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19. Rehabilitation of Problem Solving, Executive & General Cognitive Functioning Post Acquired Brain Injury

Marshall S, Harnett A, Welch-West P, Ferri C, Janzen S, Togher L, Teasell R. (2021). Rehabilitation of Problem Solving, Executive and General Cognitive Functioning Post Acquired Brain Injury. In Teasell R, Cullen N, Marshall S, Bayley M, Harnett A editors. Evidence-Based Review of Moderate to Severe Acquired Brain Injury. Version 14.0: p1-65.

Summary


Intervention Key Point

Level of Evidence

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

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

Attention training programs likely do not improve executive functioning.

–          There is level 1b evidence that an attention remediation intervention may not be superior to TBI education alone and improving executive function in patients post TBI.

–          There is level 2 evidence that dual-task training may improve not general cognitive functioning compared to a non-specific cognitive program in patients post TBI.

General cognitive training programs which include problem-solving appear to be effective for improving executive functioning following an ABI.

–          There is level 1b evidence that a comprehensive cognitive treatment strategy program (which include problem solving), compared to controls, are effective for improving metacognition 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 level 1b evidence that the specific cognitive training program ProSolv, compared to standard therapy, does not improve measures of executive functioning following an ABI.

–          There is level 2 evidence that the Intensive NeuroRehabilitation programme, compared to no treatment, does not improve executive functioning following an ABI. 

Virtual reality does not likely improve executive functioning following an ABI.

–          There is level 1b evidence that virtual-reality training is not superior to conventional cognitive training at improving cognitive and executive function outcomes post TBI.

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.

–          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.

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

–          There is level 2 evidence that goal management training may be superior (compared to motor skills training or no treatment controls) for improving goal attainment or measures of intelligence following an ABI.

Heart rate variability biofeedback may improve executive functions; however, more controlled studies are required to make further conclusions.

–          There is level 4 evidence that heart rate biofeedback may improve executive functioning following an ABI, although higher level studies are required to fully determine this.

Group-based Interventions Group goal-oriented interventions are effective for the remediation of executive functions, including comprehension and problem solving.

–          There is level 1b evidence that goal orientated group interventions are successful at improving cognitive and executive function in patients post ABI.

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.

–          There is level 1b evidence that emotional regulation group interventions are effective at improving executive function in post TBI patients compared to standard therapy.

The SMART program appears to be effective for improving executive functioning following an ABI.

–          There is level 1b evidence that the Strategic Memory and Reasoning Training program is more effective than a brain health workshop for improving executive function, metacognition, and comprehension following ABI.

Touch screen-based games which include components of metacognition may be effective for improving self-awareness.

–          There is level 4 evidence that touch screen-based games (which include components of reasoning and problem-solving) may be effective for improving self-awareness and social skills following an ABI.

Metacognitive instruction does not appear to improve comprehension or abstract reasoning; however, more studies are needed to fully evaluate its effects.

–          There is level 4 evidence that metacognitive strategy instruction may not be effective for improving executive functioning following an ABI.

General cognitive rehabilitation programs are effective for improving cognitive functioning following an ABI.

–          There is level 1b evidence that cognitive therapies compared to standard therapy are more effective than no therapy for improving generalized cognitive functioning, as well as self-perception following an ABI

–          There is level 1b evidence that cognitive therapies compared to standard therapy are more effective than no therapy for improving generalized cognitive functioning, as well as self-perception following an ABI.

–          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 2 evidence that the Trabajadora de Salud program may improve general cognitive functioning compared to standard therapy for those with an ABI.

There is limited evidence that mindfulness-based stress reduction is effective for improving cognitive functioning.

–          There is level 4 evidence that mindfulness-based stress reduction may be effective for improving general cognitive functioning and psychological health for those with an ABI.

Corrective video feedback is more effective than verbal feedback alone for improving general cognitive function and self-awareness.

–          There is level 1b evidence that corrective video feedback is more effective for improving generalized cognitive functioning and self awareness compared to verbal feedback only in those with an ABI.

Remedial and adaptive occupational therapy are equally effective for improving general cognitive functioning.

–          There is level 1b evidence that remedial occupational therapy and adaptive occupational therapy may have equal effects on generalized cognitive function in those with an ABI.

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

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

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

–          There is conflicting (level 1a) evidence regarding the effectiveness of the administration of methylphenidate, compared to placebo, following TBI for the improvement of general and executive functioning.

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

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

Amantadine Amantadine is not effective for improving generalized cognition. Its impact o executive functioning should be studied further.

–          There is level 1b evidence that Amantadine may not help to improve general functioning deficits in post TBI patients compared to placebo.

