firm conclusions.

Conclusions

There is conflicting (level 1b) evidence regarding the effectiveness of the administration of methylphenidate compared to X following brain injury for the improvement of memory in patients post TBI.

6.3.2.3 Sertraline

Key Points

Sertraline has not been shown to improve learning, or memory within the first 12 months post TBI, and may be associated with side effects.

Sertraline, better known under its trade name Zoloft (Pfizer), is a selective serotonin reuptake inhibitor (SSRI) used for the treatment of depression and mood (Khouzam et al., 2003; Jorge et al., 2016). The majority of sertraline TBI research focuses on the prevention or treatment of major depressive symptoms post brain injury. However, recent studies have shifted focus and begun to evaluate the benefits of sertraline at improving cognitive disorders (Banos et al., 2016; Jorge et al., 2016; Lee, 2005). The studies reviewed below investigated the effect of sertraline on cognitive outcomes post TBI.

Discussion

The effect of early administration of sertraline on cognitive functioning, intelligence and memory was evaluated by Banos et al. (2010) in an RCT. When comparing the sertraline group, who received 50mg per day, to a control group (placebo), there were no significant between group differences on any of the neuropsychological tests. The assessments examined attention and concentration, speed of processing, memory, and executive function at 3, 6 and 12 months. Cognitive functioning was not found to improve following the administration of sertraline. Of note, more patients in the sertraline group dropped out of the study compared to the control group when this was quantified at all assessment points— indicating the potential side effects associated with the treatment. Combined with the lack of apparent benefit to using the drug, use of sertraline is not currently recommended.

Conclusions

There is level 1b evidence that sertraline may not improve memory compared to placebo in individuals who have sustained a moderate to severe TBI.

6.3.2.4 Amantadine

Key Points

Amantadine might not be effective at improving learning and memory deficits post TBI.

Amantadine is a non-competitive N-methyl-D-aspartate receptor antagonist and has been used as an antiviral agent, prophylaxis for influenza A, treatment of neurological diseases such as Parkinson’s Disease, and the treatment of neuroleptic side-effects such as dystonia, akinthesia and neuroleptic malignant syndrome (Schneider et al., 1999). Amantadine is also thought to work pre- and post-synaptically by increasing the amount of dopamine (in… the synapse? Pre-synaptic junction? Post-synaptic cell?) (Napolitano et al., 2005). Two studies were identified that investigated the effectiveness of amantadine as a treatment for the remediation of learning and memory deficits and cognitive functioning following TBI.

Discussion

In a small sample RCT by Schneider et al. (1999) the effects of Amantadine on cognition and memory was assessed. In this six week cross-over study, patients received both placebo and amantadine. Although the study found that patients improved over the six week study period, statistical comparison of results evaluating the five subsets of attention, executive/flexibility, memory, behaviour and orientation did not demonstrate any significant effect for the use of amantadine. Similarly, Kraus et al. (2005) demonstrated that the administration of amantadine over a 12-week treatment period does not improve memory deficits or attention; however, significant improvements in executive functioning were observed. Given the quality and sample size of the current studies, future studies exploring the efficacy of amantadine for learning and memory are warranted.

Conclusions

There is level 2 evidence that amantadine may not improve learning and memory deficits in patients post TBI.

6.3.2.5 Pramiracetam

Key Points

Pramiracetam might improve memory in males post TBI; however, additional studies are required.

Pramiracetam is a nootropic (cognitive) activator that is used to facilitate learning, memory deficiencies, and other cognitive problems. Pramiracetam produces an increased turnover of acetylcholine in hippocampal cholinergic nerve terminals and it is at least 100 times more potent than its original compound piracetam (McLean et al., 1991).

Discussion

McLean Jr. et al. (1991) conducted a study evaluating Pramiracetam in four males post brain injury. Improvements were found for memory and these improvements remained at one month following discontinuation of the drug. Given the small sample size and the lack of data reported to support the findings, future studies should be conducted.

Conclusions

There is level 2 evidence that pramiracetam may improve males’ memory compared to placebo post TBI.

6.3.2.6 Physostigmine

Key Points

Physostigmine likely improves long-term memory in men with TBI.

Physostigmine is a cholinergic agonist that temporarily inhibits acetylcholinesterase. The inhibition of acetylcholinesterase in turn slows the destruction of acetylcholine, thus increasing the concentration of the neurotransmitter in the synapse. The use of physostigmine in Alzheimer’s disease has been examined at length, however it has also been proposed to improve memory in patients with head injury (McLean et al., 1987).

Discussion

In a double-blind, placebo-controlled randomized trial, oral physostigmine was administered to males with TBI as an active treatment (Cardenas et al., 1994). The authors found that physostigmine led to significant improvements in long-term memory scores in 44% (n=16) of study participants. Those who responded favourably to the treatment, as indicated by their performance on the Selective Reminding Test, also demonstrated improved balance compared to non-responders (Cardenas et al., 1994).

Conclusions

There is level 1b evidence that oral physostigmine may improve long-term memory compared to placebo in men with TBI.

6.3.2.7 Bromocriptine

Key Points

Bromocriptine may improve dual task performance and motivational deficits but its effect on memory is controversial. More research is needed before the benefits of using bromocriptine to enhance learning and memory deficits are required.

Bromocriptine is a dopaminergic agonist which primarily exerts its actions through binding and activating D2 receptors (Whyte et al., 2008). It has been suggested that dopamine is an important neurotransmitter for prefrontal function, an important area of the brain that contributes to cognitive function, memory, intelligence, language, and visual interpretation (McDowell et al., 1998; Siddiqui et al., 2008). In a study looking at the effects of bromocriptine on rats, Kline et al. (2002) noted that the animals showed improvement in working memory and spatial learning; however, this improvement was not seen in motor abilities. Two studies have been identified investigating the use of bromocriptine as an adequate treatment for the recovery of cognitive impairments following TBI.

Discussion

The question of whether bromocriptine improves learning and memory in patients with ABI was explored in one RCTs (McDowell et al., 1998; Whyte et al., 2008), and one case series (Powell et al., 1996). In an earlier investigation, low-dose bromocriptine (2.5 mg daily) improved functioning on tests of executive control including a dual task, Trail Making Test, the Stroop test, the Wisconsin Card Sorting Test and the controlled oral word association test (McDowell et al., 1998). However, bromocriptine did not significantly influence working memory tasks. Although McDowell et al. (1998) demonstrated some benefits following administration of bromocriptine, there was only a single administration of bromocriptine and the dose was considerably lower than that given by other studies that did not meet our criteria. Spontaneous recovery may have been a factor leading to the improved abilities in individuals receiving a single dose (2.5 mg daily) of the medication; however, study results did not answer this question. Powell et al. (1996) conducted a multiple baseline design on 11 patients with TBI or subarachnoid hemorrhage who received bromocriptine. Improvements were found on all measures assessed—memory, attention, motivation spontaneity— except mood. In light of the fact that the last RCT investigating the effects of bromocriptine was conducted 20 years ago, new studies are required to build on the promising results of these very early conclusions.

