Table 4 - uploaded by Junghoon Kim
Content may be subject to copyright.
Source publication
Methylphenidate (MPH), the most widely prescribed psychostimulant to treat many neuropsychiatric conditions, is reported to improve attention and speed of processing in survivors of traumatic brain injury (TBI). The neural correlate of this efficacy, however, remains unclear.
Using perfusion functional magnetic resonance imaging (fMRI) as a biomark...
Similar publications
Neuropharmacotherapy is substantially hindered by poor drug targeting, resulting in low specificity and efficacy. It is known that different behavioral tasks increase functional activity and cerebral blood flow (CBF), two key parameters controlling drug delivery and efficacy. Here, we tested a novel, non-invasive drug targeting approach (termed fun...
Methylphenidate (MPH) is a stimulant drug and an effective treatment for attention-deficit/hyperactivity disorder (ADHD) in both children and adults. Pre-clinical studies suggest that the response to stimulants is dependent on age, which may reflect the ontogeny of the dopamine (DA) system, which continues to develop throughout childhood and adoles...
Citations
... In addition, amantadine may improve attention, visuospatial function, and executive function in patients with TBI (7), and a few studies have reported the potential use of methylphenidate in patients with TBI. But there is insufficient evidence to support its use in patients with moderate to severe brain injury (8,9). NBS includes transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), and studies have suggested that NBS may have positive changes in mood, visuospatial function, language, working memory, and/or executive function. ...
Introduction
Cognitive impairment is the main clinical feature after traumatic brain injury (TBI) and is usually characterized by attention deficits, memory loss, and decreased executive function. Vagus nerve stimulation (VNS) has been reported to show potential improvement in the cognition level after traumatic brain injury in clinical and preclinical studies. However, this topic has not yet been systematically reviewed in published literature. In this study, we present a systematic review and meta-analysis of the effects of VNS on cognitive function in animal models of TBI and their underlying mechanisms.
Methods
We performed a literature search on PubMed, PsycINFO, Web of Science, Embase, Scopus, and Cochrane Library from inception to December 2021 to identify studies describing the effects of VNS on animal models of TBI.
Results
Overall, nine studies were identified in animal models (36 mice, 268 rats, and 27 rabbits). An analysis of these studies showed that VNS can improve the performance of TBI animals in behavioral tests (beam walk test: SMD: 4.95; 95% confidence interval [CI]: 3.66, 6.23; p < 0.00001) and locomotor placing tests (SMD: –2.39; 95% CI: –4.07, –0.71; p = 0.005), whereas it reduced brain edema (SMD: –1.58; 95% CI: –2.85, –0.31; p = 0. 01) and decrease TNF-α (SMD: –3.49; 95% CI: –5.78, –1.2; p = 0.003) and IL-1β (SMD: –2.84; 95% CI: –3.96, –1.71; p < 0.00001) expression level in the brain tissue. However, the checklist for SYRCLE showed a moderate risk of bias (quality score between 30% and 60%), mainly because of the lack of sample size calculation, random assignment, and blinded assessment.
Conclusion
The present review showed that VNS can effectively promote cognitive impairment and neuropathology in animal models of TBI. We hope that the results of this systematic review can be applied to improve the methodological quality of animal experiments on TBI, which will provide more important and conclusive evidence on the clinical value of VNS. To further confirm these results, there is a need for high-quality TBI animal studies with sufficient sample size and a more comprehensive outcome evaluation.
Systematic review registration
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021290797, identifier: CRD42021290797.
... The same study associated the improvement in reaction time with the magnitude of suppression of the left posterior superior parietal cortex and parieto-occipital junction on perfusion functional magnetic resonance imaging, correlating the efficacy of methylphenidate with the neuroanatomy in patients with TBI. 39 Lis-dexamphetamine showed benefits in the areas of attention, working memory, response speed and endurance, and executive functioning in patients with moderate to severe TBI with chronic attention deficits. 67 Another recent multicenter US study of at least mTBI analyzed the utility of combined cognitive rehabilitation and methylphenidate. ...
Context:
There are 3.8 million mild traumatic brain injuries (mTBIs) that occur each year in the United States. Many are left with prolonged life-altering neurocognitive deficits, including difficulties in attention, concentration, mental fatigue, and distractibility. With extensive data on the safety and efficacy of stimulant medications in treating attention deficit, concentration difficulties and distractibility seen with attention deficit disorder, it is not surprising that interest continues regarding the application of stimulant medications for the persistent neurocognitive deficits in some mTBIs.
