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

The two studies desmontrated no 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. Novack et al. (1996) found that there were no significant differences between groups at either time points; however, both groups significantly improved over time. Although the study by Lindelov et al. (2016) also found no significant treatment effects over time, in contrast to the previous study, no spontaneous recovery effects were found either. Overall, there is weak evidence in support of training programs as an effective rehabilitation intervention for attention.

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.

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). Couillet et al. (2010) found that dual-task training significantly improved attentional behaviour and reaction time compared to a non-specific cognitive program. Stablum et al. (2000) found that initially individuals with a closed head injury (CHI) performed poorly on dual-task measures; however, with additional training their completion time of dual-task measures significantly increased compared to the control group.

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).   Similarly, 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 have also shown limited effects. A small pre-post study examining the program Luminosity^TM showed improvements in attention for a minority of participants; however, this improvement did not significantly differ from those who received Attention Process Training-III (Zickefoose et al., 2013). Parrot software showed mixed results with a pilot study reporting significant improvement in attention 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.

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).

With regard to cognitive rehabilitation, therapy is typically patient-directed and driven by both long- and short-term goals (Carswell et al., 2004). The ability to self-direct towards goals is 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 focus 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).

Many studies examined the effects goal training or cognitive training (Boman et al., 2004; Chen et al., 2011; Laatsch et al., 1999; Novakovic-Agopian et al., 2011; Sohlberg et al., 2000). Levine et al. (2000) completed an RCT comparing patients using goal management training strategies to a control group 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. 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.

A more 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 (TEA) scores. Overall, both groups significantly improved on measures of attention as a result of time (Dundon et al., 2015).

Park et al. (1999) examined whether Attention Processing Training (APT) had a beneficial effect on attention measures (PASAT, Consonant Trigrams) in a  group with severe TBI (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 the APT did not have a significantly beneficial effect as performance improved on all measures across both groups (indicating practice effects and possibly spontaneous recovery). 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 to 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).  Attention process training, was also shown to have greater results in attention remediation compared to education alone (Sohlberg et al., 2000). One study examined the effects of a memory training program on attention and reported 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 in this chapter.

In a study directly comparing the effects of an attention training program with that of a memory training program, the authors found that the results were split, with individuals performing better on some measures of attention (Attention Test 2d) but not others (PASAT) (Neiman et al., 1990). The last study to use an attention training program sought to see if the presence of a therapy animal could enhance the effects of training (Gocheva et al., 2018). Both the animal therapy and non-animal therapy groups produced significant improvement on measures of attention and concentration; however, the animal therapy group had a significantly larger increase in concentration (Gocheva et al., 2018).

Emotional regulation was also examined as a potential intervention for the remediation of attention postABI (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 & Wood, 2013) found that mindful focused training significantly improved participants’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). “Cognitive pragmatic treatment’ has been found to significantly improve scores on the card sorting task; however, the specific details of this program were not stated (Bosco et al., 2018b).

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 that 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.

Donepezil, an acetylcholinesterase inhibitor, was originally developed for improving cognitive function and memory in people with Alzheimer’s disease (Cacabelos, 2007), by delaying cognitive impairment in (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).

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. Once both groups had completed donepezil treatment there were no significant differences between groups on any measures of attention. Khateb et al. (2005) found that individuals performed significantly better on measures of divided attention after donepezil treatment; however, 4 of 15 participants stopped treatment due to negative side-effects. In contrast to the positive effects found by these studies, one prospective controlled trial found no significant effects of donepezil on any measures of cognition, including attention (Campbell et al., 2018). In both the Campbell et al. (2018) and Zhang et al. (2004) studies, individuals received donepezil for approximately the same duration.

Methylphenidate is a central nervous stimulant (CNS) which inhibits the reuptake of dopamine and norepinephrine, resulting in increased dopaminergic activity. 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).