Conclusions

There is level 2 evidence that low-dose bromocriptine may improve cognitive function, but not working memory in patients post TBI.

There is level 4 evidence that bromocriptine may improve memory in patients post TBI.

6.3.2.8 Cerebrolysin

Key Points

Cerebrolysin may be beneficial for the improvement of clinical outcome and cognitive functioning following brain injury; however, controlled trials are needed to further evaluate its efficacy.

As explained by Alvarez et al. (2003), “Cerebrolysin (EBEWE Pharma, Unterach, Austria) is a peptide preparation obtained by standardized enzymatic breakdown of purified brain proteins, and comprises 25% low-molecular weight peptides and free amino acids” (pg. 272). Cerebrolysin has been demonstrated to have neuroprotective and neurotrophic effects, and has been linked to increased cognitive performance in an elderly population.

Discussion

In an open-label trial of 20 patients with TBI Alvarez et al. (2003) found that cerebrolysin was associated with improved brain bioelectrical activity, as evidenced by a significant increase in fast beta frequencies. A brief neuropsychological battery (Syndrome Kurztest) consisting of nine subtests was administered to evaluate memory and attentional functions in patients undergoing treatment with cerebrolysin. There was an overall significant improvement in performance post treatment, suggesting patients experienced cognitive benefits from cerebrolysin treatment. Improvements were also seen in terms of recovery, as measured by the Glasgow Outcome Scale (Alvarez et al., 2003). Together these findings suggest that cerebroylsin may represent an effective neuroprotective therapy with tangible cognitive benefits for individuals living with an ABI. Controlled trials are necessary to further explore the efficacy of this drug.

Conclusions

There is level 4 evidence that cerebrolysin may improve memory function post ABI.

6.3.2.9 Growth Hormone (GH) Replacement Therapy

Key Points

The administration of recombinant human Growth Hormone (rhGH) is likely not different than placebo at improving executive functioning, memory, or learning in patients post TBI; however certain aspects of patient quality of life may be improved.

The administration of recombinant human Growth Hormone (rhGH) might be superior at improving intelligence and cognition in patients with a growth hormone deficiency, versus those who do not, post TBI. Molecular markers of growth however may not be different post treatment between groups.

Following an ABI, it is not uncommon for individuals to be diagnosed with hypopituitarism. As many as 25 to 40% of individuals with a moderate to severe ABI have demonstrated chronic hypopituitarism (Bondanelli et al., 2007; Kelly et al., 2006; Schneiderman et al., 2008). Despite this, few patients are screened for growth hormone deficiencies; thus, the link between cognitive impairment and growth hormone deficiencies has not yet been definitively established (High et al., 2010). There is very little literature available on the benefits of GH replacement therapy after a TBI.

Discussion

A 2010 RCT compared the long term (6 mo and 1 yr) effects of rhGH administration to placebo in a TBI population (High Jr et al. 2010). Significant improvements were noted in processing speed, executive functioning (Wisconsin Card Sorting Test), and learning (California Verbal learning test II) for both he rhGH and placebo groups. It is important to note while processing speed also improved in both groups at 6 mo, the improvement was only sustained in the treatment group at 1 yr. Further positive results were reported in a more recent PCT by Moreau et al. (2013). Patient quality of life, instrumental activities of daily living, attention, memory and visuospatial ability improved over the treatment period in both the treatment and control group. However, the treatment group improved significantly more in the functional and personal subscales of quality of life assessments. Reimunde et al. (2011) in a cohort study looking at the benefits of administering rhGH to a group of patients who have sustained either a moderate or severe TBI. Results of the study indicate that those receiving the rhGH improved significantly on the various cognitive subtests such as: understanding, digits, numbers and incomplete figures (p<0.05) and similarities vocabulary, verbal IQ, Manipulative IQ, and Total IQ (p<0.01). The control group also showed significant improvement but only in digits and manipulative intelligence quotient (p<0.05). Of note IGF-I levels were similar between both groups at the end of the study.

Conclusions

There is level 1b evidence that recombinant human Growth Hormone (rhGH) is similar to placebo at improving processing speed (6 mo), memory, executive function and learning in patients post TBI.

There is level 2 evidence that growth hormone (GH) therapy is similar to placebo at improving quality of life, instrumental activities of daily living (iADL), attention, memory, and visuospatial ability in patients post TBI.

6.4 Remediation of Executive and General Cognitive Functioning

Executive functions refer to higher-level cognitive functions that are primarily mediated by the frontal lobes. These functions include insight, awareness, judgment, planning, organization, problem solving, multi-tasking and working memory (Lezak, 2004). Executive deficits are particularly relevant following traumatic brain injury from both a pathophysiologic as well as a psychosocial perspective. The frontal lobes tend to be one of the brain areas most likely to be injured following trauma (Greenwald et al., 2003). Frequently bilateral frontal lobe injury occurs following TBI in contrast to typical unilateral insults following vascular injury. Not only direct contusion to the frontal and temporal lobes but also diffuse axonal injury sustained as a result of TBI affects executive functioning. Patients with a TBI often present with cognitive and behavioral deficits in the presence of little physical impairment.

Cicerone et al. (2000) reviewed 14 studies dealing with executive functioning and problem-solving (Table 6.13). Only 3 of the identified studies were classified as a randomized controlled trial or non-randomized cohort study.

In the more current reviews by Cicerone et al. (2005; 2011) 9 and 18 additional studies were identified. Some of these studies were not included in our review as they did not meet our inclusion criteria. Based on the results of the studies in their review, Cicerone et al. (2000) recommended, “training of formal problem-solving strategies and their application to everyday situations and functional activities”.

Executive function deficits are particularly relevant to brain injury survivors who tend to be younger (average age less than 40) and who often desire to re-integrate back into pre-injury life roles. Patients with executive function deficits may have the capacity to be independent for basic activities of daily living where actions tend to be more ingrained and one-dimensional. However, instrumental activities of daily living such as banking, scheduling and household activities require intact executive functions due to the increased cognitive complexity and variability of the tasks. Of particular importance are the advanced tasks such as return to driving and competitive employment which are of increased relevance to the younger age demographic associated with TBI (Miller et al., 2003).

