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18. Rehabilitation of Learning and Memory Deficits Post Acquired Brain Injury

Marshall S, Harnett A, Welch-West P, Ferri C, Janzen S, Togher L, Teasell R. (2021). Rehabilitation of Learning and Memory Deficits 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: p1-98.

Summary


Intervention Key Point

Level of Evidence

Non-Pharmacological Interventions
Assistive Devices Pager and voice-organizer programs may improve a patient’s ability to complete tasks post TBI.

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

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

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

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

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

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

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

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

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

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

–          There is level 2 evidence that voice organizer programs are effective at improving recall of goals and are found to be effective by post TBI patients.

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

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

External Passive Technology or Non-Technology Aids Calendars may be effective tools for improving memory and task completion post ABI.

–          There is level 2 evidence the use of an electronic calendar is superior to the use of a diary for improving memory in individuals with an ABI.

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

The use of a diary may help to improve memory and task completion post ABI.

–          There is level 2 evidence that the presence of a diary with or without self-instructional training improves memory following an ABI.

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

Virtual Reality Virtual reality programs may enhance the recovery of memory, learning, but there is currently limited evidence supporting the use of virtual reality programs. The evidence is unclear as to which specific programs benefit memory rehabilitation and whether or not they are superior to manual training therapies.

–          There is level 4 evidence that virtual reality (VR) training may improve learning performance post ABI, even in the presence of distractions.

–          There is level 2 evidence that virtual reality training combined with exercise may be promising for improving memory outcomes and has a positive impact on visual and verbal learning when compared to no treatment.

–          There is level 2 evidence that virtual reality training may be superior to reading skills training at improving immediate and general components of memory for those with an ABI.

–          There is level 2 evidence that the format of route learning (either real or virtual reality based) does not significantly impact any improvements in memory as a result of route learning strategies for those with an ABI.

Internal Memory Strategies Internal strategies such as self-imagination, spaced retrieval and rehearsal, and multiple encoding are effective for improving memory following an ABI.

–          There is level 1b evidence to support self-imagination as an effective strategy to improve memory compared to standard rehearsal for those with an ABI.

–          There is Level 2 evidence to support that spaced retrieval training is an effective memory strategy when compared to massed retrieval or rehearsal in ABI populations.

–          There is level 2 evidence that strategies that utilize methods of multiple encoding, compared to strategies which only use singular methods, are more superior for improving memory post ABI.

–          There is level 4 evidence that errorless learning is more effective than errorful learning when it comes to improving memory in ABI populations.

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

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

–          There is level 1b evidence that the Categorization Program, and Strategic Memory and Reasoning Training (SMART) may be effective for improving memory compared to standard therapy in individuals with an ABI.

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

–          There is level 4 evidence that Cognitive Pragmatic Treatment, Cogmed QM, and RehaCom software may improve memory and cognitive function in those with an ABI.

–          There is level 2 evidence that N-back training compared to virtual search training is not effective for improving memory in those with an ABI.

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

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

Attention training programs may not be effective for improving memory, but memory training programs are.

Interventions which include multiple learning techniques such as modelling, observation, verbal instruction, etc. are more effective than interventions which include a singular learning method.

–          There is level 2 evidence that programs involving multiple learning strategies (such as modelling, reciting, verbal instruction, and observation) are more effective than singular strategies for those with an ABI.

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

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

Pharmacological Interventions
Donepezil Donepezil likely improves memory following TBI.

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

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

Methylphenidate Methylphenidate likely does not improve memory or learning following an ABI.

–          There is level 1b evidence that methylphenidate compared to placebo is not effective for improving memory following brain injury for post TBI patients.

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

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

Amantadine Amantadine is not effective for improving learning and memory deficits post ABI.

–          There is level 1b evidence that amantadine does not improve learning and memory deficits in patients post ABI.

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

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

Physostigmine Physostigmine mayimprove long-term memory in menwith TBI; however, more studies are required.

–          There is level 1b evidence that oral physostigmine may improve long-term memory compared to placebo in men with TBI, however more recent studies are required.

Bromocriptine More studies are required to determine if the positive effects of bromocriptine on verbal memory seen so far of potential value.

–          There is level 2 evidence that bromocriptine may improve verbal memory in individuals with an ABI, however, more studies are required.

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

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

Growth Hormone Replacement Therapy The administration of growth hormone complexes likely does not improve learning and memory following an ABI.

–          There is level 1b evidence that recombinant human Growth Hormone (rhGH) is similar to placebo for improving memory and learning in patients post TBI.

