Efficacy of methylphenidate in the rehabilitation of attention following traumatic brain injury: a randomised, crossover, double blind, placebo controlled inpatient trial
ABSTRACT Most previous studies evaluating the use of methylphenidate following traumatic brain injury (TBI) have been conducted many years post-injury. This study evaluated the efficacy of methylphenidate in facilitating cognitive function in the inpatient rehabilitation phase.
40 participants with moderate-severe TBI (mean 68 days post-injury) were recruited into a randomised, crossover, double blind, placebo controlled trial. Methylphenidate was administered at a dose of 0.3 mg/kg twice daily and lactose in identical capsules served as placebo. Methylphenidate and placebo administration was randomised in a crossover design across six sessions over a 2 week period. Primary efficacy outcomes were neuropsychological tests of attention.
No participants were withdrawn because of side effects or adverse events. Methylphenidate significantly increased speed of information processing on the Symbol Digit Modalities Test (95% CI 0.30 to 2.95, Cohen's d = 0.39, p = 0.02), Ruff 2 and 7 Test-Automatic Condition (95% CI 1.38 to 6.12, Cohen's d = 0.51, p = 0.003), Simple Selective Attention Task (95% CI -58.35 to -17.43, Cohen's d = 0.59, p = 0.001) and Dissimilar Compatible (95% CI -70.13 to -15.38, Cohen's d = 0.51, p = 0.003) and Similar Compatible (95% CI -74.82 to -19.06, Cohen's d = 0.55, p = 0.002) conditions of the Four Choice Reaction Time Task. Those with more severe injuries and slower baseline information processing speed demonstrated a greater drug response.
Methylphenidate enhances information processing speed in the inpatient rehabilitation phase following TBI. This trial is registered with the Australian New Zealand Clinical Trials Registry (12607000503426).
- SourceAvailable from: Dhananjay Namjoshi
[Show abstract] [Hide abstract]
- "Six of eight trials using physical rehabilitation also showed positive treatment effects, and nutrition and acupuncture were found to be beneficial in the single trials conducted thus far. Potential TBI pharmacotherapies were tested in 11 post-acute RCTs, with positive treatment effects reported in six studies, including for methylphenidate (Whyte et al., 2004; Willmott and Ponsford, 2009), CDP-choline (Calatayud Maldonado et al., 1991) and pyritinol (Kitamura, 1981). A trial of phenytoin and carbamazepine was negative (Smith et al., 1994), and sertraline, carbamazepine, rivsatigmine and modafinil were found to have no significant treatment effects (Banos et al., 2010; Jha et al., 2008; Novack et al., 2009; Tenovuo et al., 2009). "
ABSTRACT: Traumatic brain injury (TBI) is a major worldwide healthcare problem. Despite promising outcomes from many preclinical studies, the failure of several clinical studies to identify effective therapeutic and pharmacological approaches for TBI suggests that methods to improve the translational potential of preclinical studies are highly desirable. Rodent models of TBI are increasingly in demand for preclinical research, particularly for closed head injury (CHI), which mimics the most common type of TBI observed clinically. Although seemingly simple to establish, CHI models are particularly prone to experimental variability. Promisingly, bioengineering-oriented research has advanced our understanding of the nature of the mechanical forces and resulting head and brain motion during TBI. However, many neuroscience-oriented laboratories lack guidance with respect to fundamental biomechanical principles of TBI. Here, we review key historical and current literature that is relevant to the investigation of TBI from clinical, physiological and biomechanical perspectives, and comment on how the current challenges associated with rodent TBI models, particularly those involving CHI, could be improved.Disease Models and Mechanisms 09/2013; 6(6). DOI:10.1242/dmm.011320 · 4.97 Impact Factor
[Show abstract] [Hide abstract]
- "Healthy participants perceived more errors consciously when they were under the influence of MPH than in the placebo condition. MPH has also proven to be effective in the treatment of cognitive deficits that can be observed after traumatic brain injury (Willmott and Ponsford, 2009), which have been associated with reduced awareness (O'Keeffe et al., 2004). Since MPH is a DA and NE reuptake inhibitor, it can be seen as indirect DA agonist (cf. "
ABSTRACT: Becoming aware of errors that one has committed might be crucial for strategic behavioral and neuronal adjustments to avoid similar errors in the future. This review addresses conscious error perception ("error awareness") in healthy subjects as well as the relationship between error awareness and neurological and psychiatric diseases. We first discuss the main findings on error awareness in healthy subjects. A brain region, that appears consistently involved in error awareness processes, is the insula, which also provides a link to the clinical conditions reviewed here. Then we focus on a neurological condition whose core element is an impaired awareness for neurological consequences of a disease: anosognosia for hemiplegia (AHP). The insular cortex has been implicated in both error awareness and AHP, with anterior insular regions being involved in conscious error processing and more posterior areas being related to AHP. In addition to cytoarchitectonic and connectivity data, this reflects a functional and structural gradient within the insula from anterior to posterior. Furthermore, studies dealing with error awareness and lack of insight in a number of psychiatric diseases are reported. Especially in schizophrenia, attention-deficit hyperactivity disorder, (ADHD) and autism spectrum disorders (ASD) the performance monitoring system seems impaired, thus conscious error perception might be altered.Frontiers in Human Neuroscience 02/2013; 7:14. DOI:10.3389/fnhum.2013.00014 · 2.99 Impact Factor
[Show abstract] [Hide abstract]
- "Pharmacological manipulations of error-related brain activity have shown that enhancing catecholamines with amphetamine (de Bruijn et al., 2004; de Bruijn et al., 2006) or the ␣2 adrenoceptor antagonist yohimbine (Riba et al., 2005) increased the amplitude of the error-related negativity (ERN). Methylphenidate (MPH) has also been shown to be effective in treating the cognitive deficits associated with TBI (Willmott and Ponsford, 2009), in which there is a fundamental problem of reduced awareness (O'Keeffe et al., 2004). In contrast, the D 2 receptor antagonist haloperidol (Zirnheld et al., 2004) and the GABA A /benzodiazepine receptor modulators lorazepam and oxazepam (Johannes et al., 2001; de Bruijn et al., 2004) have been shown to decrease error-related dACC activity. "
ABSTRACT: How the brain monitors ongoing behavior for performance errors is a central question of cognitive neuroscience. Diminished awareness of performance errors limits the extent to which humans engage in corrective behavior and has been linked to loss of insight in a number of psychiatric syndromes (e.g., attention deficit hyperactivity disorder, drug addiction). These conditions share alterations in monoamine signaling that may influence the neural mechanisms underlying error processing, but our understanding of the neurochemical drivers of these processes is limited. We conducted a randomized, double-blind, placebo-controlled, cross-over design of the influence of methylphenidate, atomoxetine, and citalopram on error awareness in 27 healthy participants. The error awareness task, a go/no-go response inhibition paradigm, was administered to assess the influence of monoaminergic agents on performance errors during fMRI data acquisition. A single dose of methylphenidate, but not atomoxetine or citalopram, significantly improved the ability of healthy volunteers to consciously detect performance errors. Furthermore, this behavioral effect was associated with a strengthening of activation differences in the dorsal anterior cingulate cortex and inferior parietal lobe during the methylphenidate condition for errors made with versus without awareness. Our results have implications for the understanding of the neurochemical underpinnings of performance monitoring and for the pharmacological treatment of a range of disparate clinical conditions that are marked by poor awareness of errors.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2012; 32(8):2619-27. DOI:10.1523/JNEUROSCI.4052-11.2012 · 6.34 Impact Factor