6.4.1 Non-Pharmacological Interventions

6.4.1.1 Remediation of Executive Functioning

Within the typical medical and rehabilitation settings, executive function deficits themselves are difficult to identify and evaluate since there is a tendency to focus on other cognitive functions such as memory and attention. The importance of evaluating effective interventions for treating executive dysfunction following brain injury is apparent since impairment can ultimately hinder successful community re-integration. Further to this, it is also important to address the issue of self-awareness which is particularly important in those who sustain moderate to severe TBI. If individuals are not aware they have a problem they are less likely to work on compensating for it.

6.4.1.1.1 Individual Interventions

Key Points

Targeted hypnosis may improve memory, attention, and cognitive function in patients post TBI or stroke; however, only as long as the intervention is being administered.

Attention improvement interventions may be superior to non-specific cognitive or education programs at improving memory and attention in patients post TBI.

A comprehensive cognitive treatment strategy is likely superior to a computerized training package at improving task initiation and completion in patients post TBI; this intervention may also improve cerebral blood flow.

It is unclear whether virtual-reality training is superior to conventional training at improving cognitive and executive function outcomes post TBI. Conflicting evidence exists, and further studies are required.

Computer or smartphone software programs (BrainHQ, Parrot Software, ProSolv app) may not be superior to common interventions at improving memory, attention, and problem-solving skills in patients post TBI.

Goal management training may superior to motor skills training at improving every day skills (meal preparation), but not intelligence or neuropsychological outcomes in patients post TBI.

Although executive function deficits post TBI are a common there is little overall research directly addressing the impact of rehabilitation on executive function. Individual interventions aimed at improving executive and general cognitive function are reviewed below.

Discussion

A group out of Denmark investigated the effects of hypnosis, as delivered in a targetter or non targeted manner, on memory, attention, and cognitive function in a mixed TBI and stroke population (Lindelov et al. 2017). The researchers showed that working memory, attention, and cognitive function could be transiently increased during targeted hypnosis, however the benefits of the treatment were not sustained when the treatment was discontinued. This last finding call into question the practicality of the intervention, as it may not be feasible to deliver targeted hypnosis to patients post brain injury on a continual basis.

With respect to attention process training, it was shown that individuals receiving attention remediation significantly improved in memory and attention measurements compared to controls- whoTBI education alone (Sohlberg er al., 2000). Further lending support for attention training post TBI, one RCT showed that attention and information processing outcomes could be improved with dual-task training (Couillet et al., 2010; Sacco et al., 2016). Specifically, the group found that dual-task training significantly improved attentional behaviour and reaction time compared to a non-specific cognitive program.

In a recent RCT, Spikman et al. (2010) randomly divided a group of individuals who had sustained a TBI to either a multifaceted strategy training group or a control group. Those in the treatment group were taught a comprehensive cognitive strategy which allowed them to tackle the issues and problems of daily living, compared to the control group which received a computerized training package that was aimed at improving general cognitive functioning. Overall results indicate both groups improved on many aspects of executive functioning; however, those in the treatment group showed greater improvement in their ability to set and accomplish realistic goals and to plan, initiate real life tasks (Spikman et al., 2010). The findings of the previous experiment agree with the findings of the study by Laatsch et al. (1999), where cognitive rehabilitation therapy was found to increase productivity and everyday functioning. This older study also had the benefit of reporting SPECT imaging results, which revealed increases in cerebral blood flow during the intervention.

With the development of technology, the use of virtual-reality training and computer programs have gained traction as an intriguing tool used for improving executive function in patients post TBI. In terms of cognitive functioning, two RCTs found varying results executive functioning outcomes after training in a virtual environment (Jacoby et al., 2013; Man et al., 2013). One RCT focusing on vocational problem-solving skills (Man et al., 2013) identified significant improvements in both VR intervention and conventional psychoeducation control groups, but no differences between groups for cognitive or vocational outcomes except on WCST % errors and % conceptual level response (Man et al., 2013). On the other hand, Jacoby et al (2013) found that patients receiving virtual reality training improved more on multi-tasking measures and executive function when compared to the control group— who received general cognitive re-training treatment. The most recent study by Dadah et al. (2017), a pre-post investigation, investigated virtual reality interventions in a mixed ABI population. The researchers found that repetition of the Stroop test in different virtual reality environments showed limited improvement in performance on those specific tests (Dahdah et al., 2017). As a result of the mixed results reported on the efficacy of virtual reality training post ABI, it is difficult to make a conclusive decision on what aspects of executive functioning virtual reality benefits, and to what degree.

As previously mentioned, computer software programs have also been investigated for their efficacy in improving executive dysfunctions post TBI. Recently, BrainHQ, a commercially available online computerized cognitive exercise program, did not significantly improve attention outcomes over time or compared to no intervention (O’Neil-Pirozzi & Hsu, 2016).
The Parrot Software is another computer-based cognitive retraining program, and was investigated by a pre-post study assessing the efficacy of using eight modules focussed on attention and memory (Li et al., 2015; Li et al., 2013). While significant post-treatment improvements in attention and memory on the Cognistat assessment were found in a pilot study (Li et al., 2013), a subsequent study did not find significant improvements on the attention and memory subscales of the Montreal Cognitive Assessment (MoCA) or a medication-box sorting task despite significantly improved overall MoCA scores (Li et al., 2015). This lack of improvement compared to a control group was also seen by Powell et al. (2017) when the ProSolv smartphone application was used to improved pressure management and problem—solving skills. Finally, Chen et al. (1997) studied the effect of computer assisted cognitive rehabilitation versus traditional therapy methods. While measures of attention significantly improved in both groups after treatment, no significant differences were observed between groups (Chen et al., 1997). Cumulatively, by observing studies from across a period of nearly 20 years, the literature reveals little support for the use of computer software programs for the improvement of executive function post TBI.

Levine et al. (2000) completed an RCT comparing a group of patients taking goal management training strategies to a control group who were exposed to only motor skills training. The treatment group improved on paper and pencil everyday tasks as well as meal preparation-which the authors used as an example of a task heavily reliant on self-regulation- in comparison to the motor treatment group. It is important to note however that the motor group performed superiorly on timed neuropsychological tests, and no differences were found between treatments in terms of intelligence.

Conclusions

There is level 1b evidence that targeted hypnosis may transiently improve cognitive function in patients post TBI or stroke.

There is level 1b evidence that an attention remediation intervention is superior to TBI education alone and improving executive function in patients post TBI.

There is level 2 evidence that dual-task training may improve general cognitive functioning compared to a non-specific cognitive program in patients post TBI.

There is level 1b evidence that a comprehensive cognitive treatment strategy may be superior to a computerized training package at improving task initiating and goal achievement post TBI.

