Lucia M. Li

The contribution of interindividual factors to variability of response in transcranial direct current stimulation studies

There has been an explosion of research using transcranial direct current stimulation (tDCS) for investigating and modulating human cognitive and motor function in healthy populations. It has also been used in many studies seeking to improve deficits in disease populations. With the slew of studies reporting “promising results” for everything from motor recovery after stroke to boosting memory function, one could be easily seduced by the idea of tDCS being the next panacea for all neurological ills. However, huge variability exists in the reported effects of tDCS, with great variability in the effect sizes and even contradictory results reported. In this review, we consider the interindividual factors that may contribute to this variability. In particular, we discuss the importance of baseline neuronal state and features, anatomy, age and the inherent variability in the injured brain. We additionally consider how interindividual variability affects the results of motor-evoked potential (MEP) testing with transcranial magnetic stimulation (TMS), which, in turn, can lead to apparent variability in response to tDCS in motor studies.

The Surgical Approach to the Management of Increased Intracranial Pressure After Traumatic Brain Injury

Increased intracranial pressure occurring after severe traumatic brain injury is a common and potentially devastating phenomenon. It has been clearly demonstrated that increased intracranial pressure that is refractory to initial medical measures is a poor prognostic sign. Current optimal management is based on a sequential, target-driven approach combining both medical and surgical treatment strategies. The surgical measures in current common practice include external ventricular drain insertion and decompressive craniectomy. There is evidence that both of these measures reduce intracranial pressure but the effect on outcome, particularly in the long term, is equivocal. Current Brain Trauma Foundation guidelines recommend timely evacuation of mass lesions and there is clear guidance regarding the indications for intracranial pressure monitoring; however, decompressive craniectomy is only cautiously recommended as a possible option for selected patients. In this review, we highlight the ongoing debate about the use of decompressive craniectomy to control intracranial pressure after traumatic brain injury; included is a summary of review of the most recent literature on the effect of decompressive craniectomy on increased intracranial pressure after traumatic brain injury and associated long-term outcome. The RESCUEicp and DECRA studies are discussed in detail. It is hoped that these 2 randomized controlled trials, which are evaluating the short- and longer-term outcomes of decompressive craniectomy, will provide conclusive evidence regarding the role of decompressive craniectomy in managing increased intracranial pressure after trauma.

Primary decompressive craniectomy for acute subdural haematomas: results of an international survey

Dear Sir, Approximately two-thirds of patients with traumatic brain injury (TBI) undergoing emergency cranial surgery have an acute subdural haematoma (ASDH) evacuated [2]. These haematomas are frequently associated with underlying cerebral parenchymal injury, which further exacerbates brain swelling [5]. Therefore, even though craniotomy and evacuation comprise the established primary treatment for ASDH, leaving the bone flap out (i.e. decompressive craniectomy) is an option either because the brain is swollen beyond the confines of the cranium or because the patient is thought to be at high risk for worsening brain swelling during the ensuing days. The European Brain Injury Consortium survey, which was conducted in 2001, demonstrated that a decompressive craniectomy (DC) was undertaken in approximately onequarter of operations performed for ASDH [2]. Since then, there has been a resurgence of interest in the use of DC after TBI. A randomised controlled trial of early/neuroprotective DC in patients with severe diffuse TBI (but no mass lesions) was published in 2011 (DECRA), while another randomised study assessing the role of DC as a last-tier therapy for refractory post-traumatic intracranial hypertension (RESCUEicp) has now recruited 85 % of the required sample size [3, 4]. Nevertheless, there is only class III evidence with retrospective studies investigating the role of DC as a primary procedure for ASDH [1]. With the objective of examining current practice patterns of DC after TBI, we undertook a survey of members of the European Association of Neurosurgical Societies (EANS), Neurocritical Care Society, NeuroCritical Care Network (NCCNet), full members of the Society of British Neurological Surgeons (SBNS) and members of the British Neurosurgical Trainees Association (BNTA) during October and November 2011. We used a secure online survey tool to disseminate the questionnaires. The questionnaire survey was approved by the Academic Committee of the SBNS (project no. NE0026). In this letter, we wish to discuss the results of our survey regarding the use of primary DC for ASDH. As part of the survey, we asked the following question: “When evacuating a traumatic ASDH, how often do you perform a primary DC (i.e. leave the bone flap out)”? This question was answered by 283 neurosurgeons (201 board-certified Consultants or equivalent; 82 trainees). There were 138 UK/Irish, 110 from other European countries, 13North American and 22 respondents from various other countries (see Appendix 1). We decided to group together the responses of neurosurgeons working in countries with national representation to the EANS in order to have two similar-sized groups (UK/Irish A. G. Kolias : L. M. Li : I. Timofeev : E. A. Corteen : T. Santarius : J. D. Pickard : P. J. Kirkpatrick : P. J. Hutchinson Division of Neurosurgery, Addenbrooke’s Hospital & University of Cambridge, Cambridge, UK

Externally induced frontoparietal synchronization modulates network dynamics and enhances working memory performance

