Posts Tagged Clinical trials

[Abstract] Vision-Based Serious Games and Virtual Reality Systems for Motor Rehabilitation: A Review Geared Toward a Research Methodology

ABSTRACT

Background

Nowadays, information technologies are being widely adopted to promote healthcare and rehabilitation. Owing to their affordability and use of hand-free controllers, vision-based systems have gradually been integrated into motor rehabilitation programs and have greatly drawn the interest of healthcare practitioners and the research community. Many studies have illustrated the effectiveness of these systems in rehabilitation. However, the report and design aspects of the reported clinical trials were disregarded.

Objective

In this paper, we present a systematic literature review of the use of vision-based serious games and virtual reality systems in motor rehabilitation programs. We aim to propose a research methodology that engineers can use to improve the designing and reporting processes of their clinical trials.

Methods

We conducted a review of published studies that entail clinical experiments. Searches were performed using Web of Science and Medline (PubMed) electronic databases, and selected studies were assessed using the Downs and Black Checklist and then analyzed according to specific research questions.

Results

We identified 86 studies and our findings indicate that the number of studies in this field is increasing, with Korea and USA in the lead. We found that Kinect, EyeToy system, and GestureTek IREX are the most commonly used technologies in studying the effects of vision-based serious games and virtual reality systems on rehabilitation. Findings also suggest that cerebral palsy and stroke patients are the main target groups, with a particular interest on the elderly patients in this target population. The findings indicate that most of the studies focused on postural control and upper extremity exercises and used different measurements during assessment.

Conclusions

Although the research community’s interest in this area is growing, many clinical trials lack sufficient clarity in many aspects and are not standardized. Some recommendations have been made throughout the article.

via Vision-Based Serious Games and Virtual Reality Systems for Motor Rehabilitation: A Review Geared Toward a Research Methodology – ScienceDirect

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[ARTICLE] Neurotechnology-aided interventions for upper limb motor rehabilitation in severe chronic stroke – Full Text

Abstract

Upper limb motor deficits in severe stroke survivors often remain unresolved over extended time periods. Novel neurotechnologies have the potential to significantly support upper limb motor restoration in severely impaired stroke individuals. Here, we review recent controlled clinical studies and reviews focusing on the mechanisms of action and effectiveness of single and combined technology-aided interventions for upper limb motor rehabilitation after stroke, including robotics, muscular electrical stimulation, brain stimulation and brain computer/machine interfaces. We aim at identifying possible guidance for the optimal use of these new technologies to enhance upper limb motor recovery especially in severe chronic stroke patients. We found that the current literature does not provide enough evidence to support strict guidelines, because of the variability of the procedures for each intervention and of the heterogeneity of the stroke population. The present results confirm that neurotechnology-aided upper limb rehabilitation is promising for severe chronic stroke patients, but the combination of interventions often lacks understanding of single intervention mechanisms of action, which may not reflect the summation of single intervention’s effectiveness. Stroke rehabilitation is a long and complex process, and one single intervention administrated in a short time interval cannot have a large impact for motor recovery, especially in severely impaired patients. To design personalized interventions combining or proposing different interventions in sequence, it is necessary to have an excellent understanding of the mechanisms determining the effectiveness of a single treatment in this heterogeneous population of stroke patients. We encourage the identification of objective biomarkers for stroke recovery for patients’ stratification and to tailor treatments. Furthermore, the advantage of longitudinal personalized trial designs compared to classical double-blind placebo-controlled clinical trials as the basis for precise personalized stroke rehabilitation medicine is discussed. Finally, we also promote the necessary conceptual change from ‘one-suits-all’ treatments within in-patient clinical rehabilitation set-ups towards personalized home-based treatment strategies, by adopting novel technologies merging rehabilitation and motor assistance, including implantable ones.

Introduction

Stroke constitutes a major public health problem affecting millions of people worldwide with considerable impacts on socio-economics and health-related costs. It is the second cause of death (Langhorne et al., 2011), and the third cause of disability-adjusted life-years worldwide (Feigin et al., 2014): ∼8.2 million people were affected by stroke in Europe in 2010, with a total cost of ∼€64 billion per year (Olesen et al., 2012). Due to ageing societies, these numbers might still rise, estimated to increase 1.5–2-fold from 2010 to 2030 (Feigin et al., 2014).