There is level 4 evidence that cognitive rehabilitation may increase productivity in everyday functioning, and cerebral blood flow during treatment in patients post TBI.

There is conflicting (level 1b and level 2) evidence as to whether virtual-reality training is or is not superior to conventional cognitive training at improving cognitive and executive function outcomes post TBI.

There is level 2 evidence that computer or smartphone software programs, such as BrainHQ, Parrot Software, ProSolv app, may not be superior to no intervention at improving problem-solving skills and general functioning in patients post TBI.

There is level 2 evidence that goal management training may be superior to motor skills training at improving everyday skills like meal preparation, but not neuropsychological tests or intelligence in patients post TBI.

6.4.1.1.2 Group-based Interventions

Key Points

It is unclear whether goal oriented interventions delivered in a group setting are more successful than educational interventions at improving cognitive and executive function post ABI. However, no detrimental effects have been found with the intervention.

Emotional regulation interventions delivered in a group setting may improve executive function in patients post TBI; however, it is unclear if it is superior at doing so compared to conventional cognitive remediation.

It is unclear whether cognitive interventions (such as the Metacognitive Strategy Instruction program) improves language ability, and executive/ cognitive function in patients post TBI.

Although executive function deficits are a common there is little overall research directly addressing the impact of rehabilitation on executive function. However, community integration and other similar group-based interventions are highly related to executive function and it is possible that programs and interventions presented in a group-based setting may in fact be focusing efforts on instrumental activities of daily living which may reflect (or are dependent on) executive functions. The efficacy of group-based interventions on cognitive and executive function are discussed below.

Discussion

A group out of Norway investigated the effects of Goal Management Training (TG) to a Brain Health workshop (CG) group sessions on cognitive outcomes post brain injury (Tornas et al. 2016). The study showed that individuals receiving goal management training improved significantly in cognitive and executive outcomes after treatment, and a 6 mo follow up. While this study showed promising results, it is important to remember that despite its rigorous methodology, the patient population was very heterogenous and it is unclear how different injuries impacted the outcomes. Further, similar results were found in an RCT by Novakovic-Agopian et al. (2011), where a goals training group showed significant improvement on attention and execute function assessments compared to the educational group. Despite switching interventions at the 5 week mark to the educational intervention, the goal training group continued to improve significantly. Interestingly, an RCT published in the same year demonstrated that a goal training intervention (although beneficial) may not be more beneficial than other interventions such as educational training with respect to processing speed (Chen et al., 2011). In this study both groups significantly improved in attention directed goal completion.

Emotional regulation was also examined as a potential intervention for the remediation of attention and executive dysfunction post ABI (Cantor et al., 2014). While this treatment was not seen to be effective in the recovery of attention, significant improvements on executive function were noted (EF, FeSBe, PSI). Further support for emotional oriented intervention can be found in an earlier study by Rath et al. (2003). The group completed an RCT comparing two cognitive rehabilitation therapies: conventional (cognitive remediation and psychosocial components) versus an innovative rehabilitation approach focusing on emotional self regulation and clear thinking. Outcomes were measured across multiple domains of cognition including attention, memory, reasoning, psychosocial functioning, and problem solving measures. Significant changes comparing baseline to post intervention outcomes were seen for each group, however, the improvements were different for the interventions. No between-group comparisons were made.

A pre-post study by Copley et al. (2015) investigated the effects of a Metacognitive Strategy Instruction (MSI) intervention on verbal and cognitive outcomes post ABI. The program was delivered individually, in a group-setting, and at home. Despite the multi-step process, no improvements were seen in cognitive or verbal abilities from baseline after the intervention. Gabbatore et al. (2015) implemented a cognitive group rehabilitation program for patients post TBI, and discovered that compared to before the intervention, patient’s recall (IDR), attention (WCST), and communication skills (ABaCo) all significantly improved.

Parente and Stapleton (1999) in a descriptive study compared brain injury survivors who completed a cognitive skills group to comparable controls. The cognitive skills group interventions included education regarding “thinking skills” such as problem solving, concentration/ attention, decision making, remembering names and faces, study skills, functional mnemonics, prosthetic memory devices, social cognition, organizational skills and goal setting. Other important aspects of the cognitive skills group included computer training, prosthetic aid training, interviewing skills training and focus on a model of clients teaching clients. There was no statistical analysis completed, however, the return to work rate for 13 of 33 participants assigned to the cognitive skills group training was 76% as compared to 58% for the control group. Competitive employment for the intervention group was maintained at 6-month follow up.

Conclusions

There is conflicting evidence (level 1b and level 2) as to whether goal orientated group interventions are more than or equally as successful as educational interventions at improving cognitive and executive function in patients post ABI.

There is level 2 evidence that emotional regulation group interventions are effective at improving executive function in patients post TBI.

There is conflicting (level 4) evidence that group cognitive interventions (ie. Metacognitive Strategy Instruction) improves executive function in patients post TBI.

6.4.1.2 Remediation of General Cognitive Functioning

Key Points

Remedial occupational therapy is likely superior to adaptive occupational therapy at improving general cognitive functioning in patients post TBI.

Low intensity outpatient cognitive rehabilitation might improve goal attainment and cognitive function in patients post ABI.

Interventions for the treatment of cognitive deficits post TBI tend to be diverse with variability between the interventions themselves and the outcome measures used to document results.

Gordon et al. (2006) conducted an extensive review of the TBI rehabilitation literature and identified 13 studies dealing with rehabilitative treatments of cognitive deficits. Studies included in this review had a multitude of inclusion criteria. The studies identified were of limited methodological quality, but suggested that compensatory strategy training improved attention deficits and mild memory impairments (Gordon et al., 2006). Several researchers have noted that training-based therapies that target executive control, such as “attention, problem solving, and the use of metacognitive strategies” (Novakovic-Agopian et al., 2011) may improve functioning in those who sustain an ABI (Cicerone, 2002; Kennedy et al., 2008; Sohlberg et al., 2003b). Studies included in this section have examined the effects of cognitive rehabilitation strategies.

Discussion

Two studies investigating the remediation of general cognitive functioning were observed.
Neistadt (1992) divided 45 patients into one of two groups: a remedial group who received individual training with parquetry block assembly, and an adaptive group who received functional skills training over a six-week period. Outcomes for the effect of treatment for constructional test performance revealed that the remedial group improved significantly more than the adaptive group on the Parquetry Block test. However, there were no significant differences on the WAIS-R Block Design subtest after treatment. Training-specific learning appears to be an effective approach to rehabilitation as demonstrated by the treatment effect.