The majority of studies evaluating the efficacy of methylphenidate have been RCTs. 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. More 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 significantly improved the speed of information processing. A variety of studies with different dosing regimens and durations have found positive effects of methylphenidate (Gualtieri & Evans, 1988; Whyte et al., 1997; Zhang et al., 2004).

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 statistical significance. 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 et al. (2017) noted improvements in reaction time, arithmetic tests, and even mental health outcomes after intervention by methylphenidate.

A potential explanation for these conflicting results is proposed 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.

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 reflected 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.

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. However, a later study by Whyte et al. (2008) found that bromocriptine had little effect on attention and 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.

Cerebrolysin has been demonstrated to have neuroprotective and neurotrophic effects and has been linked to increased cognitive performance in an elderly population. 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).

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 in the Glasgow Outcome Scale were also observed (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.

Rivastigmine is an acetylcholinesterase inhibitor which prevents 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 impairments; however, it is also implicated in attentional processing.

Three studies have concluded that rivastigmine most likely does not improve attention following an acquired brain injury (Silver et al., 2006; Silver et al., 2009; Tenovuo et al., 2009). In Silver’s (2009) follow-up open-label cohort study to their original RCT (Silver et al., 2006), 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, after further sub-analysis controlling for order effects no significant differences were found between groups. The third study by Tenovuo et al. (2009) found that rivastigmine significantly improved vigilance following doses of 12mg/day for eight weeks. Tenovuo et al. (2009) on average had higher doses and longer duration of rivastigmine administration compared to both Silver et al. studies; however, it is unclear whether this resulted in their conflicting results. The route of rivastigmine administration (injection versus oral administration) did not appear to influence its efficacy.

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).

Presently, only one study has examined the effects of amantadine on attention and processing speed and found no significant effects on attention or processing speed following treatment. Any results which were found to be significant on other cognitive measures were not maintained at the 60-day follow-up (Hammond et al., 2018). Further studies are needed to examine whether or not amantadine may be a viable treatment for attention and processing speed deficits following an ABI.

Hyperbaric oxygen therapy involves the inhalation of pure oxygen under pressure allowing the lungs to absorb more oxygen per breath. Currently hyperbaric oxygen therapy is used to treat decompression sickness, serious infections, and delayed wound healing as a result of a comorbid illness such as diabetes (The Mayo Clinic, 2019).

From this single case series, hyperbaric oxygen therapy significantly improved both attention and processing speed following treatment five days a week (Hadanny et al., 2018). Also, general improvements in cognitive functioning and visual processing were also reported (Hadanny et al., 2018). However, without proper prospective experimental data it is challenging to make conclusions on the efficacy of this intervention.

Dextroamphetamine is a central nervous stimulant; similar to methylphenidate, it is used to treat narcolepsy and attention deficit hyperactivity disorder. Dextroamphetamine is a noncatecholamine and sympathomimetic amine that acts as a stimulant, unfortunately more direct mechanisms of action are not currently known.

Based on a single study, it does not appear that dextroamphetamine has any beneficial effects on attention or processing speed following an ABI. However, administration of dextroamphetamine did significantly increase agitation over time.

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 that may be used to support individuals with memory or learning deficits as a result of an ABI.

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

A variety of internal memory strategies exist which attempt to remediate memory deficits following an acquired brain injury. As a result of the breadth of strategies attempted and evaluated, few studies overlap in methodology and protocol limiting the conclusions that can be made about each intervention.

