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Cholinergic Augmentation With Donepezil Enhances Recovery in Short-Term Memory and Sustained Attention After Traumatic Brain Injury
Lei Zhang, MD, PhD, Rosette C. Plotkin, PhD, Gary Wang, MD, PhD, M. Elizabeth Sandel, MD, Shuko Lee, MS
ABSTRACT. Zhang L, Plotkin RC, Wang G, Sandel ME, Lee S. Cholinergic augmentation with donepezil enhances recovery in short-term memory and sustained attention after traumatic brain injury. Arch Phys Med Rehabil 2004;85: 1050-5. Objective: To examine effects of donepezil on short-term memory and sustained attention in postacute patients with traumatic brain injury (TBI). Design: A 24-week, randomized, placebo-controlled, double-blind crossover trial. Setting: Outpatient clinics in 2 teaching hospitals. Participants: Eighteen postacute TBI patients with cognitive impairment. Intervention: Patients were randomly assigned to group A or group B. Patients in group A received donepezil for the rst 10 weeks and then a placebo for another 10 weeks. The 2 treatment phases were separated by a washout period of 4 weeks. Patients in group B received the preparations in the opposite order. Main Outcome Measures: Short-term memory and sustained attention were assessed by 2 indexes (Auditory Immediate Index [AII], Visual Immediate Index [VII]) of the Wechsler Memory ScaleIII and the Paced Auditory Serial Addition Test (PASAT), at baseline, week 10, and week 24 of the trial. Results: Intragroup comparison of different phases of the trial in both groups showed that donepezil signicantly increased the testing scores of the AII and VII, as well as PASAT scores, compared with baseline. There was no signicant change in the testing scores between assessment at baseline and the end of the placebo phase in group B. Intergroup comparison at the 10-week assessment showed signicantly improved testing scores in group A with donepezil over group B with the placebo. The improved testing scores with donepezil in group A were sustained after the washout period and placebo phase, suggesting a carry-over effect of the medication. Conclusions: Donepezil increased neuropsychologic testing scores in short-term memory and sustained attention in postacute TBI patients. Cholinergic augmentation may be a viable approach to restore memory and attention after TBI. Key Words: Acetylcholine; Brain injuries; Cognition disorders; Rehabilitation. 2004 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation HARMACOLOGIC TREATMENT WITH a cholinergic agonist to facilitate cognitive recovery after traumatic brain P injury (TBI) has not been studied. Cognitive impairment associated with TBI is more persistent and debilitating than are physical disabilities.1 Management of cognitive impairment is especially challenging. Typical cognitive impairment includes decits in memory, attention, and executive function. Difculties with visuospatial perception, problem solving, and language may also be present.2 Pharmacologic strategies to improve cognitive functions after TBI are based on the theory that disrupted neurotransmitter systems are responsible for the cognitive decits and that modulation of these systems with receptor agonists or antagonists may subsequently improve cognitive functions. The specic cognition-enhancing agent to be used for a particular patient is dependent on the targeted cognitive decit, the likely neurotransmitter system involved, and the side-effect prole of the medication. Several studies have examined the efcacy of various medications that act on different neurotransmitter systems in the brain to enhance cognitive functioning. These studies were recently critically reviewed.3,4 Clinical reports performed by using cholinomimetics, however, are limited. There have been studies in which physostigmine, a cholinergic agonist, was used to enhance recovery in verbal memory and attention in patients with TBI. Cardenas et al5 reported improvement in memory in 44% of the patients in a double-blind, placebocontrolled study. Levin et al6 completed a double-blind, placebo-controlled study of the use of combined oral physostigmine and lecithin (a precursor to acetylcholine). Sustained attention was found to be markedly improved under physostigmine than placebo in 16 patients with moderate to severe TBI. Unfortunately, the pharmacologic shortcomings associated with this medication, namely, its short-acting duration and adverse effects, limited its clinical use. Our interest in using a cholinomimetic to enhance cognitive recovery was prompted by evidence that: (1) the synthesis and transport of acetylcholine are disrupted in brain injury; (2) the dysfunction of the cholinergic system may explain, in part, the cognitive impairment after TBI; and (3) the cholinergic-enhancing strategy has produced clinical, cognitive improvement in patients with Alzheimers disease (AD). Acetylcholine is synthesized mainly in neurons in the basal forebrain, including the septal nucleus, the nucleus basalis of Meynert, and the interneurons in the hippocampus. Because these structures lie in proximity to the bony protuberances of the skull base,

