6.1.1 Pharmacological Interventions

6.1.1.1  Donepezil

What is the evidence for the use of a cholinesterase inhibitor in treatment of cognitive disorders following TBI?

1.    There is level 1evidence, based on a single RCT, that Donepezil improves attention and short-term memory.

The effectiveness of the cholinesterase inhibitor, Donepezil, for improving cognitive functioning following brain injury was assessed in one study.   Zhang et al. 4conducted a randomized placebo controlled double-blind cross-over trial of 18 post acute TBI patients which demonstrated that donezpil significantly increased scores on tasks of sustained attention and short-term memory when compared to placebo and that these improved results were sustained after the wash-out period.

6.1.1.2  Methylphenidate

What is the evidence for the use of methylphenidate in the treatment of cognitive disorders post TBI?
  1. There is conflicting evidence regarding the effectiveness of the administration of methylphenidate following brain injury for the improvement of cognitive functioning.

Methylphenidate is a stimulant whose exact mechanism is unknown 5, although it is thought to act on the presynaptic nerve and acts to reduce the reuptake of serotonin and norephinephrine 6.  Methylphenidate has been extensively used as a treatment for attention deficit disorder, as well as narcolepsy 7

Four randomized controlled trials examined the efficacy of methylphenidate as a treatment for the recovery of cognitive deficits post- brain injury.  In a RCT examining the effects of methylphenidate, a psychostimulant on attention, Whyte et al. 8indicated that speed of processing, attentiveness during individual work tasks and caregiver ratings of attention were all significantly improved with methylphenidate treatment.  No treatment related improvement was seen in divided or sustained attention or in susceptibility to distraction.  Another RCT by Plenger et al. 9also found that methylphenidate significantly improved attention.  Speech et al. 10conducted a double blind placebo controlled trial evaluating the effects of the stimulant medication methylphenidate following closed head injury.  In contrast to the results noted by Whyte et al. 8and Plenger et al. 9, methylphenidate did not demonstrate significant differences compared to placebo on measures of attention, information processing speed, or learningKim et al. 6examined the effects of a single-dose treatment of methylphenidate and, although a trend was found in favour of improved working and visuospatial memory for the treatment group, these results did not reach significance.

Whyte J, Hart T, Vaccaro M, Grieb-Neff P, Risser A et al. Effects of methylphenidate on attention deficits after traumatic brain injury: A multidimensional, randomized, controlled trial. Brain Injury 2004:83(6):401-420.

  • 34 individuals who had sustained a moderate to severe TBI were selected for participation in the following randomized cross over study.
  • All were given either methylphenidate (.3mg/kg) or placebo twice daily.
  • Study results found methylphenidate had positive effects on speed of information processing (p<0.001) performance speed work task attentiveness (p=0.01), and caregiver ratings of attention (p=0.01). 
  • No treatment-related improvements observed in susceptibility to distraction, and divided or sustained attention.

According to ABIKUS Recommendations 3:

Medication for Arousal and Attention

Methylphenidate (0.25-0.30 mg/kg bid) is recommended in adults to enhance attentional function in the adult population.  Methylphenidate (0.25-0.30 mg/kg bid) is also recommended to enhance the speed of cognitive processing, although only one study provides evidence to support a change in speed in a naturalistic task. (ABIKUS A, adapted from GPT, I, p.1482) (G44-p.23)

6.1.2 Drill and Practice

What evidence is there for drill and practice in the form of structured training programs on attention post ABI?
  1. There is Level 2 evidence to suggest that specific structured training programs designed to improve attention are ineffective or at best equivocal in their effects on attention.

The following studies examined the influence of “drill & practice” exercises (either computerized and/or paper-and-pencil) on attentional functioning.

Novacket al. 11performed an RCT of severe TBI participants in acute rehabilitation and found no difference between two treatment groups “a focused group consisting of sequential, hierarchical interventions directed at specific attention mechanisms and an unstructured intervention consisting of nonsequential, nonhierarchical activities requiring memory or reasoning abilities”.  No differences were found between groups in attentional, functional and/or cognitive skills assessed, although post-intervention improvement of all subjects was demonstrated as compared to pre-intervention. It should be noted that this could reflect spontaneous recovery, as a “no-treatment”, control group was not included. 

Similarly, Parket al. 12examined whether “attention processing training (APT)” had a beneficial effect on attention measures (PASAT, Consonant Trigrams) in a severe TBI group (tested pre and post training approximately 7 months apart).  They compared their results to a “convenience” sample of controls, given the same measures one-week apart without training.  Results suggested that APT did not have a significantly beneficial effect as performance improved on all measures across both groups (indicating practice effects and possibly spontaneous recovery). 

Ponsford and Kinsella 13,using a multiple-baseline-across-subject design, looked at the performance of severe TBI participants and a matched control sample on computerized tests of attention and measures of cognitive functioning following training.  Training consisted of: (1) Phase I: 30 minutes a day for 3 weeks using computer mediated tasks of visual reaction time, visual search and selective attention and (2) Phase II: same as phase I but with feedback and reinforcement provided by the therapist.  Results indicated no effect of training with or without feedback /reinforcement and all participants improved across staggered baseline periods suggesting spontaneous recovery.

Gansler and McCaffry 14using an A-B-A design found no clinically significant effects on attention measures following an 8 week hierarchically ordered attention-remediation program (based on Posner’s 4 component model).

Niemannet al.15examined computer-assisted attention retraining in 26 moderate to severe TBI participants.  They used a multiple baseline pre-test post-test comparison of two groups: attention group (treatment) and a memory group (control).  The authors reported that the results supported attention training (better performance).  However it is unclear whether the effect was a result of practice (e.g., measures were given 11 times) or specific to one particular test.  That is, they did not indicate whether similar results occurred with repeated testing in the control group and whether each of the 6 measures increased at the same or similar rates.

6.1.3 Dual-Task Training

What is the evidence for dual-task training on speed of processing post ABI?

1.    Based on a single RCT there is Level 2 evidence that dual-task training on speed of processing is effective.

The following studies examined the effect of “dual-task” training on speed of processing.

Stablum et al. 16compared two patient groups (those suffering from a closed head injury (CHI) and those who experienced an aneurysm of the anterior communicating artery (ACoA) and matched controls) on performance on a dual-task paradigm and neuropsychological tests.  Results suggested that CHI and ACoA patients had significant difficulty compared to matched controls on dual-task reaction time measure and specific measures of executive functioning (e.g., WCST and PASAT) and compared to their own performance on a single-task reaction time measures (non-significant differences between groups on this latter measure).  With training, however, performance improved to levels similar to matched control subjects and was maintained at follow-up 3 months later.  However, what remains unclear is whether training generalized to functional gains or whether it remained specific to this specific dual-task.

Fasotti et al. 17randomly assigned  22 severe TBI patients undergoing rehabilitation to either Time Pressure Management (TPM) training (treatment group, N=12) or to a concentration group (control, N=10).  Patients were pre-selected for inclusion in this study if they demonstrated slowed processing speed (as measured by 3 tests). TPM consists of a series of cognitive strategies to compensate for reduced processing speed. There are 3 main stages: increased self-awareness of errors and deficits, acceptance and acquisition of TPM cognitive strategies (4 steps), and strategy application and maintenance in increasingly more demanding/distracting situations. The concentration-training group consisted of 4 generic suggestions (e.g., focus, don’t get distracted, etc).  Groups were compared on pre-training, post-training and follow-up on task performance (information from a video recording) and results indicated that there were no significant differences between groups (both improved task performance), although the TPM made more gains and appeared to generalize to positive effects other measures.