Improving upper limb functioning is a major therapeutic target in stroke rehabilitation (Pollock et al., 2014Veerbeek et al., 2017) to maximize patients’ functional recovery and reduce long-term disability (Nichols-Larsen et al., 2005Veerbeek et al., 2011Pollock et al., 2014). Motor impairment of the upper limb occurs in 73–88% first time stroke survivors and in 55–75% of chronic stroke patients (Lawrence et al., 2001). Constraint-induced movement therapy (CIMT), but also standard occupational practice, virtual reality and brain stimulation-based interventions for sensory and motor impairments show positive rehabilitative effects in mildly and moderately impaired stroke victims (Pollock et al., 2014Raffin and Hummel, 2018). However, stroke survivors with severe motor deficits are often excluded from these therapeutic approaches as their deficit does not allow easily rehabilitative motor training (e.g. CIMT), treatment effects are negligible and recovery unpredictable (Byblow et al., 2015Wuwei et al., 2015Buch et al., 2016Guggisberg et al., 2017).

Recent neurotechnology-supported interventions offer the opportunity to deliver high-intensity motor training to stroke victims with severe motor impairments (Sivan et al., 2011). Robotics, muscular electrical stimulation, brain stimulation, brain computer/machine interfaces (BCI/BMI) can support upper limb motor restoration including hand and arm movements and induce neuro-plastic changes within the motor network (Mrachacz-Kersting et al., 2016Biasiucci et al., 2018).

The main hurdle for an improvement of the status quo of stroke rehabilitation is the fragmentary knowledge about the physiological, psychological and social mechanisms, their interplay and how they impact on functional brain reorganization and stroke recovery. Positive stimulating and negatively blocking adaptive brain reorganization factors are insufficiently characterized except from some more or less trivial determinants, such as number and time of treatment sessions, pointing towards the more the better (Kwakkel et al., 1997). Even the long accepted model of detrimental interhemispheric inhibition of the overactive contralesional brain hemisphere on the ipsilesional hemisphere is based on an oversimplification and lack of differential knowledge and is thus called into question (Hummel et al., 2008Krakauer and Carmichael, 2017Morishita and Hummel, 2017).

Here, we take a pragmatic approach of comparing effectiveness data, keeping this lack of knowledge of mechanisms in mind and providing novel ideas towards precision medicine-based approaches to individually tailor treatments to the characteristics and needs of the individual patient with severe chronic stroke to maximize rehabilitative outcome.[…]

Continue —>   Neurotechnology-aided interventions for upper limb motor rehabilitation in severe chronic stroke | Brain | Oxford Academic

Conceptualization of longitudinal personalized rehabilitation-treatment designs for patients with severe chronic stroke. Ideally, each patient with severe chronic stroke with a stable motor recovery could be stratified based on objective biomarkers of stroke recovery in order to select the most appropriate/promising neurotechnology-aided interventions and/or their combination for the specific case. Then, these interventions can be administered in the clinic and/or at home in sequence, moving from one to another only when patient’s motor recovery plateaus. In this way, comparisons of the efficacy of each intervention (grey arrows) are still possible, and if the selected interventions and/or their combination are suitable, motor recovery could increase.

Conceptualization of longitudinal personalized rehabilitation-treatment designs for patients with severe chronic stroke. Ideally, each patient with severe chronic stroke with a stable motor recovery could be stratified based on objective biomarkers of stroke recovery in order to select the most appropriate/promising neurotechnology-aided interventions and/or their combination for the specific case. Then, these interventions can be administered in the clinic and/or at home in sequence, moving from one to another only when patient’s motor recovery plateaus. In this way, comparisons of the efficacy of each intervention (grey arrows) are still possible, and if the selected interventions and/or their combination are suitable, motor recovery could increase.

