Methylphenidate-mediated motor control network enhancement in patients with traumatic brain injury.

PRIMARY OBJECTIVE: To investigate functional improvement late (>6 months) after traumatic brain injury (TBI). To this end, we conducted a double-blind, placebo-controlled experimental medicine study to test the hypothesis that a widely used cognitive enhancer would benefit patients with TBI. RESEARCH DESIGN: We focused on motor control function using a sequential finger opposition fMRI paradigm in both patients and age-matched controls. METHODS AND PROCEDURES: Patients' fMRI and DTI scans were obtained after randomised administration of methylphenidate or placebo. Controls were scanned without intervention. To assess differences in motor speed, we compared reaction times from the baseline condition of a sustained attention task. MAIN OUTCOMES AND RESULTS: Patients' reaction times correlated with wide-spread motor-related white matter abnormalities. Administration of methylphenidate resulted in faster reaction times in patients, which were not significantly different from those achieved by controls. This was also reflected in the fMRI findings in that patients on methylphenidate activated the left inferior frontal gyrus significantly more than when on placebo. Furthermore, stronger functional connections between pre-/post-central cortices and cerebellum were noted for patients on methylphenidate. CONCLUSIONS: Our findings suggest that residual functionality in patients with TBI may be enhanced by a single dose of methylphenidate.The study was funded by the Evelyn Trust- grant number 06/20. C.D. was funded by the Clinical Academic Research Awards organized by the East of England Multi Professional Deanery. B.J.S. consults for Cambridge Cognition, Otsuka, Servier and Lundbeck. She holds a grant from Janssen/J&J and has share options in Cambridge Cognition. D.K.M. is supported by the Neuroscience Theme of the NIHR Cambridge Biomedical Research Centre and NIHR Senior Investigator awards, and by Framework Program 7 funding from the European Commission (TBIcare). He has received lecture and consultancy fees and support for research from Glaxo SmithKline, Solvay and Linde. E.A.S. is funded by the Stephen Erskine Fellowship, Queens' College, Cambridge, UK

THE EFFECTS OF ATOMOXETINE ON COGNITIVE PERFORMACE AND NEUROPLASTICITY AFTER TRAUMATIC BRAIN INJURY

Catecholaminergic neurotransmission is regionally altered following injury, and drugs aimed at these systems offer promising avenues for post-TBI pharmacotherapies. Atomoxetine is a selective norepinephrine transporter (NET) inhibitor currently indicated for treatment of attention-deficit hyperactivity disorder (ADHD). The studies in this dissertation were designed to test the efficacy of atomoxetine for treating cognitive deficits following experimental TBI and the potential mechanism for any beneficial effect. The first part of the study focused on behavioral recovery following atomoxetine treatment. Several important questions of dose, therapeutic window, and duration of treatment were addressed in these studies. Sprague-Dawley rats were subjected to lateral fluid-percussion injury (L-FPI) of moderate severity (2.08 atm +/- .05). Four experiments were performed. In the first study, atomoxetine (.3 mg/kg, 1mg/kg, 3 mg/kg, or 9 mg/kg) or vehicle was administered daily on post injury days (PID) 1-15. Cognitive assessment was performed using the Morris water maze on PID 11-15. L-FPI resulted in significant cognitive impairment when compared to Sham-Injury. Treatment with lower doses of atomoxetine (.3mg/kg, 1mg/kg, and 3mg/kg) significantly attenuated the cognitive deficits in injured animals. Treatment with the higher dosage (9mg/kg) of atomoxetine resulted in animals that were not significantly different than injured-vehicle treated animals. The optimal response was achieved using 1 mg/kg atomoxetine. In the second study, treatment with atomoxetine (1mg/kg) or vehicle was delayed for 11 days post-injury. Rats were administered atomoxetine daily for 15 days and cognitive assessment was performed on PID 25-29. In this study, treatment with atomoxetine (1 mg/kg) did not result in improved cognitive performance. In the next study atomoxetine was given daily on PID 1-7 and then treatment was terminated. The animals were tested in the MWM on PID 11-15. We found that atomoxetine treatment for 7 days post-injury provides an enhancement of cognitive deficits that is not significantly different from sham animals. We then investigated whether a single treatment of atomoxetine 24 h after brain injury could influence behavioral outcome on days 11-15. From this study, we found a single dose of atomoxetine is not as effective as chronic treatment. Finally, we investigated changes in the protein expression of brain-derived neurotrophic factor, growth-associated protein-43, and synaptophysin on day 7 PID to investigate what effect atomoxetine may have on brain plasticity and regeneration. We found that atomoxetine can enhance both GAP-43 and BDNF, but not synaptophysin at this time point. In conclusion, this is the first study to show that low doses of atomoxetine initiated early after experimental traumatic brain injury results in improved cognition. Furthermore, we show that enhancement of catecholamines via atomoxetine treatment during periods of postinjury-induced plasticity can provide long-term functional and structural benefits

Enhancing Nervous System Recovery through Neurobiologics, Neural Interface Training, and Neurorehabilitation.