–          There is level 2 evidence that growth hormone (GH) therapy is similar to placebo at improving memory ability in patients post TBI.

Rivastigmine Rivastigmine is not effective in treating memory deficits post ABI.

–          There is level 1a evidence that rivastigmine is not effective when compared to placebo for improving memory in ABI populations.

Huperzine A Huperzine A may not improve memory following TBI.

–          There is level 1b evidence that Huperzine A may not improve memory following TBI when compared to a placebo.

Hyperbaric Oxygen Therapy Hyperbaric oxygen therapy may be promising for improving memory following an ABI; however, more controlled studies are required.

–          There is level 4 evidence that hyperbaric oxygen therapy may improve memory following an ABI.

Introduction

Memory impairment is one of the most common symptoms following brain injury and it is estimated that time and cost of care would be reduced if effective treatments were found to improve memory (Walker et al., 1991). When evaluating intervention strategies to improve memory performance following brain injury, the literature indicates that there are two main approaches to rehabilitation: restoration/retraining of memory, and compensation of deficits. Compensation includes “training strategies or techniques that aim to circumvent any difficulty that arises as a result of the memory impairment.” (McLean et al., 1991). Compensatory techniques include internal aids, which are “mnemonic strategies that restructure information that is to be learned.” (McLean et al., 1991). Conversely, interventions for remediation of memory deficits range from assistive technology to visual imagery. Cappa and colleagues (2005) reviewed various strategies used to improve memory deficits without the use of electronic devices, external aids were judged to be “possibly effective.”, while specific learning strategies (e.g. errorless learning) were found to be “probably effective” depending upon the task used, the type of memory involved and the severity of the impairment. Several studies were identified examining interventions to improve learning and memory following ABI.

Non-Pharmacological Interventions for Learning and Memory

Assistive Devices

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

Cranial Electrotherapy Stimulation

Key Points

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

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

Discussion

Three randomized controlled trials have studied cranial electrotherapy stimulation and its effect on post-traumatic memory impairment in clinical care patients with brain injury (Michals et al., 1993) (Lesniak et al., 2014; Jacqueline A. Rushby et al., 2020). Although the areas of application and current strength varied between studies, none exhibited improvements in memory performance. These results suggest that CES stimulation in brain-injured patients does not improve memory functioning.

Conclusions

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

External Technology Aids

Key Points

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

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

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

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

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

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

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

Discussion

Many studies have been conducted examining the effectiveness of various active reminders used for those with memory impairment. With advances in technology, more sophisticated organizers integrating these tools into personal digital assistants (PDAs) and smartphones have been studied. Patients accustomed to using memory aids were more likely to make use of computerized organizers (Wright et al., 2001b). Dowds et al. (2011) found that two different PDAs improved task completion rates compared to a paper-based schedule book, while Lannin et al. (2014) found that the use of a PDA in addition to conventional occupational therapy significantly reduced memory failures and forgetting. Multiple other studies have also found positive effects for the use of PDAs on memory (De Joode et al., 2013; Gentry et al., 2008; Powell et al., 2012; Waldron et al., 2012). However, the variety of available electronic organizers and learning curve for use prevent clear conclusions across studies. An RCT by Powell et al. (2012) demonstrated the importance of systematic instruction, as they compared direct instructions to conventional, trial and error patient learning on a PDA. Those receiving systematic instruction were superior in the number and speed of correct PDA tasks compared to conventional trial and error learning group. No differences were found between groups based on PDA input (physical vs touch-screen keyboard), provided the three core memory aid components of appointment diary, notebook, and to-do list were maintained (Wright et al., 2001a).

Smartphones represent a relatively new area of accessible technology and provide the user with many benefits. Smartphones are already designed to send notifications about their use, as well as multiple companies design apps for each phone brand interface allowing individuals to keep their current devices and still access helpful applications. The most common advantages to smartphones are reminders/alarms and ability to combine a calendar, tasks list, contacts, mail, and phone on one device. Disadvantages include the loss of battery life and risk of dependency on the assistive device; however, these are minor inconveniences in comparison to the reported improvement in memory in some patients (Evald, 2015). The increasing availability of smartphones also creates the ability to enhance current therapies with text messages. A case series by Fish et al. (2007) demonstrated that participants could be trained to associate a text message with stopping and thinking about what needed to be done, with participants more likely to remember the instruction to call the investigators when texted the message “STOP”. On measures such as the Prospective and Retrospective Memory Questionnaire, the use of smartphones was shown to significantly reduce the number of self-reported errors (Evald, 2018). Gracey et al. (2017) also found that goal management training could be supplemented with text messages for improving achievement of everyday intentions, with individuals who received text prompt more likely to succeed in their goals compared to those not receiving prompts. This effect was not observable once the texts had stopped to both groups.