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[ARTICLE] The Importance of Therapeutic Time Window in the Treatment of Traumatic Brain Injury – Full Text

Traumatic brain injury (TBI) is a major cause of death and disability. Despite its importance in public health, there are presently no drugs to treat TBI. Many reasons underlie why drugs have failed clinical trials, one reason is that most drugs to treat TBI lose much of their efficacy before patients are first treated. This review discusses the importance of therapeutic time window; the time interval between TBI onset and the initiation of treatment. Therapeutic time window is complex, as brain injury is both acute and chronic, resulting in multiple drug targets that appear and disappear with differing kinetics. The speed and increasing complexity of TBI pathophysiology is a major reason why drugs lose efficacy as time to first dose increases. Recent Phase III clinical trials treated moderate to severe TBI patients within 4–8 h after injury, yet they turned away many potential patients who could not be treated within these time windows. Additionally, most head trauma is mild TBI. Unlike moderate to severe TBI, patients with mild TBI often delay treatment until their symptoms do not abate. Thus, drugs to treat moderate to severe TBI likely will need to retain high efficacy for up to 12 h after injury; drugs for mild TBI, however, will likely need even longer windows. Early pathological events following TBI progress with similar kinetics in humans and animal TBI models suggesting that preclinical testing of time windows assists the design of clinical trials. We reviewed preclinical studies of drugs first dosed later than 4 h after injury. This review showed that therapeutic time window can differ depending upon the animal TBI model and the outcome measure. We identify the few drugs (methamphetamine, melanocortin, minocycline plus N-acetylcysteine, and cycloserine) that demonstrated good therapeutic windows with multiple outcome measures. On the basis of their therapeutic window, these drugs appear to be excellent candidates for clinical trials. In addition to further testing of these drugs, we recommend that the assessment of therapeutic time window with multiple outcome measures becomes a standard component of preclinical drug testing.

Therapeutic Time Window is a Key Element of Drugs to Treat TBI

Despite decades of research, there are currently no treatments for TBI other than palliative care (Diaz-Arrastia et al., 2014). The reasons for the lack of therapeutics are many; drug may have failed in clinical trials since most preclinical studies dose drugs immediately or soon after experimental TBI (Diaz-Arrastia et al., 2014). This experimental design fails to take into account the well-documented clinical phenomenon of treatment gap: the time individuals wait before seeking medical care after head trauma (Tanielian and Jaycox, 2008Demakis and Rimland, 2010). In 1991, one quarter of an estimated 1.5 million patients in America did not seek medical care after receiving a TBI that did not result in death or long-term institutionalization (Sosin et al., 1996). The multiple reasons given to postpone or avoid treatment include perceived symptom resolution, as well as the time and cost of treatment (Demakis and Rimland, 2010). Military personnel are particularly at risk for TBI. Lack of access to safe and accessible transportation for deployed military personnel can delay treatment up to 72 h after TBI (Farmer et al., 2017). Thus, treatment gap likely contributes to negative outcomes after TBI. Despite the importance of treatment gap, we know relatively little about the time course of pathophysiological events that can be successfully targeted with drugs first dosed many hours to days following TBI.

The treatment of thromboembolic stroke using tissue plasminogen activator illustrates the importance of time window in neurodegenerative diseases with a rapid onset. Thromboembolic stroke produces a complex and rapidly evolving injury with an overlapping, yet distinct, pathophysiology to TBI. Tissue plasminogen activator (t-PA) is highly effective if dosed within 4.5 h of a stroke, yet its utility drops sharply after 4.5 h due to the increased probability of hemorrhage (Ahmed et al., 2013). Despite its established ability to prevent injury, only 2–5% of stroke patients receive t-PA (Miller et al., 2011). A major reason for the limited use of t-PA is its short time window (Miller et al., 2011). The experience of clinicians with t-PA to treat stoke suggests similar difficulties will arise if drugs to treat TBI have similarly short therapeutic time windows that fall off sharply.

Since no drug has received FDA-approval, a key unanswered question is: what is a clinically relevant therapeutic window for a TBI drug? Clinical trials at designated trauma centers have enrolled patients 4–7 h after a moderate to severe TBI. Even with the high skill of the clinical staff at these trauma centers; many patients could not be enrolled because treatment could not be initiated within 4–7 h. Less specialized hospitals are likely to have even longer treatment delays. To treat the largest number of patients, a drug or drug combination will likely need to retain high efficacy when first dosed 12 h after moderate to severe TBI. In contrast to those with severe or moderate TBI, patients with mild TBI often delay seeking medical help for days after injury until their symptoms do not abate (Sosin et al., 1996Tanielian and Jaycox, 2008Demakis and Rimland, 2010). Thus, drugs will need to retain efficacy when dosed days after injury to treat large numbers of patients with mild TBI.