In a more recent cohort study, Rasquin and colleagues (2010) investigated the effectiveness of a low intensity outpatient cognitive rehab program on those (n=27) who had sustained an ABI. All participants were in the chronic phase of recovery and all were asked to invite a care giver to attend sessions with them (n=25). Sessions ran for 2.5 hours each week for a total of 15 weeks. All were assessed prior to the session beginning, immediately afterward and again 6 months later. Participants worked on developing strategies to assist them with their attention, memory and problem solving difficulties. Social skills training sessions were also held. Changes were noted immediately after the cognitive rehab program ended and this improvement in goal attainment, and cognitive impairment was maintained at the 6th month follow-up.

Conclusions

There is level 1b evidence that a remedial occupational therapy intervention may be superior compared to an adaptive occupational therapy intervention at improving general cognitive functioning in patients post TBI.

There is level 4 evidence that a low intensity outpatient cognitive rehabilitation program may improve goal attainment and cognitive impairment in patients post ABI.

6.4.2 Pharmacological Interventions

6.4.2.1 Donepezil

Key Points

Donepezil might improve attention, learning and short-term memory following TBI; however, side effects may incur from its use.

The effectiveness of donepezil, a cholinesterase inhibitor, in improving cognitive and memory functions following brain injury was assessed. Cognitive impairments negatively impact patient autonomy, affecting one’s ability to return to work or school, and live alone (Masanic et al., 2001). When tested in individuals diagnosed with Alzheimer’s disease, donepezil has been found to be useful in treating memory problems (Morey et al., 2003; Walker et al., 2004). The impact of Donepezil impact on cognitive function and memory in a TBI population is explored in the table below.

Discussion

Khateb et al. (2005) found only modest improvement on the various neuropsychological tests used to measure executive function, attention, and learning and memory. Of note results from the learning phase of the Rey Auditory Verbal Memory Test (RAVMT) showed significant improvement (p<0.050). The Donepezil intervention also demonstrated improvement in executive function, as the results from the Stroop-colour naming test showed significant improvements (p<0.030). On the test for Attentional Performance a significant change was noted on the divided attention (errors) subsection of the test. Overall, donepezil was found to be effective in improving learning, memory, divided attention, and executive function. However, possible benefits of donepezil administration must be balanced against the observed side effects in 27% of the population. Further randomized control trials are required to better explore the efficacy of donepezil post TBI.

Conclusions

There is level 4 evidence that donepezil is effective in improving learning, memory, divided attention, and executive function in patients post TBI.

6.4.2.2 Methylphenidate

Key Points

The effectiveness of methylphenidate treatment to improve cognitive impairment following brain injury is unclear. Further studies with larger populations are required.

Methylphenidate is a stimulant whose exact mechanism of action in the CNS (?) is unknown (Napolitano et al., 2005). One theory is that methylphenidate acts on the presynaptic nerve to prevent the reabsorption of serotonin and norepinephrine, thereby increasing neurotransmitter concentrations within the synaptic cleft and leading to increased neurotransmission (Kim et al., 2006). In the past, methylphenidate has been extensively used as a treatment for attention deficit disorder, as well as narcolepsy (Glenn, 1998). A total of six RCTs examined the efficacy of methylphenidate as a treatment for the recovery of cognitive deficits post ABI.

Discussion

Dymowski et al. (2017) investigated the effects of short-term, 7 wk, methylphenidate administration in patients post TBI compared to a placebo (control). After analyses, it was conducted that there were no significant improvement, or difference between groups for various measures and tests of attention. Speech et al. (1993) conducted a double blind placebo controlled trial evaluating the effects of methylphenidate following closed head injury and arrived at similar conclusions, as the treatment and placebo group did not vary in any measurements of memory, intelligence, or attention. Conversely, Zhang and Wang (2017) used a larger sample size to investigate the effects of long-term (30 wk) methylphenidate use in patients post TBI. While there were no difference between the groups at baseline, the treatment group had improved reaction time, cognitive ability, attention capacity, and depression when compared to the placebo group. The contradictory on methylphenidate use post TBI creates an interesting conflict, as all studies were conducted with high methodological quality and proper controls. The study by Zhang and Wang (2017) however has a larger sample size than the other two studies combined, and thus the results may be more indicative of the true effect of methylphenidate. However, because of the inconclusive results, not conclusive statements can be confidently made regarding the efficacy or methylphenidate use post TBI.

Conclusions

There is conflicting (level 1a) evidence regarding the effectiveness of the administration of methylphenidate following TBI for the improvement of general functioning.

6.4.2.3 Sertraline

Key Points

Sertraline has not been shown to improve cognitive functioning within the first 12 months post TBI, and may be associated with side effects.

Sertraline, better known under its trade name Zoloft (Pfizer), is a selective serotonin reuptake inhibitor (SSRI) used for the treatment of depression and mood (Khouzam et al., 2003; Jorge et al., 2016). The majority of sertraline TBI research focuses on the prevention or treatment of major depressive symptoms post brain injury. However, recent studies have shifted focus and begun to evaluate the benefits of sertraline at improving cognitive disorders (Banos et al., 2010; Jorge et al., 2016; Lee, 2005). The studies reviewed below investigated the effect of sertraline on cognitive outcomes post TBI.

Discussion

The effect of early administration of sertraline on cognitive functioning was evaluated by Banos et al. (2010) in an RCT. When comparing the sertraline group, who received 50 mg per day, to a control group (placebo), there were no significant between group differences on any of the neuropsychological tests. The assessments examined attention and concentration, speed of processing, memory and executive function at 3, 6 and 12 months. Cognitive functioning was not found to improve following the administration of sertraline. . Of note, more patients in the sertraline group dropped out of the study compared to the control group when this was quantified at all assessment points— indicating the potential side effects associated with the treatment. Combined with the lack of apparent benefit to using the drug, use of sertraline is not currently recommended.

Conclusions

There is level 1b evidence that sertraline does not improve cognitive functioning in individuals who have sustained a moderate to severe TBI.

6.4.2.4 Amantadine

Key Points

Amantadine might not be effective at improving attention and memory deficits post TBI. Its impact on executive functioning should be studied further.

Amantadine is a non-competitive N-methyl-D-aspartate receptor antagonist and has been used as an antiviral agent, prophylaxis for influenza A, treatment of neurological diseases such as Parkinson’s Disease, and the treatment of neuroleptic side-effects such as dystonia, akinthesia and neuroleptic malignant syndrome (Schneider et al., 1999). Amantadine is also thought to work pre- and post-synaptically by increasing the amount of dopamine (in… the synapse? Pre-synaptic junction? Post-synaptic cell?) (Napolitano et al., 2005). Two studies were identified that investigated the effectiveness of amantadine as a treatment for the remediation of learning and memory deficits and cognitive functioning following TBI.