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

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

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

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

Conclusions

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

There is level 2 evidence that voice organizer programs are effective at improving recall of goals and are found to be effective by post TBI patients.

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

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

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

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

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

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

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

External Passive Technology or Non-Technology Aids

Key Points

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

The use of a diary may help to improve memory and task completion post ABI.

Passive devices are those that do not require specific electronic programming for their use such as paper calendars, notebooks, and planners. A variety of studies have examined the effects of these standard tools on learning and memory; however, the amount of studies has been quickly outpaced by studies examining technology as it becomes more readily available.

Discussion

Multiple RCTs have examined the use of calendars and calendar tools on learning and memory (Bergquist et al., 2009; McDonald et al., 2011; Ownsworth & McFarland, 1999; Schmitter-Edgecombe et al., 1995; Watanabe et al., 1998). In one RCT by McDonald et al. (2011), the use of a Google calendar was compared to the use of diary tracking. It was found that although both groups achieved a fair number of desired tasks, those using the Google calendar had a significant increase in task completion through the use of automated reminders and messages. A second RCT also compared the use of a calendar to diary use (Bergquist et al., 2009). However, in this instance no significant between-group differences were found with both reporting positive results on memory. In another RCT (Ownsworth & McFarland, 1999), diary use was examined alone as well as with the combination of self-instructional training. On self-reported memory scales, all subjects reported improvements in memory, as well as significant increases in the degree of memory strategies used regardless of diary training. There were no significant differences between groups on memory performance however (Ownsworth & McFarland, 1999). Comparing the use of a memory tool (notebook) to generalized supportive therapy, the use of a notebook specifically was shown to result in a greater reduction in memory failures (Schmitter-Edgecombe et al., 1995); however, this effect was lost at 6-month follow-up. Lastly, Watanabe et al. (1998), found no significant effects of calendar use on a test of orientation, compared to no calendar use when individuals were still inpatients.

Conclusions

There is level 2 evidence the use of an electronic calendar is superior to the use of a diary for improving memory in individuals with an ABI.

There is level 2 evidence that the presence of a diary with or without self-instructional training improves memory following an ABI.

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

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

Virtual Reality

Key Points

Virtual reality programs may enhance the recovery of memory, learning, but there is currently limited evidence supporting the use of virtual reality programs. The evidence is unclear as to which specific programs benefit memory rehabilitation and whether or not they are superior to manual training therapies.

Virtual reality (VR) allows individuals to interact with and experience a virtual environment in three-dimensions, realistically simulating different situations/environments/tasks through immersive (head-mounted display) or non-immersive (computer monitor or projector screen) multimedia (Sisto et al., 2002). VR systems are constantly evolving, providing a safe and motivating environment for practicing real life scenarios (Shin & Kim, 2015). A systematic review by Shin and Kim (2015) found that VR may be an effective cognitive therapy, though the limited low quality evidence has prevented strong conclusions. On observational study by Canty et al. (2014) demonstrated that VR might also be potentially helpful as an assessment tool. Individuals with a brain injury performed more poorly on a series of VR tasks compared to healthy controls (Canty et al., 2014).

Discussion

A 2013 RCT found that those who received virtual reality memory training showed a significant improvement in immediate recall of tasks and event-based performance (Yip & Man, 2013). Although the control group saw no improvements on items of memory evaluation there were no significant differences between groups on measures of community integration (Yip & Man, 2013). Sorita et al. (2013) found that practicing a route-learning task in a real urban environment or in a virtual stimulation of that environment showed similar improvements in route recall, suggesting that VR training improvements in functional tasks may be due to repetition and not the presented medium. Dahdah et al. (2017) also found that multiple Stroop tasks in VR environments resulted in improved performance on parts of those tasks. Virtual reality has been found to improve more than just memory as well, in an older RCT by Grealy et al. (1999), not only did individuals receiving VR exercise significantly improve on visual learning abilities, they also improved on reaction time.

Conclusions

There is level 4 evidence that virtual reality (VR) training may improve learning performance post ABI, even in the presence of distractions.

There is level 2 evidence that virtual reality training combined with exercise may be promising for improving memory outcomes and has a positive impact on visual and verbal learning when compared to no treatment.

There is level 2 evidence that virtual reality training may be superior to reading skills training at improving immediate and general components of memory for those with an ABI.