Evidence acquisition:
Studies were extracted from PubMed based on the topics of neurocognitive impairment, mTBI, stimulant use in mTBI, stimulants, and the association between attention deficit/hyperactivity disorder and mTBI. The search criteria included a date range of 1999 to 2020 in the English language.
Study design:
Literature review.
Level of evidence:
Level 4.
Results:
Currently, there is very limited literature, and no guidelines for evaluating the use of stimulant medication for the treatment of prolonged neurocognitive impairments due to mTBI. However, a limited number of studies have demonstrated efficacy and safety of stimulants in the treatment of neurocognitive sequelae of mTBI in the adult, pediatric, military, and athletic populations.
Conclusion:
There is limited evidence to suggest stimulant medication may be beneficial in patients with mTBI with persistent neurocognitive symtpoms. The decision to utilize stimulant medication for mTBI patients remains physician and patient preference dependent. Given the limited encouraging data currently available, physicians may consider stimulant medication in appropriate patients to facilitate the recovery of prolonged neurocognitive deficits, while remaining cognizant of potential adverse effects.
... In a two-week, double-blind, placebo-controlled crossover study, 10 pediatric subjects with hyperactivity and mild to severe TBI showed no significant changes on measures of behavior, attention, memory, or processing speed [141]. In contrast, other TBI studies found improved visuospatial and working memory, sustained attention, depression, mental fatigue, eye-hand coordination, reaction times, overall cognitive function, and subjective cognitive symptoms with MPH compared to placebo [123,[142][143][144][145][146]. No differences in efficacy based on the severity of TBI were noted across studies. ...
Children with attention deficit hyperactivity disorder (ADHD) have an increased risk of seizures, and children with epilepsy have an increased prevalence of ADHD. Adults with epilepsy often have varying degrees of attentional dysfunction due to multiple factors, including anti-seizure medications, frequent seizures, interictal discharges, underlying lesions, and psychiatric comorbidities. Currently, there are no approved medications for the treatment of epilepsy-related attentional dysfunction. Methylphenidate (MPH) is a stimulant, FDA-approved for the treatment of ADHD, and often used for ADHD in the setting of pediatric epilepsy. Large database and registry studies indicate safety of MPH in children with ADHD and epilepsy, with no significant effect on seizure frequency. Small single-dose and open-label studies suggest efficacy of MPH in adults with epilepsy-related attention deficits. Methylphenidate represents a possible treatment for attentional dysfunction due to epilepsy, but large, randomized, placebo-controlled, double-blinded studies are needed.
... Adult data don´t have a better design than some of the pediatric studies founded, so were not analyzed in the present study. However, it´s relevant to say that the majority of recent adult data revealed positive effects of methylphenidate in mental fatigue and cognitive symptoms post-TBI [89,[90][91][92][93][94], among other prior studies. Only a few adult studies failed to demonstrate significant improvement in certain cognitive skills [95,96]. ...
Introduction: Pediatric traumatic brain injury (TBI) has a significant incidence and entails great health costs related to its high morbidity and disability. Despite that, there is paucity in the literature on neuropharmacological approaches and limited evidence to support the routine use of these agents to promote cognitive recovery from TBI. Our main aim is to make a literature review of the therapeutic scheme, treatment response and effectiveness of the most used dopaminergic agents in children post-TBI. Method: A literature research was conducted using PubMed database. First it was performed a preliminary search, limited to articles published in English in the last 30 years (1990-2020) using the keywords outlined, in order to clarify the concept of cognitive function, potential predictors of prognosis and the neuropharmacological dopaminergic agents more widely used in cognitive dysfunction after pediatric TBI. A second literature research was carried out to answer to the main aim delineated, review the effects of the most commonly used dopaminergic agents on cognitive impaired faculties following pediatric TBI and the response to treatment, adding each dopaminergic agent names on keywords. Whenever pediatric data were scarce or inexistent, adult studies were incorporated. Results: The dopaminergic agents more widely used on cognitive dysfunction after pediatric TBI are amantadine, bromocriptine, levodopa and methylphenidate. After eligibility, research has resulted in eight pediatric articles for amantadine, five for bromocriptine (one pediatric and four adult articles), and three for levodopa (one pediatric and two adult articles) and eight pediatric articles for methylphenidate. Discussion: Based on our research data, amantadine has led to improvement in verbal memory, reaction time performance, executive functions and in Rancho Los Amigos Scale level. For arousal/awareness and level of consciousness, amantadine showed contradictory results. Bromocriptine and levodopa data are mainly based on adult studies. For bromocriptine, therapeutic results were controversial and inconclusive. They revealed improvement in level of consciousness and in certain cognitive skills, but a performance deterioration in working memory, attention and other cognitive functions, suggesting a