Potvin et al. (2011) used one of the more common strategies; visual imagery techniques. Following visual imagery instruction, the scores on the Test Ecologique de Memoire Prospective significantly improved for those in the visual imagery group, this group also reported significantly fewer prospective memory errors and depression. Prospective memory is an area that has been found to be positively affected by more than one imagery technique. Another RCT found that self-imagery significantly improved prospective memory compared to information rehearsal (Grilli & McFarland, 2011). Imagery techniques in general have been found to be effective for improving general memory (Twum & Parente, 1994), as well as specific areas of memory like logical memory (Kaschel et al., 2002). Overall, there is strong evidence to support the use of imagery techniques to improve memory. One study used self-imagery in combination with a variety of other encoding techniques to determine its efficacy against other encoding strategies such as semantic elaboration (Grilli & Glisky, 2013). It was found that those in the self-imagining condition showed better free recall than the control condition, but also recalled more self-descriptive adjective words than the other control and experimental conditions (Grilli & Glisky, 2013).

Another common memory strategy is retrieval practice. A variety of different retrieval strategies have been studied, such as spaced retrieval, massed retrieval, and cued retrieval (Sumowski et al., 2014). The use of retrieval strategies has been shown to significantly improve goal mastery (Bourgeois et al., 2007), delayed recall (Hillary et al., 2003; Sumowski et al., 2010), and immediate recall (Hillary et al., 2003). Bourgeois et al. (2007) found that compared to didactic strategy instruction, spaced retrieval significantly improved goal mastery; however, both groups achieved significant improvements in memory and memory errors. In a follow-up study to Berg et al. (1991), which found significant improvements on all memory measures as a result of individual strategies, Milders et al. (1995) found that at four-year follow-up the group which experienced ‘drill and practice” retrieval strategies had the best long-term memory outcomes. Although a general trend has shown spaced retrieval and cued retrieval to be effective, it should be noted that the highlighted studies did not overlap in terms of their application of this strategy. Multiple studies have shown that massed retrieval or “cramming” is not an effective strategy for improving memory (Hillary et al., 2003; Sumowski et al., 2010).

Strategies which use multiple encoding techniques have also been found to be effective. Milders 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). This was shown to improve memory and recall (Milders et al., 1998). 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). Twum and Parente (1994) randomly assigned 60 patients with a TBI into one of four groups (one control and three mnemonic strategy groups) counterbalanced. The research demonstrated improved performance for subjects who were taught a strategy (either verbal labeling or visual imagery, or both) while learning paired-associations. Treatment groups showed greater efficiency in learning and greater delayed recall information. This conclusion is supported by other studies which have found general improvements in memory when combining multiple encoding cues such as visual imagery and verbal/written cues (Manasse et al., 2005). In a final study examining encoding, individuals were taught word association pairs and found that when primed with the first word of the pair, individuals were able to recall the second word more effectively (Schefft et al., 2008).

The remaining interventions have been explored in limited studies. 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. A pre-post study examined the type of errorless learning to take place (self-generated or examiner generated) and found that self-generated errorless learning resulted in significantly higher recall (Tailby & Haslam, 2003). However, examiner errorless learning was observed to be better than errorful learning. Lastly, an interaction effect was seen with regard to injury severity such that those of a mild to moderate ABI responded better to treatment than those with a severe injury (Tailby & Haslam, 2003). A combination of internal memory strategies was also found to be effective for improving memory compared to a convenience sample of controls (O’Neil-Pirozzi et al., 2010a). Similar to the previous study, it was seen that those with mild to moderate ABIs gained the most from treatment, while those with a severe injury were not able to perform as well over all (O’Neil-Pirozzi et al., 2010a).

Following a brain injury, one of the most persistent problems are memory deficits (Hasegawa & Hoshiyama, 2009). 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., 2010a).