Bromocriptine Bromocriptine may improve other measures of cognition such as attention, but its effects on generalized cognition are conflicting. More research is required.

–          There is conflicting level 2 (against) and level 4 (for) evidence as to whether or not bromocriptine may improve executive or general cognitive functioning following ABI.

Growth Hormone Replacement Therapy The administration of human growth hormones appears to have positive (although sometimes limited effects) on general and executive functioning in those with an ABI.

–          There is level 1b evidence that recombinant human Growth Hormone (rhGH) is superior 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 effective for 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.

Rivastigmine Rivastigmine is not effective in treating general or executive dysfunction post ABI.

–          There is level 1b evidence that rivastigmine is not effective for improving general or executive cognitive functioning, compared to placebo, following an ABI.

Hyperbaric Oxygen Therapy Hyperbaric oxygen therapy may be beneficial for improving general and executive functioning following an ABI; however, more research is needed.

–          There is level 4 evidence that hyperbaric oxygen therapy may improve general and executive functioning following an ABI.

Dextroamphetamine There is moderate evidence to suggest that dextroamphetamine is not effective for the remediation of general functioning.

–          There is level 1b evidence that dextroamphetamine is not effective for the remediation of general cognitive functioning following an ABI.

Introduction

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 which in contrast to typically unilateral insults following vascular injury. Direct contusion to the frontal and temporal lobes can occur 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 examining executive functioning and problem-solving (Table 6.13). Only three of the identified studies included a control group and were classified as a randomized controlled trial or non-randomized cohort study.

In later reviews by Cicerone et al. (2005; 2011) 9 and 18 additional studies, respectively, 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 years) 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).

Non-Pharmacological Interventions for Problem Solving, Executive & General Cognitive Functioning

Rehabilitation 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. It is vital to evaluate interventions for executive functioning as 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.

Individual Interventions

Key Points

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

Attention training programs likely do not improve executive functioning.

General cognitive training programs which include problem-solving appear to be effective for improving executive functioning following an ABI.

Virtual reality does not likely improve executive functioning following an ABI.

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 be superior to motor skills training at improving everyday skills (meal preparation), but not intelligence or neuropsychological outcomes in patients post TBI.

Heart rate variability biofeedback may improve executive functions; however, more controlled studies are required to make further conclusions.

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.

Discussion

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 investigated (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. With respect to attention process training, it was shown that this intervention may have indirectly improved executive function as individuals with higher vigilance achieved higher executive function scores, but it was not explicitly demonstrated that training resulted in increased vigilance (Sohlberg et al., 2000).

Siponkoski et al. (2020) investigated the effects of 20 sessions of music therapy (rhythmical training, structured cognitive-motor training and assisted music playing) on measures of executive function. Compared to the control group, significant improvements on measures of executive function were observed for those receiving music therapy.

Dual-task training which is also used as a form of attention training was also evaluated in another RCT and although individuals were improved on measures of attention to a significantly greater extent than controls, no such relationship was found for measures of executive function (Couillet et al., 2010).

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 for 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; however, there were no significant between-group differences for cognitive or vocational outcomes except on WCST % errors and % conceptual level response (Man et al., 2013). Conversely, 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. In a pre-post study, Dadah et al. (2017) 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, showed mixed results for improving executive function post ABI (O’Neil-Pirozzi & Hsu, 2016). Although individuals self-reported improvements in daily functioning, no significant results were seen on objective measures (O’Neil 2016). 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 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 reported 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 on any measures related to executive function (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.

In an 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 and 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) and Freeman et al. (1992), where cognitive rehabilitation therapy was found to increase productivity and everyday functioning. This older study (Laatsch et al., 1999) also had the benefit of reporting SPECT imaging results, which revealed increases in cerebral blood flow during the intervention. It should be noted that one study has found mixed results on measures of executive functioning after administering a cognitive training program, with individuals improving on some measures of executive functioning, such as metacognition, but not others (Fong & Howie, 2009). It should be noted that none of the above studies were completed by the same groups or had overlapping methodology and although the results suggest cognitive training programs are effective for improving executive functioning following an ABI, programs themselves should be considered unique.

A specific cognitive program (Categorization Program) was evaluated in an RCT by Constantinidou et al. (2008). The authors found that after 13 weeks of therapy (mean 4.5 hr/day), individuals significantly improved on measures of executive functioning such as object recognition. Although the Categorization Program treatment group and standard therapy therapy group showed improvement on the community reintegration questionnaire and adaptability measures, there were greater executive function gains in the treatment group (Constantinidou et al., 2008). The Intensive NeuroRehabilitation Programme investigated by Holleman et al. (2018) resulted in significantly reduced depression and anxiety compared to the control group but did not improve measures of executive functioning. Similarly, a novel program – Cognitive Applications for Life Management, did not find significant improvements in measure of executive functioning (Elbogen et al., 2019). Although the program did improve measures of emotion and behavioural regulation (Elbogen et al., 2019).