selective positive effect in only cognitive processes involving prefrontal damage causing specifically executive impairment. All levodopa studies showed improvement in level of consciousness. Despite hardly any pediatric data and scarce adult data, their favorable safety and effectiveness results are promising. Methylphenidate data have shown improvement in SADHD symptoms, executive functions, responsiveness and other cognitive impairments, which confer a good basis for a formal indication of methylphenidate in pediatric post-TBI patients, however, the most effective and safe drug scheme and formulation aren´t fully clarified. Conclusions: Brain dopaminergic pathways are associated with complex mental functions and are crucial for cognition improvement post-TBI. This review grant evidence supporting the effectiveness and safety of amantadine in cognitive improvement after pediatric TBI, but, for arousal/awareness and level of consciousness, provide contradictory results. Regarding bromocriptine, data don´t confer sufficient evidence to make a recommendation of its use in pediatric TBI population with the drug schemes applied, because of its contradictory results and poor tolerability. The effective and safe results founded of levodopa justify further pediatric studies in order to make plausible recommendations of its use. Methylphenidate studies support its effectiveness and safety in cognitive impairment after TBI in children and are a good foundation to a formal indication of its use in pediatric post-TBI patients. Further studies with better methodology and larger samples are needed in order to clarify the contradictory results founded and achieve a solid evidence, in order to be the basis of future evidence-based treatment recommendations and protocols.
... The authors concluded that methylphenidate has the potential to mostly enhancing attentional capacity but not memory or processing speed. There have been indications that some pharmacological approaches may be useful in addressing aspects of executive dysfunction [65,66], but no studies have been forthcoming from the Eastern Mediterranean. This feasibility trial suggests that treatment with the catecholaminergic agonist, methylphenidate, impacted executive dysfunction. ...
Background:
Road traffic accidents are known to be the main cause of traumatic brain injury (TBI). TBI is also a leading cause of death and disability. This study, by means of the idiographic approach (single-case experimental designs using multiple-baseline designs), has examined whether methylphenidate (MPH - trade name Ritalin) had a differential effect on cognitive measures among patients with TBI with the sequel of acute and chronic post-concussion syndromes. The effect on gender was also explored.
Methods:
In comparison with healthy controls, patients with TBI (acute and chronic) and accompanying mild cognitive impairment (MCI) were screened for their integrity of executive functioning. Twenty-four patients exhibiting executive dysfunction (ED) were then instituted with the pharmacological intervention methylphenidate (MPH). The methylphenidate was administered using an uncontrolled, open label design.
Results:
The administration of methylphenidate impacted ED in the TBI group but had no effect on mood. Attenuation of ED was more apparent in the chronic phases of TBI. The effect on gender was not statistically significant with regard to the observed changes.
Conclusions:
To our knowledge, this is the first feasibility trial from the Arabian Gulf to report the performance of a TBI population with mild cognitive impairment according to the IQCODE Arabic version. This investigation confirms anecdotal observations of methylphenidate having the potential to attenuate cognitive impairment; particularly those functions that are critically involved in the integrity of executive functioning. The present feasibility trial should be followed by nomothetic studies such as those that adhere to the protocol of the randomized controlled trial. This evidence-based research is the foundation for intervention and future resource allocation by policy- or public health decision-makers.
... Dexamphetamine and lisdexamfetamine have also shown effective in controlling post-injury agitation and improvement in the speed of information processing, executive function, and working memory in TBI patients on 3 weeks and 12 weeks treatment respectively. However, the evidence for improvement in recovery is still needed to investigate in detail [284,[306][307][308]. ...
According to the World Health Organization, Traumatic brain injury the major cause of death and disability and will surpass the other diseases by the year 2020. Patients who suffer traumatic brain injury (TBI) face many difficulties which negatively affects their social and personal life. TBI patients suffer from changes in mood, impulsivity, poor social judgment and memory deficits. Both open and closed head injuries have their own consequences. Open head injury associated problems are specific in nature e.g. loss of motor functions whereas closed head injuries are diffused in nature like poor memory, problems in concentration etc. Brain injury may have a detrimental effect on the biochemical processes responsible for the homeostatic and physiological disturbances in the brain. Although significant research has been done in order to decrease the overall TBI-related mortality, many individuals suffer from a life-long disability. In this article, we have discussed the causes of TBI, its consequence and the pathobiology of secondary injury. We have also tried to discuss the evidence-based strategies which are shown to decline the devastating consequences of TBI.