Similar to internal memory strategies, many potential interventions have been studied, with little overlap between studies themselves in terms of methodology. A variety of trademarked cognitive programs have been evaluated in an attempt to improve learning and memory following an ABI. Constantinidou et al. (2008) evaluated the Categorization Program for 13 weeks in an RCT, and found that although individuals who received the program performed better on measures of executive function, there were no significant improvements seen in learning or memory. 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 (Sandry et al., 2016). In a prospective cohort study, Johansson and Tornmalm (2012) examined the benefits of 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 6-month follow up. RehaCom software has also been evaluated in a single study (Fernández et al., 2012). Individuals significantly improved on the Wechler Memory Scale for overall memory and also on measures of attention (Fernández et al., 2012). 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. 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). However, in one RCT Dou et al. (2006) demonstrated that computer assisted memory training may not be superior to therapist administered memory training as both groups improved on measures of memory over time compared to a no-treatment control group, but did not significantly differ from each other. 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. It should be noted no specific software program was evaluated in more than one study; ,therefore limited conclusions can be made on their efficacy compared to therapist administered therapy or to each other. However, cognitive-based computer programs have generally been shown to be effective on measures of cognitive functioning (Johansson 2012).

Several specific non-computerized learning and memory interventions have also been evaluated in singular studies. 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 group 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.

With respect to attention process training, it was shown that individuals receiving attention remediation significantly improved in memory and attention measurements compared to controls who had education alone (Sohlberg et al., 2000). Conversely, 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. Two older RCTs have evaluated attention training programs directly to memory training programs with limited results. An RCT from 1990 evaluated a non-specified memory training program and compared it directly to an attention training program and found that neither program actually improved measures of memory (Niemann et al., 1990). However, the attention training program did improve some measures of attention, but this was not consistent across all measures of attention evaluated (Niemann et al., 1990). Ryan & Ruff (1988) found similar results where neither the applied memory training program nor the attentional program significantly improved measures of memory or learning in individuals. Overall there is weak evidence in support of training programs as an effective rehabilitation intervention for attention.

In another RCT, 45 individuals were randomly assigned into one of four treatment groups (Shum et al., 2011). The treatment groups consisted of four 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 finished. 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.

The effects of hypnosis, as delivered in a targeted or non targeted manner, on memory, attention, and cognitive function in a mixed TBI and stroke population has been studied (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. Another unique intervention aimed at improving memory following an ABI was an RCT evaluating meatball making (Eakman & Nelson, 2001). Individuals received either hands-on or verbal instructions for making meatballs and were required to reproduce the meatballs at a later time. In this instance meatballs were used as an example to explore the benefits of modelling compared to verbal instruction only on memory consolidation. It was found that the hands-on meatball making group remembered significantly more steps in the making process compared to the verbal instruction only group (Eakman & Nelson, 2001) suggesting that modelling may be more effective than verbal instruction alone. Another study which compared the type of instruction given showed that asking individuals to describe procedures in detail and providing retrieval prompts was significantly more beneficial for recall than individuals training by describing procedures alone (Hewitt et al., 2006). These studies support the use of a combination of modelling and instructional techniques to improve memory.

Thickpenny-Davis and Barker-Collo (2007) randomly assigned 14 individuals to either the treatment or control group. 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 1-month follow-up time period. 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. 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).

Only one study (Serino et al., 2007) described a specific task that was successful in improving memory. This cognitive task involved mental addition in combination with two other standardized tasks and was an effective strategy for improving working memory. Boman et al. (2004) in a study of ten individuals with mild or moderate TBI, after completing 1 hour of an individual cognitive training three times a week for 3 weeks, significant improvement was noted on the Rivermead Behavioural Memory Test at 3-month follow-up compared to pre-test scores. Changes on the Claeson-Dahl Memory test did not increase pre to post to 3-month follow-up. The findings of the previous study support 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. Similar findings were reported in an RCT by Novakovic-Agopian et al. (2011), which examined the effects of goals training and education in an RCT crossover study. While education was shown to minimally improve memory, specific goals training significantly improved working memory, mental flexibility, learning and delayed recall (Novakovic-Agopian et al., 2011). A Cognitive Pragmatic Treatment program was evaluated over the course of 24 sessions with participants being assessed at four different time points (Bosco et al., 2018a). The results showed strong effects on communication and activities of daily living, with verbal span only improving immediately following treatment but differences were not maintained at follow-up (Bosco et al., 2018a).