Discussion

In a small sample RCT by Schneider et al. (1999) the effects of Amantadine on cognition and behaviours was assessed. In this six week cross-over study, patients received both placebo and amantadine for 2 weeks each, with a 2 week washout period in between. Although the study found that patients improved over the six week study period, statistical comparison of results evaluating the five subsets of attention, executive/flexibility, memory, behaviour and orientation did not demonstrate any significant effect for the use of Amantadine. Similarly, Kraus et al. (2005) demonstrated that the administration of amantadine over a 12-week treatment period does not improve memory deficits or attention; however, significant improvements in executive functioning were observed. Given the quality and sample size of the current studies, future studies exploring the efficacy of amantadine for learning and memory are warranted.

Conclusions

There is level 2 evidence that Amantadine may not help to improve general functioning deficits in patients post TBI compared to placebo.

6.4.2.5 Pramiracetam

Key Points

Bromocriptine may improve some executive cognitive functions such as dual task performance and motivational deficits. More research is needed before the benefits of using bromocriptine to enhance cognitive functioning are known.

Bromocriptine is a dopaminergic agonist which primarily exerts its actions through binding and activating D2 receptors (Whyte et al., 2008). It has been suggested that dopamine is an important neurotransmitter for prefrontal function, an important area of the brain that contributes to cognitive function, memory, intelligence, language, and visual interpretation (McDowell et al., 1998; Siddiqui et al., 2008). In a study looking at the effects of bromocriptine on rats, Kline et al. (2002) noted that the animals showed improvement in working memory and spatial learning; however, this improvement was not seen in motor abilities. Two studies have been identified investigating the use of bromocriptine as an adequate treatment for the recovery of cognitive impairments following TBI.

Discussion

The question of whether bromocriptine improves cognitive function in patients with ABI was explored in one RCTs (McDowell et al., 1998; Whyte et al., 2008), and one case series (Powell et al. 1996). In an earlier investigation, low-dose bromocriptine (2.5 mg daily) improved functioning on tests of executive control including a dual task, Trail Making Test, the Stroop test, the Wisconsin Card Sorting Test and the controlled oral word association test (McDowell et al., 1998). However, bromocriptine did not significantly influence working memory tasks. Although McDowell et al. (1998) demonstrated some benefits following administration of bromocriptine, there was only a single administration of bromocriptine and the dose was considerably lower than that given by other studies that did not meet our criteria. Spontaneous recovery may have been a factor leading to the improved abilities in individuals receiving a single dose (2.5 mg daily) of the medication; however, study results did not answer this question. Powell et al. (1996) conducted a multiple baseline design on 11 patients with TBI or subarachnoid hemorrhage who received bromocriptine. Improvements were found on all measures assessed (memory, attention, motivation spontaneity) except mood. In light of the fact that the last RCT investigating the effects of bromocriptine was conducted 20 years ago, new studies are required to build on the promising results of these very early conclusions.

Conclusions

There is level 2 evidence that low-dose bromocriptine may improve cognitive function in patients post TBI.

There is level 4 evidence that bromocriptine may improve motivational deficits in patients post TBI.

6.4.2.6 Growth Hormone (GH) Replacement Therapy

Key Points

The administration of recombinant human Growth Hormone (rhGH) is likely not different than placebo at improving executive functioning, memory, or learning in patients post TBI; however certain aspects of patient quality of life may be improved.

The administration of recombinant human Growth Hormone (rhGH) might be superior at improving intelligence and cognition in patients with a growth hormone deficiency, versus those who do not, post TBI. Molecular markers of growth however may not be different post treatment between groups.

Following an ABI, it is not uncommon for individuals to be diagnosed with hypopituitarism. It is estimated that as many as 25 to 40% of individuals with a moderate to severe ABI demonstrate chronic hypopituitarism (Bondanelli et al., 2007; Kelly et al., 2006; Schneiderman et al., 2008). Despite this, few patients are screened for GH deficiencies; thus, the link between cognitive impairment and growth hormone deficiencies has not yet been definitively established (High et al., 2010). The benefits of GH replacement therapy on patient’s executive function post TBI will be investigated below.

Discussion

A 2010 RCT compared the long term (6 mo and 1 yr) effects of rhGH administration to placebo in a TBI population (High Jr et al. 2010). Significant improvements were noted in processing speed, executive functioning (Wisconsin Card Sorting Test), and learning (California Verbal learning test II) for both he rhGH and placebo groups. It is important to note while processing speed also improved in both groups at 6 mo, the improvement was only sustained in the treatment group at 1 yr. Further positive results were reported in a more recent PCT by Moreau et al. (2013). Patient quality of life, instrumental activities of daily living, attention, memory and visuospatial ability improved over the treatment period in both the treatment and control group. However, the treatment group improved significantly more in the functional and personal subscales of quality of life assessments. Reimunde et al. (2011) in a cohort study looking at the benefits of administering rhGH to a group of patients who have sustained either a moderate or severe TBI. Results of the study indicate that those receiving the rhGH improved significantly on the various cognitive subtests such as: understanding, digits, numbers and incomplete figures (p<0.05) and similarities vocabulary, verbal IQ, Manipulative IQ, and Total IQ (p<0.01). The control group also showed significant improvement but only in digits and manipulative intelligence quotient (p<0.05). Of note IGF-I levels were similar between both groups at the end of the study.

Conclusions

There is level 1b evidence that recombinant human Growth Hormone (rhGH) is similar to placebo at improving processing speed (6 mo), executive function and learning in patients post TBI.

There is level 2 evidence that growth hormone (GH) therapy is similar to placebo at improving quality of life, instrumental activities of daily living (iADL), attention, memory, and visuospatial ability in patients post TBI.

There is level 2 evidence that recombinant human Growth Hormone (rhGH) administration improves intelligence and other cognitive subtests in TBI patients with growth hormone deficiency compared to TBI patients without; however, insulin-like growth factor-1 (IGF-1) levels may be the same between groups.

6.4.2.7 Acetylcholinesterase Inhibitors

Key Points

Rivastigmine may not be effective in treating memory deficits post-ABI.

Acetylcholinesterase inhibitors prevent the enzyme acetylcholinesterase from breaking down acetylcholine. This increases the concentration of acetylcholine in synapses. Acetylcholine has been most strongly linked with the hippocampus and memory deficits, however it is also implicated in attentional processing.