There is level 2 evidence that the format of route learning (either real or virtual reality based) does not significantly impact any improvements in memory as a result of route learning strategies for those with an ABI.

Internal Memory Strategies

Key Points

Internal strategies such as self-imagination, spaced retrieval and rehearsal, and multiple encoding are effective for improving memory following an ABI.

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

Discussion

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; Raskin et al., 2019; Sumowski et al., 2010), and immediate recall (Hillary et al., 2003; Raskin et al., 2019). 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).

Conclusions

There is level 1b evidence to support self-imagination as an effective strategy to improve memory compared to standard rehearsal for those with an ABI.

There is Level 2 evidence to support that spaced retrieval training is an effective memory strategy when compared to massed retrieval or rehearsal in ABI populations.

There is level 2 evidence that strategies that utilize methods of multiple encoding, compared to strategies which only use singular methods, are more superior for improving memory post ABI.

There is level 4 evidence that errorless learning is more effective than errorful learning when it comes to improving memory in ABI populations.

Learning and Memory Training Programs

Key Points

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

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

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

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

Attention training programs may not be effective for improving memory, but memory training programs are.

Interventions which include multiple learning techniques such as modelling, observation, verbal instruction, etc. are more effective than interventions which include a singular learning method.

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).

Discussion

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 two studies (Fernández et al., 2012; Leśniak et al., 2019). Fernandez et al. (2012) found that Individuals significantly improved on the Wechler Memory Scale for overall memory and also on measures of attention (Fernández et al., 2012). Although Lesniak et al. (2019) found improvements in memory, the results did not persist past follow-up. 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. In contrast, Das Nair et al. (2019) examined the effects of a 10-hour group memory rehabilitation program versus usual care and found no significant improvements in memory. Additionally, the authors performed a health economic analysis, which found the intervention was unlikely to be cost effective.

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., 2018). 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., 2018).

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 (Meike Holleman et al., 2018). 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., 2018).

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)

Conclusions

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

There is level 1b evidence that individual memory therapy is no more effective than group memory therapy for those with an ABI.

There is level 2 evidence that programs involving multiple learning strategies (such as modelling, reciting, verbal instruction, and observation) are more effective than singular strategies for those with an ABI.

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

There is level 1b evidence that the Categorization Program, and Strategic Memory and Reasoning Training (SMART) may be effective for improving memory compared to standard therapy in individuals with an ABI.

There is level 2 evidence that time pressure management training is no more effective than concentration training at improving memory for those with an ABI.

There is level 2 evidence that N-back training compared to virtual search training is not effective for improving memory in those with an ABI.

There is level 4 evidence that Cognitive Pragmatic Treatment, Cogmed QM, and RehaCom software may improve memory and cognitive function in those with an ABI.

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

There is level 2 evidence that finger sequence training, compared to no training, may not be effective for improving memory following an ABI.

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

There is level 2 evidence that general memory rehabilitation programs are effective, compared to standard therapy, at improving memory for those with an ABI.

There is level 2 evidence that the Intensive Neurorehabilitation Programme is not effective for improving memory compared to controls in those with an ABI.

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

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

There is level 2 evidence that non-specific computer-based memory retraining compared, self-paced or otherwise, may not be effective at improving memory in those with an ABI.

There is conflicting level 1b evidence as to whether or not attention training programs may be effective for improving memory compared to no therapy, but positive level 1b evidence that it is not more effective than memory training programs.

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

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

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

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

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

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

Pharmacological Interventions for Learning and Memory

Amantadine

Key Points

Amantadine is not effective for improving learning and memory deficits post ABI.

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 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.

Conclusions

 There is level 1b evidence that amantadine does not improve learning and memory deficits in patients post ABI.

Bromocriptine

Key Points

More studies are required to determine if the positive effects of bromocriptine on verbal memory seen so far of potential value.

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.

Discussion

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. Spontaneous recovery may have been a factor leading to the improved abilities in individuals receiving a single dose (2.5 mg daily) of the medication; however, study results did not answer this question. Powell et al. (1996) conducted a multiple baseline design on 11 patients with TBI or subarachnoid hemorrhage who received bromocriptine. Improvements were found on all measures assessed (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.

Conclusions

There is level 2 evidence that bromocriptine may improve verbal memory in individuals with an ABI, however, more studies are required

Cerebrolysin

Key Points

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

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)

Discussion

In an open-label trial of 20 patients with TBI Alvarez et al. (2003) found that cerebrolysin was associated with improved brain bioelectrical activity, as evidenced by a significant increase in fast beta frequencies. A brief neuropsychological battery (Syndrome Kurztest 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.