Specific interventions which were not shown to have positive effects on memory include time pressure management (Fasotti et al., 2000), individual versus group therapy (Leśniak et al., 2018), finger sequencing tasks (Korman et al., 2018), and the Intensive Neurorehabilitation Programme (Holleman et al., 2018b). Lesnaik et al. (2018), compared the effects of individual versus group therapy on memory and found that although both groups improved over time, there were no significant differences between groups. Similar to the previous study, time pressure management was not shown to significantly improve memory outcomes compared to control (Fasotti et al., 2000). With finger sequencing tasks, individuals who were trained versus untrained on the task showed no significant differences in the number of errors made, however the trained group saw a significant increase in performance speed compared to the control group (Korman et al., 2018). In a recent prospective controlled trial, a formal protocol for the Intensive Neurorehabilitation Programme showed no significant effects on the Rivermead Behavioral Memory Test, however depression and anxiety were seen to be significantly reduced (Holleman et al., 2018a).

General components of effective programs have been shown to be behavioral interventions, metacognitive strategies, and restorative approaches which tackle multiple areas of functioning and processes (Raskin et al., 2009). One study demonstrated that a memory program which included all of these components elevated memory scores in individuals with an ABI similar to that of healthy controls (Raskin 2009). A small 1991 RCT also provides support that memory programs which include memory strategies can also significantly decrease dependence on memory aids for those with an ABI {Jennett, 1991 #243}

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.

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.

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). Donepezil’s impact on cognitive function and memory in a TBI population is explored in the table below.

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.

Methylphenidate is a stimulant which inhibits the reuptake of dopamine and norepinephrine and increases activity in the prefrontal cortex. In the past, methylphenidate has been extensively used as a treatment for attention deficit disorder, as well as narcolepsy (Glenn, 1998). A total of four RCTs examined the efficacy of methylphenidate as a treatment for the recovery of cognitive deficits post ABI.

Dymowski et al. (2017) investigated the effects of short-term, 7-week, methylphenidate administration (0.6 mg/kg/d) in post TBI patientscompared 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 two 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 scores on the Wechsler Memory Scale but for measures of attention and concentration only compared to a placebo. 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 suggests 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. Although methylphenidate has been shown to significantly improve measures of attention, no reliable effects on learning and memory have been shown specifically in studies examining ABI populations.

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). The majority of sertraline research in the TBI population focuses on the prevention or treatment of major depressive symptoms. However, recent studies have shifted focus and begun to evaluate the benefits of sertraline at improving cognitive disorders (Banos et al., 2010).

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 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.

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 (Napolitano et al., 2005). Three studies have been identified that investigate the effectiveness of amantadine as a treatment for the remediation of learning and memory deficits and cognitive functioning following TBI.

In a large sample RCT by Hammond et al. (2018) individuals either received 200 mg of amantadine or placebo for 60 days. Not only was it found that there was no significant effect of amantadine on learning and memory, the control group had significantly higher scores on the Learning and Memory Index (Hammond et al., 2018). In a smaller RCT by Schneider et al. (1999) patients received both placebo and amantadine as well, and no significant effects on learning and memory were found between groups.  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.

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).

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.

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).

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).

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 an animal 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.

The question of whether bromocriptine improves learning and memory in patients with ABI has been explored in one RCT (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, only verbal memory. Although McDowell et al. (1998) demonstrated some benefits following administration of bromocriptine, there was only a single dose administered. pontaneous 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 (i.e., verbal 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.

Cerebrolysin has been demonstrated to have neuroprotective and neurotrophic effects and has been linked to increased cognitive performance in an elderly population. 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).

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 test) 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 noted on the Glasgow Outcome Scale as well (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.

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 for cognitive deficits after ABI.