Another unique study used heart rate variability biofeedback in an attempt to increase awareness and cognitive control (Kim et al., 2018). In this study it was noted that individuals who underwent heart rate biofeedback significantly improved scores of executive functioning on the Category Test. However, this study consisted of a pre-post design and lacked a control group for comparison, and as such results should be interpreted with caution. Only one study evaluated the effects of repetitive transcranial magnetic stimulation on executive function; however, no significant improvements were observed between groups (Neville et al., 2019).

Levine et al. (2000) completed an RCT comparing a group of patients using goal management training strategies to a control group who were received 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. Two other studies evaluated goal management training and did not find any significant results suggesting that goal management training improves executive functioning following an ABI (Cizman Staba et al., 2020; Levack et al., 2009). A single older study reported positive affects of a goal setting program in its ability to help an individual achieve goals (Webb & Glueckauf, 1994). The execution of goals themselves requires executive functioning; however, no objective measures of executive function were directly evaluated in this study.

Conclusions

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

There is level 1b evidence that an attention remediation intervention may not be superior to TBI education alone and improving executive function in patients post TBI.

There is level 2 evidence that dual-task training may improve not 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 program (which include problem solving), compared to controls, are effective for improving metacognition 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 level 1b evidence that virtual-reality training is not superior to conventional cognitive training at improving cognitive and executive function outcomes post TBI.

There is level 1b evidence that the specific cognitive training program ProSolv, compared to standard therapy, does not improve measures of executive functioning following an ABI.

There is level 2 evidence that the Intensive NeuroRehabilitation programme, compared to no treatment, does not improve executive functioning following an ABI. 

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 4 evidence that heart rate biofeedback may improve executive functioning following an ABI, although higher level studies are required to fully determine this.

There is level 2 evidence that goal management training may be superior (compared to motor skills training or no treatment controls) for improving goal attainment or measures of intelligence following an ABI.

Group-based Interventions

Key Points

Group goal-oriented interventions are effective for the remediation of executive functions, including comprehension and problem solving.

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.

The SMART program appears to be effective for improving executive functioning following an ABI.

Touch screen-based games which include components of metacognition may be effective for improving self-awareness.

Metacognitive instruction does not appear to improve comprehension or abstract reasoning; however, more studies are needed to fully evaluate its effects.

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.

Discussion

Several studies have evaluated the effects of group goal management training. One study has compared the effect of group Goal Management Training (TG) to a group Brain Health workshop (CG) 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 at 6-month 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. In a five-year follow-up to this study, Tornas et al. (2019) examined the long-term benefits to goal management training, and found no significant difference between groups on measures of executive function. Similar results of goal management training were found in an RCT by Novakovic-Agopian et al. (2011), where a goals training group showed significant improvement on attention and executive 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 also demonstrated that goal training is beneficial for executive functions (Chen et al., 2011). In this study both groups significantly improved in attention directed goal completion. A final RCT evaluated group goal attainment interventions compared to educational interventions (Ownsworth et al., 2008). This study found that all individuals who received goal attainment interventions significantly improved over time on measures of executive functioning, regardless of group assignment at 3-month follow-up based on self-ratings, and relative’s ratings (Ownsworth et al., 2008).

Emotional regulation was also examined as a potential intervention for the remediation of attention and executive dysfunction post ABI (Cantor et al., 2014; Rath et al., 2003). While this treatment was not found to be effective in the recovery of attention, significant improvements on executive function were noted (EF, FeSBe, PSI) (Cantor et al., 2014). 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 on problem-solving measures; 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 observed 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. Specifically, the ABaCo was used to measure linguistic comprehension and context comprehension.

In addition to its use as a memory intervention the Strategic Memory and Reasoning Training (SMART) program is also an effective intervention for executive functioning. Vas et al. (2001) compared its use to that of a brain health workshop. The SMART group had significantly higher scores on the Test of Strategic Learning, and Wechsler Adult Intelligence Scale III for sections examining inhibition, non-verbal reasoning, and cognitive flexibility, demonstrating an overall improvement in metacognition and comprehension.

Only one study using a technology-based intervention met our inclusion criteria. Llorens et al. (2012) used an interactive touch screen game in an attempt to improve social skills and self-awareness following ABI. Although no formal statistical analysis took place, at the end of the treatment period all participants had an accurate perception of their deficits (compared to 4/10 at baseline), and six of ten participants showed alterations in their social skills (Llorens et al., 2012).