Traumatic brain injury has a complex pathophysiology whether initiated by a blunt impact, penetration through the skull into the brain, or exposure to explosive blast (Dixon, 2017). TBI produces mechanical injury within seconds to neurons, glia, and vessels. This primary injury rapidly triggers a secondary injury that evolves for weeks to months (Dixon, 2017). Both primary and secondary injury damages both gray and white matter. Within minutes after primary injury, neurons lose the ability to control ion homeostasis, which results in accumulation of intracellular calcium, cell depolarization, excitotoxic release of glutamate and additional disruptions of ionic gradients (Weber, 2012Guerriero et al., 2015). Impaired mitochondrial function leads to energy failure; calcium accumulation and elevated reactive oxygen species are additional early events in secondary injury (Bains and Hall, 2012Weber, 2012Hill et al., 2017). Damage to vessels reduces cerebral blood flow resulting in hypoxia, hypoglycemia, and breakdown of the blood-brain barrier (Price et al., 2016). Inflammation rapidly follows TBI and persists for weeks to months after injury (Hinson et al., 2015). Acute inflammation is initiated by release by necrotic cells of damage associated molecular patterns (DAMPS) that activate astrocytes and microglia. Release of proinflammatory cytokines and chemokines lead to further breakdown of the blood brain barrier and recruitment of peripheral inflammatory cells. Microglia and astrocyte activation occurs rapidly in both gray and white matter; neuroinflammation may become chronic and continue to injure brain for months or years after injury. Later events in secondary injury include induction of cytogenic and vasogenic edema, increased intracerebral pressure, oxidative damage and necrotic and apoptotic cell loss (Bains and Hall, 2012Hill et al., 2017). Early events in white matter include damage to axons, impaired transport and swelling. Damage to oligodendrocytes leads to demyelination and oligodendrocyte loss (Narayana, 2017). White matter damage evolves for weeks resulting in Wallerian axonal degeneration.

The pathophysiological events of secondary injury are highly interconnected. If dosed before, or soon after TBI, a variety of drugs with diverse modes of action (anti-oxidants, glutamate receptor antagonists, and anti-inflammatories) greatly limit the scope of secondary injury (Diaz-Arrastia et al., 2014). These drugs are effective despite targeting only one component of secondary injury. This suggests that, early after TBI, multiple pathophysiological events trigger the spread of secondary injury. Thus, early blockade of any one of these many injury mechanisms results in a substantial, long-term therapeutic effect. As secondary injury evolves, the efficacy of most drugs rapidly diminish through loss of drug targets; the intensification of secondary injury greatly diminishes the therapeutic effect of inhibiting one injury mechanism. Drugs that retain efficacy when dosed at longer intervals after injury may target pathophysiological events that initiate slowly after injury. Alternatively, drugs with good therapeutic windows have multiple targets that can still reduce secondary injury even after its intensification over time.