A RCT compared the long term (6 months and 1 year) 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 the rhGH and placebo groups, with neither group being significantly different from the other. It is important to note while processing speed also improved in both groups at 6 months, the improvement was only sustained in the treatment group at 1 year. Similar 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, but not memory. Reimunde et al. (2011) performed a cohort study examining the benefits of rhGH administration among those with moderate to severe TBI. Results of the study indicate that those receiving rhGH improved significantly on various cognitive subtests such as: understanding, digits, numbers and incomplete figures (p<0.05) as well as “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.

Rivastigmine is an acetylcholinesterase inhibitor which prevents 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.

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 suggest that rivastigmine does not improve memory. In two RCTs Silver et al. (2006;2009) evaluated the effects of rivastigmine on verbal learning. Neither study yielded significant results for any cognitive measures compared to placebo.

Hyperbaric oxygen therapy involves the inhalation of pure oxygen under pressure allowing the lungs to absorb more oxygen per breath. Currently hyperbaric oxygen therapy is used to treat decompression sickness, serious infections, and delayed wound healing as a result of a comorbid illness such as diabetes (The Mayo Clinic, 2019).

One recent study has evaluated the effects of hyperbaric oxygen therapy on memory deficits following an ABI (Hadanny et al., 2018). The results of this study indicated that hyperbaric oxygen therapy may have positive effects on memory as individuals significantly improved on memory scores following 60-90 minutes of exposure five days a week. It should be noted that this study is retrospective and did not make use of a control group and therefore spontaneous recovery may have influenced recovery.

Gordon et al. (2006) conducted an extensive review of the TBI rehabilitation literature and identified 13 studies examining treatments for cognitive deficits. Studies included in that review had a multitude of inclusion criteria. Additionally, 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., 2008a; Sohlberg et al., 2003b). Studies included in this section have examined the effects of cognitive rehabilitation strategies.

Goverover et al. (2007) used an RCT to study individualized cognitive treatments (such as making lunch or a telephone call) on the ability to remediate self-awareness and generalized processing skills. Groups did not significantly differ at baseline; however, following treatment individuals in the treatment group experienced a significant increase in their self-regulation, and processing skills (Goverover et al., 2007). In a study, Rasquin and colleagues (2010) they 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 caregiver to attend sessions with them (n=25). Sessions lasted 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 improvement was maintained at the 6-month follow-up. Laatsch et al. (1999) found similar results where cognitive rehabilitation therapy helped individuals increase productivity in their daily lives and found improvements on neuropsychological measures.

Two other RCTs have evaluated specific training programs attempting to improve generalized cognitive functioning (Linton & Kim, 2018) (Schmidt et al., 2013). The more recent RCT had individuals participate in the in-home program (Trabajadora de Salud) and found that although both groups improved on physical measures over time, only the experimental group saw a significant increase in cognitive FIM scores. The second study involved individuals receiving task completion instructions in a variety of formats to determine how feedback might influence general cognition (Schmidt et al., 2013). Those in the video feedback group (compared to verbal feedback) saw significant improvements in self-perception, and general awareness. The video feedback condition showed a recording of the individual performing the meal preparation task required with corrective feedback, compared to the verbal feedback group which only received verbal corrective feedback (Schmidt et al., 2013).

Mindfulness-based stress reduction was evaluated in an attempt to improve self-awareness and overall cognitive health (Combs et al., 2018). Individuals participated in weekly mindfulness sessions for 60 minutes and were asked to self-report on their general cognitive functioning. Individuals reported a significant reduction in cognitive symptoms which was positively correlated to the number of sessions they attended. This was true for both general cognitive functioning as well psychological wellbeing. Although this single pre-post study offers insight into the benefits of mindfulness-based stress reduction, more research is needed.

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.

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.

Methylphenidate is a stimulant which inhibits the reuptake of dopamine and norepinephrine and increases activity in the prefrontal cortex. In the past, methylphenidate has been extensively used as a treatment for attention deficit disorder, as well as narcolepsy (Glenn, 1998). A total of three RCTs examined the efficacy of methylphenidate as a treatment for the recovery of executive and general cognitive deficits post ABI.