Discussion

In two studies rivastigmine was administered to patients who had sustained a moderate to severe TBI (Silver et al., 2006; Silver et al., 2009). Results from both studies indicate that rivastigmine improved cognitive function and memory impairment, although results were not significant. In Silver’s (2009) follow-up open-label cohort study to their original RCT, participants (n=98) showed significant improvement on the CANTAB RVIP A’, the HVLT and the trail A and B scales at the end of 38 week study period; however when further sub-analysis was performed depending on what group the patient previously belonged to, , those in the ex-rivastigmine group to those in the ex-placebo group, the improvements were not significant.

Conclusions

There is conflicting (level 1b and level 4) evidence that rivastigmine may not be effective in improving memory in ABI populations.

6.5 Conclusions

Cognitive interventions target a large variety of cognitive functions and deficits. The rehabilitation of these functions is complicated by the lack of consensus on the definition of attention, cognition, and general and executive functioning.

Comparing the efficacy of various remediation efforts is also complicated by cross-study variability in treatment duration (e.g. from 30 minutes once a day for 5 days to 5 hours, every day for 6 weeks). Severity of injury and time since injury may also fluctuate from study to study. Over the past several years, Cicerone et al. (2000; 2005; 2011) reviewed a series of studies investigating the effectiveness of attentional retraining interventions during rehabilitation following traumatic brain injury and stroke.
Not all patients respond equally to all intervention strategies and no study in the current review indicated whether severity of memory impairment (or memory profile) interacts with a particular external memory aid. Technology has increased the availability of external aids, although some seem more feasible to use than others (e.g., cell phones or hand-held recorders). Unfortunately, the studies reviewed did not specify the length of time subjects required to master compensatory strategies or the nature of the long-term effects. Generally if these electronic appliances are used before the injury, they will are more likely to be used post injury. It was nuclear from the studies if any of the participants had had some knowledge of these appliances.

Most studies examined only tasks of word list recall and paired-associate learning suggesting that the mnemonic strategies reviewed may not generalize to other types of information (particularly real-world or functional information outside the laboratory). Errorless learning appears to be one procedure that can be used to enhance learning conditions. One study highlighted the difference between severity of impairment and ability to benefit from internal strategies.

Frequency of intervention has an impact on learning and retention, although the exact parameters of this are unclear at the present time. The optimal duration of a program is also open for speculation. No studies reviewed examined the number of sessions required for memory groups to be effective and only one study evaluated a difference in effectiveness between mild and severely impaired individuals after sessions. Pharmacologic intervention does not appear to be effective in improving learning and memory deficits.

Summary


There is level 2 evidence that training programs designed to improve attention in general may be effective compared to unstructured stimulation in ABI populations.

There is level 3 evidence that attention processing training may improve attention compared to visual search training in ABI populations.

There is level 2 evidence that dual task training may be effective in improving attention task performance in ABI populations compared to non-specific training.

There is level 2 evidence that neither general nor name brand computer-based rehabilitation intervention may improve attention outcomes compared to usual care in ABI populations.

There is level 4 evidence that attention performance can be improved in ABI populations through repetition of tasks, either through computer-based or virtual reality environments.

There is level 2 evidence that adaptive training is no more effective than non-adaptive training in remediating attention in ABI populations.

There is level 1b evidence that emotional regulation therapy is not effective in treating attentional disorders compared to waitlist controls in ABI populations.

There is level 2 evidence that mindfulness training compared to no intervention may improve an individual’s ability to correctly reject inappropriate stimuli post ABI.

There is level 2 evidence to suggest goal management training, when compared to education, may be effective at improving attention in post-ABI individuals.

There is level 2 evidence that goal management training is more effective in remediating task completion times than motor skill training, however is not more effective in treating attention deficits, in post-ABI individuals.

There is conflicting (level 2) evidence that attentional control or processing training may not significantly improve attention in post-ABI individuals compared to control training.

There is level 4 evidence that summation tasks may be effective at improving attention in individuals post ABI.

There is level 4 evidence that a working memory training program may remediate attention in post-ABI individuals.

There is level 4 evidence that cognitive rehabilitation therapy may not be effective for improving attention post-ABI.

There is level 2 evidence that transcranial direct current stimulation compared to sham stimulation may improve divided attention in individuals post ABI.

There is level 1b evidence that donepezil may improve attention compared to placebo post ABI.

There is conflicting level 1b evidence regarding the effectiveness of methylphenidate following brain injury for the improvement of attention and concentration in individuals post ABI.

There is level 1a evidence that methylphenidate improves reaction time of working memory compared to placebo in individuals post ABI.

There is level 1b evidence that bromocriptine compared to placebo does not improve performance on attention tasks in patients post TBI.

There is level 2 evidence that bromocriptine improves attention, compared to placebo post ABI.

There is level 4 evidence that cerebrolysin may improve attention scores post ABI.

There is level 1b evidence that Rivastigmine compared to placebo may not be effective for improving concentration or attention in individuals post

There is level 4 evidence that the NeuroPage system may increase a patient’s ability and efficiency to complete tasks post TBI.

There is level 4 evidence that voice organizer programs are effective at improving recall of goals, and are found to be effective by patients post TBI.

There is level 2 evidence that personal digital assistants (PDAs) are superior to a paper-based schedule book at improving task completion rates post TBI.

There is level 1b evidence that the use of a personal digital assistant (PDA) in combination with conventional occupational therapy is superior to occupational therapy alone at improving memory in patients post TBI.

There is level 1b evidence that use of a personal digital assistant (PDA) after receiving systematic instructions is superior to PDA trial and error learning at improving the number and speed of correct tasks post TBI.

There is level 4 evidence that conventional or touch-screen personal digital assistant (PDA) use are similar at improving memory post TBI.

There is level 1b evidence that reminder text messages sent to patients through their smartphones, whether alone or in combination with goal management training, may improve goal completion post TBI.

There is level 2 evidence that a television assisted prompting (TAP) system is superior to traditional methods of memory prompting (paper planners, cell phones, computers) at improving the amount of completed tasks post TBI.

There is level 1b evidence that the audio-verbal interactive micro-prompting system, Guide, can reduce the amount of support-staff prompts needed for the patient to complete a task post TBI.

There is level 4 evidence that a computerized tracking system that sends reminders to patients when they are moving in the wrong direction reduces the amount of support-staff prompts needed for patients to complete a task post TBI.

There is conflicting (level 2) evidence regarding whether or not the use of a calendar, compared to diary training, is effective for improving memory post ABI.

There is level 2 evidence that the presence of a calendar may not improve orientation post ABI.

There is level 2 evidence that diary training in combination with self-instructional traning may be more effective than diary training alone at improving memory and task completion post ABI.

There is level 4 evidence that virtual reality (VR) training may improve learning performance post ABI, although the effect may not be different from non-VR training.