Parente and Stapleton (1999) 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 level 1b evidence that goal orientated group interventions are successful at improving cognitive and executive function in patients post ABI.

There is level 1b evidence that emotional regulation group interventions are effective at improving executive function in post TBI patients compared to standard therapy.

There is level 1b evidence that the Strategic Memory and Reasoning Training program is more effective than a brain health workshop for improving executive function, metacognition, and comprehension following ABI.

There is level 4 evidence that metacognitive strategy instruction may not be effective for improving executive functioning following an ABI.

There is level 4 evidence that touch screen-based games (which include components of reasoning and problem-solving) may be effective for improving self-awareness and social skills following an ABI.

Rehabilitation of General Cognitive Functioning

Key Points

General cognitive rehabilitation programs are effective for improving cognitive functioning following an ABI.

There is limited evidence that mindfulness-based stress reduction is effective for improving cognitive functioning.

Corrective video feedback is more effective than verbal feedback alone for improving general cognitive function and self-awareness.

Remedial and adaptive occupational therapy are equally effective for improving general cognitive functioning.

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 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., 2008; Sohlberg et al., 2003b). Studies included in this section have examined the effects of cognitive rehabilitation strategies.

Discussion

Seven studies investigating the remediation of general cognitive functioning were found meeting our inclusion criteria. 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.

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.

Conclusions

There is level 1b evidence that cognitive therapies compared to standard therapy are more effective than no therapy for improving generalized cognitive functioning, as well as self-perception following an ABI.

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 2 evidence that the Trabajadora de Salud program may improve general cognitive functioning compared to standard therapy for those with an ABI.

There is level 1b evidence that corrective video feedback is more effective for improving generalized cognitive functioning and self awareness compared to verbal feedback only in those with an ABI.

There is level 1b evidence that remedial occupational therapy and adaptive occupational therapy may have equal effects on generalized cognitive function in those with an ABI.

There is level 4 evidence that mindfulness-based stress reduction may be effective for improving general cognitive functioning and psychological health for those with an ABI.

Pharmacological Interventions for Problem Solving, Executive & General Cognitive Functioning

Amantadine

Key Points

Amantadine is not effective for improving generalized cognition. Its impact o 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 (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.

Discussion

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.

Conclusions

There is level 1b evidence that Amantadine may not help to improve general functioning deficits in post TBI patients compared to placebo.

Bromocriptine

Key Points

Bromocriptine may improve other measures of cognition such as attention, but its effects on generalized cognition are conflicting. More research is 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 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.

Conclusions

There is conflicting level 2 (against) and level 4 (for) evidence as to whether or not bromocriptine may improve executive or general cognitive functioning following ABI.

Dextroamphetamine

Key Points

There is moderate evidence to suggest that dextroamphetamine is not effective for the remediation of general functioning.

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.

Discussion

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.

Conclusions

There is level 1b evidence that dextroamphetamine is not effective for the remediation of general cognitive functioning following an ABI.

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.

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.

Growth Hormone Replacement Therapy

Key Points

The administration of human growth hormones appears to have positive (although sometimes limited effects) on general and executive functioning in those with an ABI.

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.

Discussion

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.

Conclusions

There is level 1b evidence that recombinant human Growth Hormone (rhGH) is superior 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 effective for 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.

Hyperbaric Oxygen Therapy

Key Points

Hyperbaric oxygen therapy may be beneficial for improving general and executive functioning following an ABI; however, more research is needed.

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).

Discussion

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.

Conclusions

There is level 4 evidence that hyperbaric oxygen therapy may improve general and executive functioning following an ABI.

Methylphenidate

Key Points

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

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.

Discussion

Dymowski et al. (2017) investigated the effects of short-term, 7-week, methylphenidate administration in post TBI patients compared 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. This is similar to the findings of Al-Adawi et al. (2020), where they found short term use of methylphenidate significantly improved measures of executive functioning. The controversy 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.

Conclusions

There is conflicting (level 1a) evidence regarding the effectiveness of the administration of methylphenidate, compared to placebo, following TBI for the improvement of general and executive functioning.

Rivastigmine

Key Points

Rivastigmine is not effective in treating general or executive dysfunction post ABI.

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.

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). 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.

Conclusions

There is level 1b evidence that rivastigmine is not effective for improving general or executive cognitive functioning, compared to placebo, following an ABI.

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). The study 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, compared to placebo, in individuals who have sustained a moderate to severe TBI.

Conclusion

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 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.

Frequency of intervention has an impact on general and executive cognitive functioning, 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 to be effective and only one study evaluated a difference in effectiveness between mild and severely impaired individuals after sessions.

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