The importance of therapeutic time window in treating TBI is illustrated by comparing the preclinical testing of progesterone and CDP-choline with the design of Phase III clinical trials testing the same drugs. Progesterone was tested in two recent Phase III trials for TBI. The PROTECT III trial (NCT00822900) recruited patients with moderate to severe TBI (Glasgow Coma Score 4–12) within 4 h post-injury while the SYNAPSE trial (NCT01143064) recruited patients with severe TBI (Glasgow Coma Score < 7) within 7 h (Skolnick et al., 2014Wright et al., 2014). Both trials were unable to demonstrate a therapeutic effect for progesterone. Prior to Phase III testing, numerous laboratories demonstrated a diverse set of therapeutic effects of progesterone in multiple rodent TBI models (Stein and Sayeed, 2018). Progesterone reduced glutamate release, prevented vasogenic edema, restored the blood brain barrier, improved aerobic respiration, and increased myelin and neurotrophin synthesis. Most importantly, progesterone reduced brain damage and improved multiple functional outcomes. Few drugs have had such wide preclinical testing on so many therapeutic outcomes. Virtually all of these studies, however, first dosed progesterone within 1 h or less after injury (Stein and Sayeed, 2018). Only three studies dosed progesterone between 4 and 6 h after injury and none of these studies performed a careful analysis of how the efficacy of progesterone changed after injury (Peterson et al., 20122015). A first dose of progesterone 4 h after experimental TBI decreased gray matter damage, improved motor function and limited astrocyte activation (Peterson et al., 20122015). A first dose at 6 h produced small improvements on expression of Nogo-A, GFAP, and GAP-43 (Liu et al., 2014). None of these studies examined multiple therapeutic time windows so it remains unknown how the efficacy of progesterone changed with increasingly longer times to first dose. A study of a first dose of progesterone 1 or 6 h post-stroke showed good retention of drug efficacy in a rat cerebral ischemia model (Yousuf et al., 2014). Little is understood, however, of how the analysis of therapeutic time window in animal models of stroke tells us whether an equivalent therapeutic window exists for TBI. The PROTECT III and SYNAPSE trials provided important information of how rapidly we could recruit and treat patients after moderate to severe TBI, however, due to the lack of appropriate preclinical testing, we do not know if progesterone retained sufficient potency to treat TBI when first dosed at 4–7 h after injury.

The Phase 3 COBRIT study tested the efficacy of CDP-choline on mild, moderate and severe TBI (Zafonte et al., 2012). Most patients (86%) received drugs within the first 24 h after injury. The COBRIT study did not show improvement in any outcome measures. Compared to progesterone, there was relatively little preclinical testing of CHP-choline. Dixon et al. showed that a first dose of CDP-choline beginning 24 h after injury produced mild improvements on beam balance and beam walk, and on acquisition of Morris water maze (Dixon et al., 1997). Two additional studies that dosed CDP-choline immediately after injury reported decreased lesion volume, increased neuroprotection, improvements in neurological tests, edema and protection of the blood brain barrier (Başkaya et al., 2000Dempsey and Raghavendra Rao, 2003). A potential hypothesized mechanism of action of CDP-choline was to improve lipid metabolism, yet no study examined whether CDP-choline limited white matter injury. As with progesterone, there are no studies examining the efficacy of CDP-choline at different therapeutic time windows. Thus, inadequate drug potency at the time when patients were treated may have contributed to the futility of the PROTECT III, SYNAPSE, and COBRIT trials.

TBI Pathophysiology is a Major Determinant of Therapeutic Time Window

The speed of secondary injury after TBI results in the rapid appearance and disappearance of drug targets (Dixon, 2017). Studies of the therapeutic time windows of methyl-d-aspartate (NMDA) receptor agonists and antagonists illustrate how therapeutic time windows arise from the interaction of drugs with changes in TBI pathophysiological changes over time (Guerriero et al., 2015). Excessive glutamate release activates NMDA receptors within minutes after the onset of TBI (Guerriero et al., 2015). NMDA receptor activation produces calcium overload and activation of calcium-activated catabolic enzymes (Weber, 2012). If dosed soon after injury, NMDA antagonists prevent this calcium overload and prevent neuronal loss (Shohami and Biegon, 2013). The short therapeutic time window of NMDA receptor antagonists is the consequence of the speed of the calcium overload after TBI (Shohami and Biegon, 2013Campos-Pires et al., 2015). Ongoing secondary injury subsequently produces a long-lasting downregulation of NMDA receptor expression. The loss of NMDA receptor function impairs synaptic plasticity and results in cognitive and memory deficits. The partial NMDA receptor agonist D-cycloserine when first dosed at 24 or 72 h post-injury improves Neurological Severity Score (NSS). A first dose of d-cycloserine at 24 h PI also improved performance of hippocampal-dependent tasks (Temple and Hamm, 1996Adeleye et al., 2010Sta Maria et al., 2017). A first dose of cycloserine at 24 h post-injury was also effective in rat model of pediatric TBI (Sta Maria et al., 2017). D-cycloserine improved performance on Novel Object Recognition and produced a mild improvement in acquisition, but not retention of Morris Water Maze (Sta Maria et al., 2017). Earlier dosing of d-cycloserine was ineffective at 8 or 16 h post-injury when NMDA receptors were downregulated (Adeleye et al., 2010). Thus, the different therapeutic time windows of NMDA receptor antagonists and agonists results from the differential consequences of NMDA receptor activation after TBI (Shohami and Biegon, 2013).