... The pooled estimates with 95% CI were computed using inverse variance method with a random-effects model to account for the heterogeneity between studies. Crossover studies [11,15,16,23,26] were treated as paired groups, with the correlation coefficient between intervention and placebo set as 0.5. In studies where the outcomes were reported as the median and interquartile range [28], the sample mean and standard deviation were estimated based on previous literature [29]. ...
... The characteristics of the included studies, with a total of 462 patients are summarized in Table 1. With regards to the severity of TBIs, most of the studies reported moderate to severe injuries [14,16,19,[21][22][23]25,26]. Others were mild to moderate [15,18], mild to severe [11,12,24,27], and mild [17]. ...
This meta-analysis evaluated the effects of methylphenidate (MPH) on cognitive outcome and adverse events in adults with traumatic brain injuries (TBI). We searched PubMed, EMBASE, and PsycINFO for randomized controlled trials (RCTs) published before July 2019. Studies that compared the effects of MPH and placebos in adults with TBI were included. The primary outcome was cognitive function, while the secondary outcome was adverse events. Meta-regression and sensitivity analysis were conducted to evaluate heterogeneity. Seventeen RCTs were included for qualitative analysis, and ten RCTs were included for quantitative analysis. MPH significantly improved processing speed, measured by Choice Reaction Time (standardized mean difference (SMD): −0.806; 95% confidence interval (CI): −429 to −0.182, p = 0.011) and Digit Symbol Coding Test (SMD: −0.653; 95% CI: −1.016 to −0.289, p < 0.001). Meta-regression showed that the reaction time was inversely associated with the duration of MPH. MPH administration significantly increased heart rate (SMD: 0.553; 95% CI: 0.337 to 0.769, p < 0.001), while systolic or diastolic blood pressure did not exhibit significant differences. Therefore, MPH elicited better processing speed in adults with TBI. However, MPH use could significantly increase heart rate. A larger study is required to evaluate the effect of dosage, age, or optimal timing on treatment of adults with TBI.
... Studies of moderate to severe TBI using single-dose pharmacological challenge approaches have also provided evidence for alterations in working memory activation following MPH administration (17,18). Manktelow et al. (18) used a double blind, placebo-controlled crossover design to study the effects of a single 30 mg. dose in 15 patients with moderate to severe TBI and 15 healthy controls. ...
... In TBI patients the drug increased task-related activation within a portion of the left cerebellum to a level comparable to controls and this change was correlated with the improvement in working memory performance. Kim et al. (17) used perfusion fMRI and a block design visual letters n-back task with 21 moderate to severe TBI patients. The pharmacological challenge consisted of a single dose (0.3 mg/kg) of MPH that was delivered as part of a randomized double-blind, placebo-controlled crossover study design. ...
... Visual attention and response inhibition are cognitive functions that have also been studied in moderate to severe TBI patients using MPH (17,19). In addition to the n-back working memory paradigm that was described above, Kim et al. (17) also employed the Visual Sustained Attention Task (VSAT) block design fMRI paradigm with 18 of their study participants. ...
Positive effects of methylphenidate (MPH) on attention and cognitive processing speed have been reported in studies of patients with moderate to severe traumatic brain injury (TBI). Studies which have acquired functional brain imaging before and while using MPH have also found alteration of brain activation while performing a cognitive task; in some studies, this alteration of activation in selective brain regions was also related to improved performance on cognitive tests administered outside of the scanning environment. Enhanced cognitive performance has been reported after single doses of MPH and after daily treatment over durations of up to and exceeding 1 month. Preclinical research and both positron emission tomography and single photon emission tomography of humans have shown that MPH increases extracellular dopamine and norepinephrine; the dose effects of MPH have an inverted U-shaped function where high doses may cause insomnia, nervousness, and increased heart rate among other symptoms and impair cognitive performance, whereas too low a dose fails to improve cognitive performance. In the past 5 years, small clinical trials, and experimental pilot studies have found therapeutic effects of single and repeated low doses of MPH in patients with mild TBI who reported cognitive dysfunction. This literature also suggests that MPH may interact with concurrent cognitive interventions to enhance their effects. This focused review will critically evaluate the recent literature on MPH effects on cognitive dysfunction after mild to moderate TBI. To elucidate the neural mechanisms of MPH effects, this review will also include recent imaging research, preclinical, and experimental human studies.