From the Department of Rehabilitation Medicine, University of Texas Health Science Center, San Antonio, TX (Zhang); Department of Veterans Affairs Medical Center, San Antonio, TX (Zhang, Lee); University of Pennsylvania Medical Center, Philadelphia, PA (Plotkin); State University of New York, Upstate Medical University at Syracuse, Syracuse, NY (Wang); and Kaiser Foundation Rehabilitation Center, Vallejo, CA (Sandel). Supported in part by the University of Pennsylvania School of Medicine and Texas Health Science Center at San Antonio. No commercial party having a direct nancial interest in the results of the research supporting this article has or will confer a benet upon the authors(s) or upon any organization with which the author(s) is/are associated. Correspondence to Lei Zhang, MD, PhD, San Antonio Brain and Spine Consultants, 19114 La Verita, San Antonio, TX 78258, e-mail: neurorehab@yahoo.com. Reprints are not available from the author. 0003-9993/04/8507-8667$30.00/0 doi:10.1016/j.apmr.2003.10.014

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acceleration-deceleration forces may cause contusion of these structures, leading to a reduced synthesis of acetylcholine. In animal models, microdialysis studies performed 2 weeks after TBI showed decreased release of acetylcholine in the injured brain.7,8 The activity of the key enzyme of acetylcholine synthesis, choline acetyltransferase, was reduced in the animal hippocampus after percussion injury to the brain.9 A recent study10 of human postmortem brain tissue conrmed neuronal damage in the nucleus basalis of Meynert in fatally braininjured patients. These studies suggest cholinergic hypofunction after TBI. In addition to the reduced biosynthesis of acetylcholine, the transport of acetylcholine to various parts of the brain may also be disrupted. Diffuse axonal injury (DAI), an established pathology of TBI, may damage cholinergic afferent and efferent connections, resulting in decient acetylcholine at the target structures crucial for cognitive functions.11-14 Axonal projections from the septal nucleus and the nucleus basalis provide innervations to the entire cortex and the hippocampus. In turn, these acetylcholine-producing nuclei receive afferent projections from the limbic system, the hypothalamus, and the brainstem. The cholinergic network is extensive and topographically nonselective. After TBI, cholinergic activity was markedly reduced in human cortex15 and animal hippocampus and cortex.9 Given the pathophysiology of the brain injury, both neuronal contusion (reducing acetylcholine synthesis) and DAI (damaging the network), it is likely that there is a decreased level of acetylcholine available to the target regions of the brain, such as the cerebral cortex and the hippocampal formation. Data from both human and animal studies indicate that a decreased acetylcholine availability may cause impaired cognitive functions, especially in learning, memory, and attention.16,17 Cholinergic augmentation strategies have been used with some success to improve memory in patients with AD. The cholinomimetics commonly used reversibly inhibit acetylcholinesterase, which increases the availability of acetylcholine at the cholinergic synapses. One cholinomimetic currently approved by the US Food and Drug Administration for use in patients with AD is donepezil hydrochloride (Aricept).18,19 Its benecial effects have previously been reported in patients with TBI. In a case report, Taverni et al20 described improvement in recalls and problem solving in 2 TBI patients after taking donepezil. In a noncontrolled study, Whelan et al21 reported benecial effects of donepezil on cognitive functioning of patients with TBI who also had psychiatric complications such as depression, anxiety, or mood instability. More recently, in an open-label study, Masanic et al22 reported clinical improvement with donepezil in learning capability, specifically in long- and short-term recall in 4 patients with chronic, severe TBI. There has not been a controlled trial involving cholinomimetics in patients with TBI. Given the impact of TBI on the cholinergic system, evidence of improved cognitive functions with donepezil in AD, and anecdotal evidence of its efcacy in TBI patients, cholinergic augmentation may be a viable approach for memory and attentional impairment after TBI. We report here the results of a pilot study that examined the effects of donepezil on cognitive functions in postacute TBI patients by using a randomized controlled design. METHODS We recruited patients from 2 neurorehabilitation clinics and randomized them to a 24-week, placebo-controlled, doubleblind, and crossover trial. Patients in each group underwent a