Are Studies of Therapeutic Time Window in Animal Models Relevant to Human TBI?

Animal models of TBI have been invaluable for our understanding of TBI pathophysiology (Xiong et al., 2013). Most of the secondary injury events that occur in clinical TBI also occur in animal models. This has validated the use of animal models to find drug targets to treat TBI. Virtually all studies of therapeutic time window have used rodent TBI models (Table 1 and Supplementary Table 1). Studies of therapeutic time window in rodents not only assume similar TBI pathophysiology in animals and people, but that these pathophysiological events occur with similar kinetics. Both humans and rodents rapidly develop edema, elevated extracellular glutamate, excitotoxicity and elevated intracellular Ca++2 after TBI or experimental TBI (Palmer et al., 1993Bullock et al., 1995Vespa et al., 1998Markgraf et al., 2001Hutchinson, 2005Weber, 2012). The increase in reactive oxygen species and its accompanying oxidative damage also occurs rapidly in animals and people (Bains et al., 2013Cornelius et al., 2013). A variety of plasma biomarkers (GFAP, UCh-1, Tau, and S100β) show similar kinetics in rodent TBI models and clinical TBI (Mondello et al., 2016Caprelli et al., 2017Korley et al., 2018Shahjouei et al., 2018). In both human TBI and TBI animal models, there is an acute and rapid increase in the levels of pro-inflammatory markers (Clausen et al., 2018Huie et al., 2018). These data suggest that studies using rodent TBI model can provide important insights into the therapeutic window of a drug to treat clinical TBI.

Table 1. Drugs with a therapeutic time window of 12 h or greater in animal models of TBI.

[…]

 

Continue —>  Frontiers | The Importance of Therapeutic Time Window in the Treatment of Traumatic Brain Injury | Neuroscience

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[Abstract] Effects of constraint-induced movement therapy for lower limbs on measurements of functional mobility and postural balance in subjects with stroke: a randomized controlled trial

Background: Constraint-induced movement therapy (CIMT) is suggested to reduce functional asymmetry between the upper limbs after stroke. However, there are few studies about CIMT for lower limbs.

Objective: To examine the effects of CIMT for lower limbs on functional mobility and postural balance in subjects with stroke.

Methods: A 40-day follow-up, single-blind randomized controlled trial was performed with 38 subacute stroke patients (mean of 4.5 months post-stroke). Participants were randomized into: treadmill training with load to restraint the non-paretic ankle (experimental group) or treadmill training without load (control group). Both groups performing daily training for two consecutive weeks (nine sessions) and performed home-based exercises during this period. As outcome measures, postural balance (Berg Balance Scale – BBS) and functional mobility (Timed Up and Go test – TUG and kinematic parameters of turning – Qualisys System of movement analysis) were obtained at baseline, mid-training, post-training and follow-up.

Results: Repeated-measures ANOVA showed improvements after training in postural balance (BBS: F = 39.39, P < .001) and functional mobility, showed by TUG (F = 18.33, P < .001) and by kinematic turning parameters (turn speed: F = 35.13, P < .001; stride length: F = 29.71, P < .001; stride time: F = 13.42, P < .001). All these improvements were observed in both groups and maintained in follow-up.

Conclusions: These results suggest that two weeks of treadmill gait training associated to home-based exercises can be effective to improve postural balance and functional mobility in subacute stroke patients. However, the load addition was not a differential factor in intervention.

 

via Effects of constraint-induced movement therapy for lower limbs on measurements of functional mobility and postural balance in subjects with stroke: a randomized controlled trial: Topics in Stroke Rehabilitation: Vol 24, No 8

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[Poster] Feasibility of Online Training and Certification for the Fugl-Meyer Motor Assessment in Stroke Recovery Trials

Abstract

Introduction: Standardized measurement of clinical outcomes across sites and over time is critical to clinical trials. Barriers to outcome measure training include availability of standardized materials and time to train, plus wide geographic distribution of trial personnel. To address these, an online training and certification program based on NIHSS testing was developed and implemented for the Fugl Meyer Motor Assessment (FMMA) in support of multisite stroke recovery trials.