After an initial period of recovery, human neurological injury has long been thought to be static. In order to improve quality of life for those suffering from stroke, spinal cord injury, or traumatic brain injury, researchers have been working to restore the nervous system and reduce neurological deficits through a number of mechanisms. For example, neurobiologists have been identifying and manipulating components of the intra- and extracellular milieu to alter the regenerative potential of neurons, neuro-engineers have been producing brain-machine and neural interfaces that circumvent lesions to restore functionality, and neurorehabilitation experts have been developing new ways to revitalize the nervous system even in chronic disease. While each of these areas holds promise, their individual paths to clinical relevance remain difficult. Nonetheless, these methods are now able to synergistically enhance recovery of native motor function to levels which were previously believed to be impossible. Furthermore, such recovery can even persist after training, and for the first time there is evidence of functional axonal regrowth and rewiring in the central nervous system of animal models. To attain this type of regeneration, rehabilitation paradigms that pair cortically-based intent with activation of affected circuits and positive neurofeedback appear to be required-a phenomenon which raises new and far reaching questions about the underlying relationship between conscious action and neural repair. For this reason, we argue that multi-modal therapy will be necessary to facilitate a truly robust recovery, and that the success of investigational microscopic techniques may depend on their integration into macroscopic frameworks that include task-based neurorehabilitation. We further identify critical components of future neural repair strategies and explore the most updated knowledge, progress, and challenges in the fields of cellular neuronal repair, neural interfacing, and neurorehabilitation, all with the goal of better understanding neurological injury and how to improve recovery

Does non-invasive brain stimulation modify hand dexterity? Protocol for a systematic review and meta-analysis

peer reviewedIntroduction: Dexterity is described as coordinated hand and finger movement for precision tasks. It is essential for day-to-day activities like computer use, writing or buttoning a shirt. Integrity of brain motor networks is crucial to properly execute these fine hand tasks. When these networks are damaged, interventions to enhance recovery are frequently accompanied by unwanted side effects or limited in their effect. Non-invasive brain stimulation (NIBS) are postulated to target affected motor areas and improve hand motor function with few side effects. However, the results across studies vary, and the current literature does not allow us to draw clear conclusions on the use of NIBS to promote hand function recovery. Therefore, we developed a protocol for a systematic review and meta-analysis on the effects of different NIBS technologies on dexterity in diverse populations. This study will potentially help future evidence-based research and guidelines that use these NIBS technologies for recovering hand dexterity. Methods and analysis: This protocol will compare the effects of active versus sham NIBS on precise hand activity. Records will be obtained by searching relevant databases. Included articles will be randomised clinical trials in adults, testing the therapeutic effects of NIBS on continuous dexterity data. Records will be studied for risk of bias. Narrative and quantitative synthesis will be done. Ethics and dissemination: No private health information is included; the study is not interventional. Ethical approval is not required. The results will be reported in a peer-review journal. © 2017 Article author(s). All rights reserved

Overview of Crosstalk Between Multiple Factor of Transcytosis in Blood Brain Barrier.

Blood brain barrier (BBB) conserves unique regulatory system to maintain barrier tightness while allowing adequate transport between neurovascular units. This mechanism possess a challenge for drug delivery, while abnormality may result in pathogenesis. Communication between vascular and neural system is mediated through paracellular and transcellular (transcytosis) pathway. Transcytosis itself showed dependency with various components, focusing on caveolae-mediated. Among several factors, intense communication between endothelial cells, pericytes, and astrocytes is the key for a normal development. Regulatory signaling pathway such as VEGF, Notch, S1P, PDGFβ, Ang/Tie, and TGF-β showed interaction with the transcytosis steps. Recent discoveries showed exploration of various factors which has been proven to interact with one of the process of transcytosis, either endocytosis, endosomal rearrangement, or exocytosis. As well as providing a hypothetical regulatory pathway between each factors, specifically miRNA, mechanical stress, various cytokines, physicochemical, basement membrane and junctions remodeling, and crosstalk between developmental regulatory pathways. Finally, various hypotheses and probable crosstalk between each factors will be expressed, to point out relevant research application (Drug therapy design and BBB-on-a-chip) and unexplored terrain