Dymowski et al. (2017) investigated the effects of short-term, 7-week, methylphenidate administration in post TBI patientscompared to a placebo control group. There was no significant improvement, or difference between groups for various measures and tests of attention and cognition. 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 was 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. Zhang and Wang (2017) used a fraction of the dose of methylphenidate compared to the Dymowski et al. (2017) study. Although methylphenidate has been found to be effective for the management of specific cognitive functions, such as attention, its effects on general and executive function remains inconclusive.

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). The study reviewed below investigated the effect of sertraline on cognitive outcomes post TBI.

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.

Amantadine is a non-competitive N-methyl-D-aspartate receptor antagonist and has been used as an antiviral agent, prophylaxis for influenza A, as a treatment of neurological diseases such as Parkinson’s Disease, and for the treatment of neuroleptic side-effects such as dystonia, akinthesia and neuroleptic malignant syndrome (Schneider et al., 1999). Amantadine is also thought to interact pre- and post-synaptically (Napolitano et al., 2005). Three studies were identified that investigated the effectiveness of amantadine as a treatment for the remediation of cognitive functioning following TBI.

In a small sample RCT by Schneider et al. (1999) the effects of Amantadine on cognition and behaviours were 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. No significant differences were found between groups on measures of executive or general cognitive functioning. A recent RCT reinforces these findings after finding no significant differences on measures of cognition following 6-weeks of amantadine treatment (Ghalaenovi et al, 2018). 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.

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.

The effect of bromocriptine on cognitive function in patients with ABI was explored in one RCT (McDowell et al., 1998), and one case series (Powell et al. 1996). 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. pontaneous 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, creating conflicting results between these two studies. The last RCT investigating the effects of bromocriptine was conducted 20 years ago; newer studies are required to fully determine the potential of bromocriptine as a treatment for general and executive cognitive functions.

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 and general cognitive function post TBI is investigated below.

A 2010 RCT compared the long term (6 months and 1 year) 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 year. 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) also examined the use of recombinant human growth hormone in a cohort study. 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),  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.

Rivastigmine is an acetylcholinesterase inhibitor which prevents 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.

In two studies rivastigmine was administered to patients who had sustained a moderate to severe TBI (Silver et al., 2006; Silver et al., 2009). Neither RCT found significant effects of rivastigmine on measures of general or executive function. However, after controlling for order-effects, there were no significant effects of treatment.

Hyperbaric oxygen therapy involves the inhalation of pure oxygen under pressure allowing the lungs to absorb more oxygen per breath. Currently hyperbaric oxygen therapy is used to treat decompression sickness, serious infections, and delayed wound healing as a result of a comorbid illness such as diabetes (The Mayo Clinic, 2019).

One recent case series has evaluated the potential benefits of hyperbaric oxygen therapy on general and executive functioning (Hadanny et al., 2018). This study used NeuroTrax to evaluate all neurocognitive measures. Both measures of general and executive functioning saw a significant improvement over the treatment period. However, it should be noted that this study did not contain a control group and therefore it is difficult to separate the effects of the treatment from spontaneous recovery.

Dextroamphetamine is another central nervous stimulant, and similar to methylphenidate it is used to treat narcolepsy and attention deficit hyperactivity disorder. Dextroamphetamine is a non-catecholamine and sympathomimetic amine that acts as a stimulant, unfortunately more direct mechanisms of action are not currently known.

One RCT has recently evaluated the effects of dextroamphetamine on general and executive functioning using a variety of outcomes (Hart et al., 2018). Although dextroamphetamine was seen to significantly reduce agitation compared to the placebo group, no significant effects were seen on measures of cognition. Given the use of dextroamphetamine in other attentional disorders such as attention deficit hyperactivity disorder, the lack of results on any cognitive measures between these two studies is unexpected.