Methods: This program includes Fugl Meyer Arm (FMA) and Leg (FML) components, runs on a web host, and is based on a valid, reliable approach to FMMA testing known to decrease variance in scoring (See et al, NNR, 2013;27:732-741). The website hosts training courses, reference manuals, video patient cases for formal certification testing plus 3 rounds of recertification; each round has 2 separate patients. A passing score of 90% is required. After each course, feedback is given.

Results: This program has served as the primary training, certification, and recertification mechanism for 4 multisite recovery trials, including 1 NIH-funded US trial and 3 industry-sponsored international trials. Three trials certify on both FMA and FML, and 1 on FMA only, as primary endpoint. Evaluators are recertified every 4-6 months. The 299 clinicians from 5 countries registered include PT/OT (n=136), MD (n=37), and RN/NP/PA (n=15). For FMA training, 299 persons have registered and 197 completed. For the first round of FMA certification, 267 have registered and 171 passed (mean 1.89 attempts to pass). For the second FMA (first recertification), 78 registered and 65 passed. The passing rate increased with successive rounds of recertification. Similar numbers have been achieved for FML training, certification, and recertification.

Conclusions: The FMMA has established value for capturing treatment-related motor gains in stroke recovery trials. The current online training program is efficient and effective for training, certifying, and recertifying examiners in arm and leg FMMA. Clinical trial assessors training with this program can be expected to provide more accurate and less variable FMMA scores, which increases statistical power, reduces sample sizes, and reduces the cost of clinical trials.

 

via Abstract TP141: Feasibility of Online Training and Certification for the Fugl-Meyer Motor Assessment in Stroke Recovery Trials | Stroke

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[REVIEW] Photobiomodulation for Traumatic Brain Injury and Stroke – Abstract

Abstract

There is a notable lack of therapeutic alternatives for what is fast becoming a global epidemic of traumatic brain injury (TBI). Photobiomodulation (PBM) employs red or near-infrared (NIR) light (600–1100nm) to stimulate healing, protect tissue from dying, increase mitochondrial function, improve blood flow, and tissue oxygenation. PBM can also act to reduce swelling, increase antioxidants, decrease inflammation, protect against apoptosis, and modulate microglial activation state. All these mechanisms of action strongly suggest that PBM delivered to the head should be beneficial in cases of both acute and chronic TBI. Most reports have used NIR light either from lasers or from light-emitting diodes (LEDs). Many studies in small animal models of acute TBI have found positive effects on neurological function, learning and memory, and reduced inflammation and cell death in the brain. There is evidence that PBM can help the brain repair itself by stimulating neurogenesis, upregulating BDNF synthesis, and encouraging synaptogenesis. In healthy human volunteers (including students and healthy elderly women), PBM has been shown to increase regional cerebral blood flow, tissue oxygenation, and improve memory, mood, and cognitive function. Clinical studies have been conducted in patients suffering from the chronic effects of TBI. There have been reports showing improvement in executive function, working memory, and sleep. Functional magnetic resonance imaging has shown modulation of activation in intrinsic brain networks likely to be damaged in TBI (default mode network and salience network).

via Photobiomodulation for Traumatic Brain Injury and Stroke – Hamblin – 2017 – Journal of Neuroscience Research – Wiley Online Library

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[Abstract+References] Cell Therapy in Stroke—Cautious Steps Towards a Clinical Treatment

Abstract

In the future, stroke patients may receive stem cell therapy as this has the potential to restore lost functions. However, the development of clinically deliverable therapy has been slower and more challenging than expected. Despite recommendations by STAIR and STEPS consortiums, there remain flaws in experimental studies such as lack of animals with comorbidities, inconsistent approaches to experimental design, and concurrent rehabilitation that might lead to a bias towards positive results. Clinical studies have typically been small, lacking control groups as well as often without clear biological hypotheses to guide patient selection. Furthermore, they have used a wide range of cell types, doses, and delivery methods, and outcome measures. Although some ongoing and recent trial programs offer hints that these obstacles are now being tackled, the Horizon2020 funded RESSTORE trial will be given as an example of inconsistent regulatory requirements and challenges in harmonized cell production, logistic, and clinical criteria in an international multicenter study. The PISCES trials highlight the complex issues around intracerebral cell transplantation. Therefore, a better understanding of translational challenges is expected to pave the way to more successful help for stroke patients.