10-week donepezil phase and a 10-week placebo phase. The 2 phases were separated with a 4-week washout period. We assessed patients short-term memory and sustained attention by using 2 indexes of the Wechsler Memory ScaleIII23 (WMS-III) and the Paced Auditory Serial Addition Test24 (PASAT), at baseline before randomization and at weeks 10 and 24 of the trial. Scores of the testing were statistically analyzed. Participants Patients were recruited from 2 neurorehabilitation clinics in 2 teaching hospitals. Thirty-eight patients with TBI and cognitive difculties were invited during regular follow-up visits to participate in the trial and 31 agreed to do so. Twenty patients met the study criteria, and 18 patients completed the trial. Inclusion criteria were (1) history of TBI (regardless of severity), (2) attention or short-term memory impairment as shown by the 2 indexes of the WMS-III or PASAT, and (3) enrollment from 2 to 24 months after brain injury. Exclusion criteria were (1) medical complications (cardiac arrhythmia by electrocardiogram regardless of etiology, history of cardiac contusion, uncontrolled posttraumatic seizures, uncorrected electrolyte imbalance, endocrine dysregulation, infection, gastrointestinal bleeding); (2) cognitive and behavioral functioning at level V (confused, nonagitated) or below on the Rancho Los Amigos (RLA) Levels of Cognitive Functioning25; (3) neurologic or psychiatric complications or comorbidity (stroke, epilepsy, major depression, neurologic degenerative disorders [ie, AD or Parkinsons disease]); (4) taking psychotropic medications (eg, antidepressants, anticonvulsants, antipsychotics, neurostimulants); and (5) communication impairment (aphasia, dysarthria) that would interfere with neuropsychologic testing. The majority of subjects were ambulatory at an independent or a modied independent level. Guidance and supervision from family members were usually required in their daily activities. Glasgow Outcome Scale scores were 4 or 5, and RLA level scores ranged from 7 to 8. Informed consent was obtained from the patients after the nature of the trial was fully explained. The study was approved by the institutional review boards at all the participating institutions. Research Design This 24-week outpatient clinical trial used a randomized, double-blinded, placebo-controlled, crossover experimental design (g 1). Randomization to group A or group B was made in a hospital pharmacy that used 2 different sets of 30 numbers from 2 tables of random numbers. The pharmacy managed the randomization coding system, which was consistently followed. To control for order effect, the pharmacy used blocks of 4 subjects (ie, 2 subjects started with donepezil, 2 started with placebo) within each set of 30 numbers. Patients in group A received donepezil by mouth for the rst 10 weeks, followed by a washout period of 4 weeks; the subjects then received a placebo in the second 10 weeks. Patients in group B received the preparations in the opposite order, that is, the placebo phase, the washout period, and the donepezil phase. During the donepezil phase, the medication was administered at a dose of 5mg/d for the rst 2 weeks and 10mg/d for the remaining 8 weeks. This titration schedule was intended to minimize the side effects of donepezil. The placebo was a visually identical tablet, given in the same manner as donepezil. Assessment of all study items was performed at baseline and weeks 10 and 24 of the trial.

