The effects of Donepezil on traumatic brain injury acute rehabilitation outcomes

Walker, William C.; Seel, Ronald T.; Gibellato, Marilisa G.; Lew, Henry L.; Cornis-Pop, Micaela; Jena, T; Silver, Timothy M.

doi:10.1080/02699050310001646224

Cited by 50 publications

(25 citation statements)

References 17 publications

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“…The critical role that cholinergic systems have in rehabilitation-linked plasticity raises the possibility that agents augmenting cholinergic functioning, such as cholinesterase inhibitors, may also enhance functional recovery in the setting of rehabilitation after cortical damage resulting from stroke or traumatic brain injury. A few small studies have addressed this possibility, although none have been sufficiently powered to draw clear conclusions (24)(25)(26)(27). These findings support the rationale for proceeding with appropriately designed and powered studies to determine whether augmentation of cholinergic function will improve clinical outcomes after cortical injury; cholinesterase inhibitors are clinically approved to enhance function in patients with Alzheimer's disease (28) and well-tolerated in patients with cortical damage (24).…”

Section: Discussionmentioning

confidence: 78%

Rehabilitation drives enhancement of neuronal structure in functionally relevant neuronal subsets

Wang

Conner

Nagahara

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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We determined whether rehabilitation after cortical injury also drives dynamic dendritic and spine changes in functionally distinct subsets of neurons, resulting in functional recovery. Moreover, given known requirements for cholinergic systems in mediating complex forms of cortical plasticity, including skilled motor learning, we hypothesized that cholinergic systems are essential mediators of neuronal structural and functional plasticity associated with motor rehabilitation. Adult rats learned a skilled forelimb grasping task and then, underwent destructive lesions of the caudal forelimb region of the motor cortex, resulting in nearly complete loss of grasping ability. Subsequent intensive rehabilitation significantly enhanced both dendritic architecture and spine number in the adjoining rostral forelimb area compared with that in the lesioned animals that were not rehabilitated. Cholinergic ablation markedly attenuated rehabilitation-induced recovery in both neuronal structure and motor function. Thus, rehabilitation focused on an affected limb robustly drives structural compensation in perilesion cortex, enabling functional recovery.cell filling | corticospinal neurons | cholinergic | morphology | plasticity S tudies over the past decade have indicated that the adult brain is structurally dynamic (1-3). Indeed, dendritic spines dynamically turn over in the adult brain (3, 4), and learning of novel tasks is associated with further increases in spine turnover (4). Moreover, total and stable increases in spine number together with enhanced dendritic complexity can be detected when analyses are focused specifically on neuronal subpopulations that are functionally related to a newly learned motor skill (5). For example, we recently reported that cortical layer V pyramidal neurons, which project to spinal segment C8 and are specifically engaged when learning a skilled forelimb grasping task, elaborate a 22% increase in apical dendritic spines and exhibit significant increases in dendritic branching and total dendritic length (5); an adjoining control population of cortical layer V pyramidal neurons that project to C4, which are not specifically shaped by the skilled motor task, exhibits no change in spines or dendritic complexity when the same task is learned (5). The detection of stable structural increases in neurons engaged by skilled motor learning in contrast to a lack of change in adjacent neurons that are not engaged by learning advances our understanding of mechanisms underlying experience-dependent cortical plasticity.Damage to the adult CNS also generates adaptive brain plasticity. For example, focal cortical lesions evoke cortical map plasticity (6, 7), extension of new axonal connections (7,8), and neurogenesis (9). A very important and unresolved question in the neural plasticity and injury fields is whether rehabilitation-that is, specific retraining of injured neural circuits-can drive, alter, or enhance neural plasticity subsequent to brain lesions. Whereas extensive literature has shown that rehab...