There is level 2 evidence that virtual reality training alone may be promising for improving memory outcomes, and has a positive impact on visual and verbal learning when in combination with exercise.

There is level 1b evidence that hypnosis compared to no treatment may not be effective at improving memory in individuals post ABI.

There is level 1b evidence that the Short Memory Technique may not be more effective than standard memory therapy at improving memory in individuals post ABI.

There is level 2 evidence that participation in a goals training program, followed by an educational program, may be more effective for improving memory in individuals post ABI compared to receiving the treatment conditions in reverse order.

There is level 1b evidence that compensatory memory strategies, self-awareness training, and participation in memory group sessions may be effective for improving memory in individuals post ABI compared to no treatment.

There is level 2 evidence that Strategic Memory and Reasoning Training (SMART) may improve learning and working memory compared to no memory training in individuals post ABI.

There is level 2 evidence that dual-task training may be effective for improving memory in individuals post ABI when presented before the control condition, compared to the reverse.

There is level 2 evidence that both computer-administered and therapist-administered memory training may be more effective than no treatment for improving memory in ABI participants. However, no treatment appears to be better than the other.

There is level 2 evidence that both cognitive remediation and emotional self-regulation may be effective at improving different elements of memory in individuals post ABI.

There is level 1b evidence that attention processing training compared to supportive listening may improve memory in individuals post ABI.

There is level 2 evidence that BrainHQ is not an effective program for improving memory and learning compared to no intervention in individuals post ABI.

There is level 4 evidence that using mental representations and role-playing may not be effective at improving memory in individuals post ABI.

There is level 4 evidence that Cogmed training software may improve working memory performance and occupational performance in individuals post ABI.

There is conflicting (level 4) evidence regarding whether or not Parrot software is effective at improving memory and learning in individuals post ABI.

There is level 4 evidence that mental addition tasks may improve working memory in individuals post ABI.

There is level 1b evidence that cranial electrotherapy stimulation may not improve memory and recall compared to sham stimulation post TBI.

There is level 1b evidence that donepezil improves short-term memory compared to X post ABI.

There is level 4 evidence that donepezil may be effective in improving short-term, long-term, verbal, and visual memory post ABI.

There is conflicting (level 1b) evidence regarding the effectiveness of the administration of methylphenidate compared to X following brain injury for the improvement of memory in patients post TBI.

There is level 1b evidence that sertraline may not improve memory compared to placebo in individuals who have sustained a moderate to severe TBI.

There is level 2 evidence that amantadine may not improve learning and memory deficits in patients post TBI.

There is level 2 evidence that pramiracetam may improve males’ memory compared to placebo post TBI.

There is level 1b evidence that oral physostigmine may improve long-term memory compared to placebo in men with TBI.

There is level 2 evidence that low-dose bromocriptine may improve cognitive function, but not working memory in patients post TBI.

There is level 4 evidence that bromocriptine may improve memory in patients post TBI.
There is level 4 evidence that cerebrolysin may improve memory function post ABI.

There is level 1b evidence that recombinant human Growth Hormone (rhGH) is similar to placebo at improving processing speed (6 mo), memory, executive function and learning in patients post TBI.

There is level 2 evidence that growth hormone (GH) therapy is similar to placebo at improving quality of life, instrumental activities of daily living (iADL), attention, memory, and visuospatial ability in patients post TBI.

There is level 1b evidence that rivastigmine may be effective in improving memory in ABI populations.

There is level 1b evidence that targeted hypnosis may transiently improve cognitive function in patients post TBI or stroke.

There is level 1b evidence that an attention remediation intervention is superior to TBI education alone and improving executive function in patients post TBI.

There is level 2 evidence that dual-task training may improve general cognitive functioning compared to a non-specific cognitive program in patients post TBI.

There is level 1b evidence that a comprehensive cognitive treatment strategy may be superior to a computerized training package at improving task initiating and goal achievement post TBI.

There is level 4 evidence that cognitive rehabilitation may increase productivity in everyday functioning, and cerebral blood flow during treatment in patients post TBI.

There is conflicting (level 1b and level 2) evidence as to whether virtual-reality training is or is not superior to conventional cognitive training at improving cognitive and executive function outcomes post TBI.

There is level 2 evidence that computer or smartphone software programs, such as BrainHQ, Parrot Software, ProSolv app, may not be superior to no intervention at improving problem-solving skills and general functioning in patients post TBI.

There is level 2 evidence that goal management training may be superior to motor skills training at improving everyday skills like meal preparation, but not neuropsychological tests or intelligence in patients post TBI.

There is conflicting evidence (level 1b and level 2) as to whether goal orientated group interventions are more than or equally as successful as educational interventions at improving cognitive and executive function in patients post ABI.

There is level 2 evidence that emotional regulation group interventions are effective at improving executive function in patients post TBI.

There is conflicting (level 4) evidence that group cognitive interventions (ie. Metacognitive Strategy Instruction) improves executive function in patients post TBI.

There is level 1b evidence that a remedial occupational therapy intervention may be superior compared to an adaptive occupational therapy intervention at improving general cognitive functioning in patients post TBI.

There is level 4 evidence that a low intensity outpatient cognitive rehabilitation program may improve goal attainment and cognitive impairment in patients post ABI.

There is level 4 evidence that donepezil is effective in improving learning, memory, divided attention, and executive function in patients post TBI.

There is conflicting (level 1a) evidence regarding the effectiveness of the administration of methylphenidate following TBI for the improvement of general functioning.

There is level 1b evidence that sertraline does not improve cognitive functioning in individuals who have sustained a moderate to severe TBI.

There is level 2 evidence that Amantadine does not help to improve general functioning deficits in patients post TBI compared to placebo.

There is level 2 evidence that low-dose bromocriptine may improve cognitive function in patients post TBI.

There is level 4 evidence that bromocriptine may improve motivational deficits in patients post TBI.

There is level 1b evidence that recombinant human Growth Hormone (rhGH) is similar to placebo at improving processing speed (6 mo), executive function and learning in patients post TBI.

There is level 2 evidence that growth hormone (GH) therapy is similar to placebo at improving quality of life, instrumental activities of daily living (iADL), attention, memory, and visuospatial ability in patients post TBI.

There is level 2 evidence that recombinant human Growth Hormone (rhGH) administration improves intelligence and other cognitive subtests in TBI patients with growth hormone deficiency compared to TBI patients without; however, insulin-like growth factor-1 (IGF-1) levels may be the same between groups.

There is conflicting (level 1b and level 4) evidence that rivastigmine is effective in improving memory in ABI populations.

There is conflicting (level 1b and level 4) evidence that rivastigmine may not be effective in improving memory in ABI populations.

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