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Statistical Analysis We analyzed data from 18 patients (9 patients in each group) who completed the trial. Demographic characteristics of groups A and B were compared by using t test comparisons. Differences in assessment scores were analyzed for the effects of donepezil and placebo at different phases of the trial within each treatment group, and also between treatment groups at baseline, at week 10, and at week 24 by using a mixed linear model.31 All data were analyzed by Statistical Analysis Software, version 8.a Our limited preliminary data ruled out a prespecied power calculation. In post hoc analysis, the power and sample size calculations were based on the analysis of variance which indicated that the effect size32 was more than .93 and had more than 90% of power to detect signicant differences between donepezil and placebo, with a P value less than .05 and a sample size of 9 patients in each treatment group. The power calculation was by Power Analysis and Sample Size software.b An of .05 was used to determine signicance. RESULTS Eighteen of 20 patients enrolled completed the study. One patient in group A had negative side effects from the medication, namely, increased bowel frequency and incontinence after 1 week in the donepezil phase. A patient in group B was transfered to an assisted living facility in another city. Demographic characteristics of the patients in the 2 study groups did not differ signicantly in age, gender, severity of the brain injury (measured by the lowest Glasgow Coma Scale33 [GCS] score at 24 to 48h after injury), level of education, and number of months postinjury (table 1). No signicant difference was observed in scores of neuropsychologic testing between the 2 groups at baseline (tables 2, 3). Neuropsychologic testing showed moderate to severe impairment in memory and attention at baseline compared with the normative data.23,29 Intragroup comparison showed statistically signicant increases in the testing scores with donepezil in both groups (table 2). In group A, in which patients received donepezil for the rst 10 weeks, the scores of the AII and VII improved by 31.74.9 and 27.61.9, respectively, from baseline. Similarly in group B, donepezil increased the AII score by 40.14.5 and the VII score by 31.63.3 from baseline. The differences in scores between baseline and the end of the placebo phase in group B were not statistically signicant in either the AII (P.19) or the VII (P.77). Interestingly, in group A, an expected dramatic decrease in testing scores after the washout period and the placebo phase did not materialize; the AII increased by 10.84.2 and the VII score decreased by only 2.62.9 at week 24. In group B, both the AII and VII scores increased by 10.74.2 and 1.52.9, respectively, from baseline to the end of the placebo phase. Intergroup comparison at week 10 between the donepezil phase of group A and the placebo phase of group B showed
Table 1: Summary of Sociodemographic Characteristics
Group A Group B P Value

Fig 1. Prole of the randomized controlled crossover trial.

Outcome Measures Short-term memory and sustained attention were the primary cognitive domains measured. The instruments used included 2 indexes of the WMS-III and the PASAT. All tests were administered by 2 experienced psychometricians by using standard administration procedures. The WMS-III was updated in 1997; it is a revised and expanded version of the previous edition of the Wechsler Memory ScaleRevised, one of the most commonly used memory scales in neuropsychologic testing,26 and a primary scale for declarative episodic memory. In the study, scores from the Auditory Immediate Index (AII) and the Visual Immediate Index (VII) of the WMS-III were calculated to assess immediate auditory and visual memory, respectively. These indexes measure recall immediately (510s) after information is presented audibly or visually. The specic subtests that comprise the AII are logical memory I and verbal paired associates I. The subtests that comprise the VII are faces I and family pictures I. Age-adjusted norms were used to obtain scores. The index scores were statistically analyzed to examine the treatment effect. Both indexes have a mean of 100 and a standard deviation of 15. A score of 100 denes average performance in a healthy population. The WMS-III is valid and sensitive in detecting and monitoring changes in cognitive decits in patients with moderate to severe TBI.27 A recent study28 of this scale also showed both internal consistency and test-retest reliability of the indexes and subtests used in the trial. The cognitive processes evaluated by the PASAT are sustained attention, working memory, and information-processing speed. Four series of 61 digits are presented verbally to the patients, each at a xed rate, every 2.4, 2.0, 1.6, or 1.2 seconds. The subject is required to add a digit to the digit immediately preceding it and to give the answer verbally. The scores for the PASAT are expressed as the number of correct responses (maximum scores of 60 for each series) for each age range on each of 4 trials.29 This test is most useful when administered repeatedly throughout the course of recovery. This task is sensitive to attention decits in mild and severe TBI.30

Age (y) Male (%) Education (y) GCS score (2448h) Postinjury (mo)

332 (1957) 67 131.1 (1017) 9.31.1 (414) 4.60.7 (20)

312 (2349) 78 141.3 (915) 8.91.0 (315) 3.90.5 (311)

0.602 1.000 0.611 0.770 0.756

NOTE. Values are mean standard error (SE) (range) or n.