... Many studies have found that methylphenidate treatment enhances processing speed in both adult and pediatric TBI populations (Willmott & Ponsford, 2009). Similar results have been found on measures of attention in both adult and pediatric TBI populations (Kim et al., 2012;Konrad, Gunther, Hanisch, & Herpertz-Dahlmann, 2004;Mahalick et al., 1998). The results of the current study add to the literature by demonstrating the efficacy of using dose titration to determine an optimal dose. ...
... The results of the current study add to the literature by demonstrating the efficacy of using dose titration to determine an optimal dose. Previous studies have utilized only one (Kim et al., 2012;Mahalick et al., 1998;Willmott & Ponsford, 2009) or two (Konrad et al., 2004) weight-dependent doses of methylphenidate. As assessments were administered while participants were taking their optimal dose, these results may be more representative of the performance of individuals being treated with methylphenidate in the long term. ...
Objective:
To investigate the effects of methylphenidate on long-term executive and neuropsychological functioning in children with attention problems following TBI, as well as the relationship between methylphenidate associated changes in lab-based neuropsychological measures of attentional control, processing speed, and executive functioning and parent- or self-report measures of everyday executive functioning.
Method:
26 children aged 6-17 years, who were hospitalized for moderate-to-severe blunt head trauma 6 or more months previously, were recruited from a large children's hospital medical center. Participants were randomized into a double-masked, placebo-controlled cross-over clinical trial. Participants completed a comprehensive neuropsychological battery and parent- and self-report ratings of everyday executive functioning at baseline, and at 4 weeks and 8 weeks following upward titration of medication to an optimal dose or while administered a placebo.
Results:
Methylphenidate was associated with significant improvements in processing speed, sustained attention, and both lab-based and everyday executive functioning. Significant treatment-by-period interactions were found on a task of sustained attention. Participants who were randomized to the methylphenidate condition for the first treatment period demonstrated random or erratic responding, with slower and more variable response times when given placebo during the second period.
Conclusion:
Results indicate that methylphenidate treatment is associated with positive outcomes in processing speed, sustained attention, and both lab-based and everyday measures of executive functioning compared to placebo group. Additionally, results suggest sustained attention worsens when discontinuing medication.
... The inferior to middle temporal cortex have been less associated with ADHD pathophysiology, but greater activation of those regions have been shown to be related to low response time variability (Spinelli et al. 2011). In addition, MPH elicited downregulation of the bilateral SPC regions, which was significantly correlated with improvement of symptom severity and attentional performance (An et al. 2013b;Cho et al. 2007;Kim et al. 2012). Taking that evidence into account, we can consider that the normalization of baseline hyperactivity in SPC and upregulation of IFG, DLPFC and ITG might be We could not find a significant ALFF/fALFF difference between the TDC and PreTx groups as previous studies reported (An et al. 2013a;Zang et al. 2007). ...
Methylphenidate is a first-line therapeutic option for treating attention-deficit/hyperactivity disorder (ADHD); however, elicited changes on resting-state functional networks (RSFNs) are not well understood. This study investigated the treatment effect of methylphenidate using a variety of RSFN analyses and explored the collaborative influences of treatment-relevant RSFN changes in children with ADHD. Resting-state functional magnetic resonance imaging was acquired from 20 medication-naïve ADHD children before methylphenidate treatment and twelve weeks later. Changes in large-scale functional connectivity were defined using independent component analysis with dual regression and graph theoretical analysis. The amplitude of low frequency fluctuation (ALFF) was measured to investigate local spontaneous activity alteration. Finally, significant findings were recruited to random forest regression to identify the feature subset that best explains symptom improvement. After twelve weeks of methylphenidate administration, large-scale connectivity was increased between the left fronto-parietal RSFN and the left insula cortex and the right fronto-parietal and the brainstem, while the clustering coefficient (CC) of the global network and nodes, the left fronto-parietal, cerebellum, and occipital pole-visual network, were decreased. ALFF was increased in the bilateral superior parietal cortex and decreased in the right inferior fronto-temporal area. The subset of the local and large-scale RSFN changes, including widespread ALFF changes, the CC of the global network and the cerebellum, could explain the 27.1% variance of the ADHD Rating Scale and 13.72% of the Conner’s Parent Rating Scale. Our multivariate approach suggests that the neural mechanism of methylphenidate treatment could be associated with alteration of spontaneous activity in the superior parietal cortex or widespread brain regions as well as functional segregation of the large-scale intrinsic functional network.