Conclusions

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

Donepezil

Key Points

Donepezil likely improves memory following TBI.

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

Discussion

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

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

Conclusions

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

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

Growth Hormone Replacement Therapy

Key Points

The administration of growth hormone complexes likely does not improve learning and memory following an ABI.

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.

Discussion

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.

Conclusions

There is level 1b evidence that recombinant human Growth Hormone (rhGH) is similar to placebo for improving memory and learning in patients post TBI.

There is level 2 evidence that growth hormone (GH) therapy is similar to placebo at improving memory ability in patients post TBI.

Huperzine A

Key Points

Huperzine A may not improve memory following TBI.

Huperzine A is a cholinesterase inhibitor derived from Huperzia serrata, a herb commonly referred to as club moss (Zafonte et al., 2020). It has exhibited neuroprotective effects in several models and is a non-competitive antagonist of N-methyl-D-aspartate (MDA) receptor (Zafonte et al., 2020).

Discussion

One randomized controlled trial examined the effects of Huperzine A on memory and learning in individuals with moderate-severe TBI. Huperzine A has been hypothesized to exert its neuroprotective effects through the modulation of primary and secondary injury mechanisms that occur in the acute and chronic phases of brain injury. Although promising in animal studies, this study was the first to examine the effects of Huperzine A on memory in humans. Participants received Huperzine A or a placebo for 12 weeks and were evaluated on several occasions and outcome measures. Despite promising evidence in animal trials, Zafonte et al. (2020) did not find any significant improvements in memory between groups. Although the results of this study found that Huperzine A was not effective, further research is necessary to draw any conclusions.

Conclusions

There is level 1b evidence that Huperzine A may not improve memory following TBI when compared to a placebo.

Hyperbaric Oxygen Therapy

Key Points

Hyperbaric oxygen therapy may be promising for improving memory following an ABI; however, more controlled studies are required.

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 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.

Conclusions

There is level 4 evidence that hyperbaric oxygen therapy may improve memory following an ABI

Methylphenidate

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 five RCTs examined the efficacy of methylphenidate as a treatment for the recovery of cognitive deficits post ABI.

Discussion

Dymowski et al. (2017) investigated the effects of short-term, 7-week, methylphenidate administration (0.6 mg/kg/d) in post TBI patients compared to a placebo (control). After analysis, it was concluded that there was no significant improvement, or difference between groups for various measures and tests of attention. More than 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.

Physostigmine

Key Points

Physostigmine may improve long-term memory in men with TBI; however, more studies are required.

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

Discussion

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

Conclusions

There is level 1b evidence that oral physostigmine may improve long-term memory compared to placebo in men with TBI, however more recent studies are required.

Pramiracetam

Key Points

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

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

Discussion

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

Conclusions

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

Rivastigmine

Key Points

Rivastigmine is not effective in treating memory deficits 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). 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.

Conclusions

There is level 1a evidence that rivastigmine is not effective when compared to placebo for improving memory in ABI populations.

Sertraline

Key Points

Sertraline has not been shown to improve learning, or memory ewithin 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). 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).

Discussion

The effect of early administration of sertraline on cognitive functioning, intelligence and memory was evaluated by Banos et al. (2010) in an RCT. When comparing the sertraline group, who received 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 may not improve memory compared to placebo in individuals who have sustained a moderate to severe TBI.

Conclusion

The rehabilitation of learning & memory is complicated by cross-study variability in treatment duration (e.g. from 30 minutes once a day for 5 days to 5 hours, every day for 6 weeks). Severity of injury and time since injury may also fluctuate from study to study. Over the past several years, Cicerone et al. (2000; 2005; 2011) reviewed a series of studies investigating the effectiveness of attentional retraining interventions during rehabilitation following traumatic brain injury and stroke. Not all patients respond equally to all intervention strategies and only a limited number of studies in the current review indicated whether severity of injury was related to the efficacy of a given intervention.

Technology has increased the availability of external aids, although some seem more feasible to use than others (e.g., cell phones or hand-held recorders). Unfortunately, the studies reviewed did not specify the length of time subjects required to master compensatory strategies or the nature of the long-term effects. Generally, if these electronic appliances are used before the injury, they are more likely to be used post-injury as well. It was unclear from the studies if any of the participants had previous knowledge of these tools.

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

Frequency of intervention has an impact on learning and retention, although the exact parameters of this are unclear at the present time. The optimal duration of a program is also open for speculation. No studies reviewed examined the number of sessions required for memory groups to be effective and only one study evaluated a difference in effectiveness between mild and severely impaired individuals after sessions.

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