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DONEPEZIL AND COGNITIVE RECOVERY, Zhang Table 2: Index Scores of WMS-III

Group A Group B P Value

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All Baseline Week 10 Week 24 VII Baseline Week 10 Week 24

63.72.5 95.44.5* 105.94.5 65.92.6 93.53.0* 91.33.0

62.32.0 73.64.5 102.44.5* 63.33.2 64.93.0 94.93.0*

.611 .002 .588 .116 .001 .397

NOTE. Values are mean SE. *Scores obtained with donepezil treatment.

statistically signicant benecial effects of donepezil on testing scores. Patients taking donepezil had signicant increases in test scores group B subjects taking the placebo of the AII (P.002; table 2) and the VII (P.000; table 2). Increased scores from taking donepezil in group A were sustained after washout and placebo treatment, and there was an increase in test scores of group B after receiving donepezil treatment. Consequently, no statistically signicant difference was detected between the 2 groups at the week-24 assessment on either the AII (P.588) or the VII (P.397). Similar benecial effects of donepezil were also observed with the PASAT (table 3). Increases in PASAT scores at all 4 testing rates at the end of the donepezil phase were statistically signicant (P.001), compared with baseline in group A and with the placebo phase in group B. No signicant change in scores was detected between the baseline and the placebo phase in group B at any of the testing rates. Again, the higher scoring with donepezil treatment was sustained after washout and placebo phase. At week 10, signicant increases in testing scores were observed in the donepezil group over the placebo group, which suggests the efcacy of the medication. No signicant differences were detected at week 24 between the 2 groups because of the sustained high scores in group A after the washout and the placebo phase. DISCUSSION This study is the rst clinical trial involving donepezil in the treatment of cognitive impairment in postacute TBI patients. Our data show that cholinergic augmentation by the acetylcholinesterase inhibitor donepezil facilitates cognitive recovery in postacute TBI, particularly in short-term memory and sustained attention, as evidenced by improvement in neuropsychologic testing scores. In an era with few pharmacologic treatment options for people with TBI and cognitive impairments, these results are encouraging. The mechanisms underlying the improved neuropsychologic performance in the study are unclear. It is conceivable that an increase in bioavailability of acetylcholine in the brain that is insufcient in cholinergic synthesis and transmission after TBI could exert direct excitatory stimulation on postsynaptic nicotinic and muscarinic receptors in the hippocampus and cortex, both of which are considered important structures in learning and memory.34 Activation of these cholinergic receptors could in turn restore pathways or cortical activation critical for memory and attention. Recent studies have also shown indirect effects of cholinergic transmission, such as modulatory roles by regulating neurotransmitter release, including -aminobutyric acid and glutamate.35 In addition, there is evidence that acetylcholine induces neuroplasticity and generates long-lasting increases in neural responsiveness.36 Neuroimaging studies

have shown that long-term use of donepezil increases cerebral blood ow in many regions of the brain in patients with AD.37 It is interesting that the improved neuropsychologic testing scores achieved with donepezil in patients in group A were sustained after a 4-week washout and after the placebo phase for an additional 10 weeks. We think this was most likely a carryover effect associated with donepezil in this particular group of patients. It is unlikely that the carryover effect was caused by insufcient washout because the half-life of donepezil is only about 70 hours. There is evidence that donepezil may act as a neurotrophic factor for cholinergic neurons to increase the activity of choline acetyltransferase,38 a primary enzyme in the biosynthesis of acetylcholine, which would lead to a prolonged effect. In addition, the postulated mechanisms mentioned earlier may have restorative effects on cognition, resulting in a continued improvement in neuropsychologic testing. We caution, however, against the conclusion that patients with TBI would benet from a short period of cholinergic augmentation with donepezil because of the carryover effect. Additional studies should address questions of the duration of treatment with donepezil, the timing of initiation of the medication, and the adverse effects associated with its short- or long-term use. The detected carryover effect also has important implications for the design of future clinical trials involving donepezil. A controlled, parallel group comparison may simplify the interpretation of the data. The spontaneous recovery in cognitive functions is a wellobserved phenomenon in TBI. We believe some degree of spontaneous recovery also occurred in patients in this trial. The drug effect, however, was distinguished from spontaneous recovery by the studys design. First, comparison of the 2 groups at week 10 showed signicant improved scoring with donepezil in group A over the placebo in group B. This nding convincingly argues for the drug effect because there was no other noticeable difference between the 2 groups. Second, there would have been signicant increases in the testing scores in group B from baseline to the end of the placebo phase had there been a marked spontaneous recovery. In fact, the differences between testing scores during this time frame in group B did not reach a level of signicance. This research design also minimized the confounding of a practice effect that might have