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Section: Discussionmentioning

confidence: 78%

Rehabilitation drives enhancement of neuronal structure in functionally relevant neuronal subsets

Wang

Conner

Nagahara

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…However, in a study by Kaye, Townsend, and Ivins (2003), there were no improvements in memory although participants did report improvement in processing speed. In another study, Walker et al (2004) found no significant improvements in cognition as measured on the Functional Independence Measure Score (FIM) between those on donepezil and controls. In addition to memory and processing-speed improvements, donepezil, as well as other AChE inhibitors, have been found to improve attention and have been associated with an overall increased ability to concentrate, improvements in learning and divided attention (Khateb, Ammann, Annoni, & Diserens, 2005;Tenovuo, 2005;.…”

Section: Traumatic Brain Injury (Tbi)mentioning

confidence: 95%

Relevance of Donepezil in Enhancing Learning and Memory in Special Populations: A Review of the Literature

Yoo

Valdovinos

Williams

2007

J Autism Dev Disord

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This review discusses the laboratory and clinical research supporting the rationale for the efficacy of donepezil (Aricept USA) in enhancing cognition in autism, Alzheimer disease, Down syndrome, traumatic brain injury, Attention Deficit Hyperactivity Disorder (ADHD), and schizophrenia. While preliminary animal models have shown effective, human studies exclusive of Alzheimer disease are sparse. Although attention and memory are unlikely a sole operation of the cholinergic system, evidence indicates a promising direction for further examination of this hypothesis in autism. Studies that examine changes in operationally defined behaviors and reliable and valid measure of changes in attention and memory are needed.

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“…Determining how much recovery is occurring spontaneously, and how much is due to stimulation is particularly difficult in the first six months after injury when it is more likely for patients to have dramatic improvements. The FIM+FAM scale has previously been able to show significant levels of improvement after an intervention with 18 treated TBI patients versus untreated controls 167 . If we see a trend towards benefit with stimulation, but without statistical significance, then we would propose a follow-up trial with a greater number of patients and longer experimental period (e.g.…”

Section: Va Author Manuscriptmentioning

confidence: 99%

Vagus nerve stimulation to augment recovery from severe traumatic brain injury impeding consciousness: a prospective pilot clinical trial

Chen

Flanagan

Samadani

2013

Neurological Research

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Objectives-Traumatic brain injury has a high morbidity and mortality in both civilian and military populations. Blast and other mechanisms of traumatic brain injury damage the brain by causing neurons to disconnect and atrophy. Such traumatic axonal injury can lead to persistently vegetative and minimally conscious states, for which limited treatment options exist, including physical, occupational, speech and cognitive therapies.More than 60,000 patients have received vagus nerve stimulation for epilepsy and depression. In addition to decreased seizure frequency and severity, patients report enhanced mood, reduced daytime sleepiness independent of seizure control, increased slow wave sleep, and improved cognition, memory, and quality of life.Early stimulation of the vagus nerve accelerates the rate and extent of behavioral and cognitive recovery after fluid percussion brain injury in rats.Methods-We recently obtained FDA approval for a pilot prospective randomized crossover trial to demonstrate objective improvement in clinical outcome by placement of a vagus nerve stimulator in patients who are recovering from severe traumatic brain injury. Our hypothesis is that stimulation of the vagus nerve results in increased cerebral blood flow and metabolism in the forebrain, thalamus and reticular formation, which promotes arousal and improved consciousness, thereby improving outcome after traumatic brain injury resulting in minimally conscious or persistent vegetative states.Discussion-If this study demonstrates that vagus nerve stimulation can safely and positively impact outcome, then a larger randomized prospective crossover trial will be proposed.

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The effects of Donepezil on traumatic brain injury acute rehabilitation outcomes

Cited by 50 publications

References 17 publications

Rehabilitation drives enhancement of neuronal structure in functionally relevant neuronal subsets

Rehabilitation drives enhancement of neuronal structure in functionally relevant neuronal subsets

Relevance of Donepezil in Enhancing Learning and Memory in Special Populations: A Review of the Literature

Vagus nerve stimulation to augment recovery from severe traumatic brain injury impeding consciousness: a prospective pilot clinical trial

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