Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
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Transcranial magnetic stimulation (TMS) is a diagnostic and therapeutic modality that is being developed as both an acute and preventive treatment for migraine. TMS delivers a fluctuating magnetic field from the scalp surface to induce current in the subjacent cortex. Magnetic pulses are delivered one at a time in single-pulse TMS (sTMS) or as a train of pulses in repetitive TMS (rTMS). ⋯ Based on the theory that rTMS alters brain excitability and neurotransmitter activity, rTMS has been studied as a preventive migraine treatment. A small body of evidence suggests that rTMS may have a role, but further studies are needed. In this review, we summarize the data on TMS as a treatment of migraine, and we suggest directions for future research.
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Calcitonin gene-related peptide (CGRP) is expressed throughout the central and peripheral nervous systems, consistent with control of vasodilatation, nociception, motor function, secretion, and olfaction. alphaCGRP is prominently localized in primary spinal afferent C and ADelta fibers of sensory ganglia, and betaCGRP is the main isoform in the enteric nervous system. In the CNS there is a wide distribution of CGRP-containing neurons, with the highest levels occurring in striatum, amygdala, colliculi, and cerebellum. The peripheral projections are involved in neurogenic vasodilatation and inflammation, and central release induces hyperalgesia. ⋯ At the central synapses in the trigeminal nucleus caudalis, CGRP acts postjunctionally on second-order neurons to transmit pain signals centrally via the brainstem and midbrain to the thalamus and higher cortical pain regions. Recently developed CGRP receptor antagonists are effective at aborting acute migraine attacks. They may act both centrally and peripherally to attenuate signaling within the trigeminovascular pathway.
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Clinical trials in traumatic brain injury (TBI) pose complex methodological challenges, largely related to the heterogeneity of the population. The International Mission on Prognosis and Clinical Trial Design in TBI study group has explored approaches for dealing with this heterogeneity with the aim to optimize clinical trials in TBI. Extensive prognostic analyses and simulation studies were conducted on individual patient data from eight trials and three observational studies. ⋯ The statistical analysis should use an ordinal approach, based on either sliding dichotomy or proportional odds methodology. Broad inclusion criteria, prespecified covariate adjustment, and an ordinal analysis will promote an efficient trial, yielding gains in statistical efficiency of more than 40%. This corresponds to being able to detect a 7% treatment effect with the same number of patients needed to demonstrate a 10% difference with an unadjusted analysis based on the dichotomized Glasgow outcome scale.
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Traumatic brain injury (TBI) remains a serious health concern, and TBI is one of the leading causes of death and disability, especially among young adults. Although preventive education, increased usage of safety devices, and TBI management have dramatically increased the potential for surviving a brain injury, there is still a need to develop reliable methods to diagnose TBI, the secondary pathologies associated with TBI, and predicting the outcomes of TBI. ⋯ Although some of these changes have been reported to correlate with mortality and outcome, further research is required to identify prognostic biomarkers. This need is punctuated in mild injuries that cannot be readily detected using current techniques, as well as in defining patient risk for developing TBI-associated secondary injuries.
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In this article, we review past and current experience in clinical trials of traumatic brain injuries (TBIs), we discuss limitations and challenges, and we summarize current directions. The focus is on severe and moderate TBIs. A systematic literature search of the years from 1980 to 2009 revealed 27 large phase III trials in TBI; we were aware of a further 6 unpublished trials. ⋯ The disappointing results in trials on neuroprotective agents in TBI have led to a critical reappraisal of clinical trial methodology. This has resulted in recommendations for preclinical workup and has triggered extensive analysis on approaches to improve the design and analysis of clinical trials in TBI. An interagency initiative toward standardization on selection and coding of data elements across the broad spectrum of TBI is ongoing, and will facilitate comparison of research findings across studies and encourage high-quality meta-analysis of individual patient data in the future.