Table 3: Results of PASAT

Group A Group B P Value

Presentation rate Baseline Week 10 Week 24 Presentation rate Baseline Week 10 Week 24 Presentation rate Baseline Week 10 Week 24 Presentation rate Baseline Week 10 Week 24

2.4s 24.111.65 42.701.95* 44.801.95 2.0s 22.001.64 37.741.20* 37.971.20 1.6s 18.781.51 31.441.39* 32.781.39 1.2s 12.891.23 21.981.11* 21.641.11

27.221.73 29.081.95 46.531.95* 23.891.75 26.481.20 35.031.20* 21.111.64 21.891.39 32.221.39* 16.671.29 14.691.11 23.021.11*

.212 .001 .545 .443 .001 .102 .310 .001 .783 .050 .001 .410

NOTE. Values are mean SE. *Scores obtained with donepezil treatment.

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entered into neuropsychologic testing, especially for the indexes of the WMS-III. Further investigation is needed to determine whether improvement in cognitive functions with donepezil can translate to global functional gains or clinical improvement in these patients. In a retrospective study, Whelan et al21 examined 53 TBI patients with residual cognitive impairment in a psychiatric clinic. They found that use of donepezil was associated with moderate to signicant clinical improvement when assessed subjectively by physicians. Furthermore, the patients clinical improvement associated with donepezil was more evident than that of psychologic testing in their study. In a serial case report, Masanic et al22 observed minimal functional improvement in 4 chronic, severely brain-injured patients after donepezil use for 12 weeks, despite improvement in neuropsychologic testing. Future studies will be performed to examine changes associated with donepezil in self-care, mobility, life satisfaction, and social behavior. There were some limitations to our study. The selection of patients with moderate to severe TBI limits the generalization of the results to the mild TBI population that constitutes the majority of the patients with TBI. In addition, the neuropsychologic testing we used primarily focused on short-term memory and sustained attention. Other aspects of memory and attention and other cognitive domains such as executive function are yet to be examined. In addition, although all but 1 patient tolerated this medication, systemic evaluation of the adverse effects associated with it is warranted in a study with a larger number of subjects. It remains to be determined whether the cholinergic augmentation strategy is more efcacious than medications that act on other neurotransmitter systems, especially the dopaminergic stimulants. We were unable to determine whether the ultimate level of recovery can be elevated with donepezil. The available data only indicate that the rate of cognitive recovery has been facilitated. CONCLUSIONS Our study shows that augmentation of the cholinergic activity by inhibiting acetylcholinesterase with donepezil improved neuropsychologic testing scores in memory and attention in postacute TBI patients. The cholinergic system in the brain should be a pharmacologic target for cognitive restoration after TBI.
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37. Staff RT, Gemmell HG, Shanks MF, Murray AD, Venneri A. Changes in the rCBF images of patients with Alzheimers disease receiving Donepezil therapy. Nucl Med Commun 2000;21:37-41. 38. Kato K, Hayako H, Ishihara Y, Marui S, Iwane M, Miyamoto M. TAK-147, an acetylcholinesterase inhibitor, increases choline acetyltransferase activity in cultured rat septal cholinergic neurons. Neurosci Lett 1999;260:5-8. Suppliers a. SAS Institute Inc, 100 SAS Campus Dr, Cary, NC 27513. b. NCSS Statistical Software, 329 N 1000 E, Kaysville, UT 84037.

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