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via Cell Therapy in Stroke—Cautious Steps Towards a Clinical Treatment | SpringerLink

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[Abstract] Effects of dextroamphetamine in subacute traumatic brain injury: A randomized, placebo‐controlled pilot study

 Abstract

Psychostimulants that affect neurotransmitters implicated in cognitive function and neural plasticity have potential to enhance the rate and extent of recovery after traumatic brain injury (TBI). Ten milligrams dextroamphetamine (DEX) or an identical placebo was administered daily for 3 weeks to 32 participants with moderate to severe TBI, engaged in inpatient rehabilitation, at a mean of 2 months post injury. A variety of outcome measures assessing cognitive function and overall functional status was administered at weekly intervals, to examine effect sizes that may inform a larger trial, and to evaluate safety. Results indicated trivial-to-small effect sizes for DEX-placebo differences, with the largest effects seen on speed of information processing (more improvement with DEX) and agitation (exacerbation with DEX). Examination of adverse events and vital signs suggested safety of DEX, but the pattern of results did not suggest accelerated recovery due to the drug. Future trials of DEX in this population need to consider the impact of floor effects of commonly used measures of cognitive and physical function, and the heterogeneity of TBI. Although the small sample precludes definitive conclusions, these findings are not encouraging with regard to clinical trials of DEX in subacute TBI.

Source: Effects of dextroamphetamine in subacute traumatic brain injury: A randomized, placebo‐controlled pilot study

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[REPORT] Progress report on new antiepileptic drugs: A summary of the Eleventh Eilat Conference (EILAT XI) – Full Text HTML

Summary

The Eleventh Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT XI, took place in Eilat, Israel from the 6th to 10th of May 2012.

About 100 basic scientists, clinical pharmacologists and neurologists from 20 countries attended the conference, whose main themes included “Indications overlapping with epilepsy” and “Securing the successful development of an investigational antiepileptic drug in the current environment”.

Consistent with previous formats of this conference, a large part of the program was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 1994. Like the EILAT X report, the current manuscript focuses only on the preclinical and clinical pharmacology of AEDs that are currently in development. These include brivaracetam, 2-deoxy-glucose, ganaxolone, ICA-105665, imepitoin, NAX 801-2, perampanel and other AMPA receptor antagonists, tonabersat, valnoctamide and its homologue sec-propylbutylacetamide (SPD), VX-765 and YK3089.

Since the previous Eilat conference, retigabine (ezogabine) has been marketed and four newer AEDs in development (NAX 810-2, SPD, tonabersat and VX-765) are included in this manuscript.

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Full Text HTML –> Progress report on new antiepileptic drugs: A summary of the Eleventh Eilat Conference (EILAT XI).

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[ARTICLE] Applications of Brain–Machine Interface Systems in Stroke Recovery and Rehabilitation – Full Text HTML

Abstract

Stroke is a leading cause of disability, significantly impacting the quality of life (QOL) in survivors, and rehabilitation remains the mainstay of treatment in these patients.

Recent engineering and technological advances such as brain–machine interfaces (BMI) and robotic rehabilitative devices are promising to enhance stroke neurorehabilitation, to accelerate functional recovery and improve QOL.

This review discusses the recent applications of BMI and robotic-assisted rehabilitation in stroke patients. We present the framework for integrated BMI and robotic-assisted therapies, and discuss their potential therapeutic, assistive and diagnostic functions in stroke rehabilitation.

Finally, we conclude with an outlook on the potential challenges and future directions of these neurotechnologies, and their impact on clinical rehabilitation.

Full Text HTML–> Applications of Brain–Machine Interface Systems in Stroke Recovery and Rehabilitation – Springer.

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