Cognitive functions such as working memory (WM) are emergent properties of large-scale network interactions. Synchronisation of oscillatory activity might contribute to WM by enabling the coordination of long-range processes. However, causal evidence for the way oscillatory activity shapes network dynamics and behavior in humans is limited. Here we applied transcranial alternating current stimulation (tACS) to exogenously modulate oscillatory activity in a right frontoparietal network that supports WM. Externally induced synchronization improved performance when cognitive demands were high. Simultaneously collected fMRI data reveals tACS effects dependent on the relative phase of the stimulation and the internal cognitive processing state. Specifically, synchronous tACS during the verbal WM task increased parietal activity, which correlated with behavioral performance. Furthermore, functional connectivity results indicate that the relative phase of frontoparietal stimulation influences information flow within the WM network. Overall, our findings demonstrate a link between behavioral performance in a demanding WM task and large-scale brain synchronization. DOI: http://dx.doi.org/10.7554/eLife.22001.001

Cross-Sectional Analysis of Data from the U.S. Clinical Trials Database Reveals Poor Translational Clinical Trial Effort for Traumatic Brain Injury, Compared with Stroke

Traumatic brain injury (TBI) is an important public health problem, comparable to stroke in incidence and prevalence. Few interventions have proven efficacy in TBI, and clinical trials are, therefore, necessary to advance management in TBI. We describe the current clinical trial landscape in traumatic brain injury and compare it with the trial efforts for stroke. For this, we analysed all stroke and TBI studies registered on the US Clinical Trials (www.clinicaltrials.gov) database over a 10-year period (01/01/2000 to 01/31/2013). This methodology has been previously used to analyse clinical trial efforts in other specialties. We describe the research profile in each area: total number of studies, total number of participants and change in number of research studies over time. We also analysed key study characteristics, such as enrolment number and scope of recruitment. We found a mismatch between relative public health burden and relative research effort in each disease. Despite TBI having comparable prevalence and higher incidence than stroke, it has around one fifth of the number of clinical trials and participant recruitment. Both stroke and TBI have experienced an increase in the number of studies over the examined time period, but the rate of growth for TBI is one third that for stroke. Small-scale (<1000 participants per trial) and single centre studies form the majority of clinical trials in both stroke and TBI, with TBI having significantly fewer studies with international recruitment. We discuss the consequences of these findings and how the situation might be improved. A sustained research effort, entailing increased international collaboration and rethinking the methodology of running clinical trials, is required in order to improve outcomes after traumatic brain injury.

Prevalence and correlates of vitamin D deficiency in adults after traumatic brain injury

Traumatic brain injury (TBI) is a major cause of long‐term disability with variable recovery. Preclinical studies suggest that vitamin D status influences the recovery after TBI. However, there is no published clinical data on links between vitamin D status and TBI outcomes. The aim was to determine the (i) prevalence of vitamin D deficiency/insufficiency, and associations of vitamin D status with (ii) demographic factors and TBI severity, and with (iii) cognitive function, symptoms and quality of life, in adults after TBI.

The effect of oppositional parietal transcranial direct current stimulation on lateralized brain functions

Cognitive functions such as numerical processing and spatial attention show varying degrees of lateralization. Transcranial direct current stimulation (tDCS) can be used to investigate how modulating cortical excitability affects performance of these tasks. This study investigated the effect of bi‐parietal tDCS on numerical processing, spatial and sustained attention. It was hypothesized that tDCS would have distinct effects on these tasks because of varying lateralization (numerical processing left, spatial attention right) and that these effects are partly mediated by modulation of sustained attention. A single‐blinded, crossover, sham‐controlled study was performed. Eighteen healthy right‐handed participants performed cognitive tasks during three sessions of oppositional parietal tDCS stimulation: sham; right anodal with left cathodal (RA/LC); and right cathodal with left anodal (RC/LA). Participants performed a number comparison task, a modified Posner task, a choice reaction task (CRT) and the rapid visual processing task (RVP). RA/LC tDCS impaired number comparison performance compared with sham, with slower responses to numerically close numbers pairs. RA/LC and RC/LA tDCS had distinct effects on CRT performance, specifically affecting vigilance level during the final block of the task. No effect of stimulation on the Posner task or RVP was found. It was demonstrated that oppositional parietal tDCS affected both numerical performance and vigilance level in a polarity‐dependent manner. The effect of tDCS on numerical processing may partly be due to attentional effects. The behavioural effects of tDCS were specifically observed under high task demands, demonstrating the consequences of an interaction between stimulation type and cognitive load.

Decompressive craniectomy for acute subdural hematomas: time for a randomized trial.

Dear Sir, We thank Honeybul et al. for their thoughtful comments on our paper. Decompressive craniectomy (DC) has fallen in and out of vogue a number of times in the last few decades. Historically, the main concern has been that DC may be shifting patients from mortality to vegetative state or severe disability. In order to obtain class I evidence, two randomized multicenter trials were launched in 2002–2004: the RESCUEicp and the DECRA. The DECRA study failed to show clinical benefit with early/neuroprotective DC for severe diffuse TBI (no mass lesions) [2]. The RESCUEicp (www.rescueicp.com), which is examining the role of DC as a last-tier therapy for post-traumatic refractory raised ICP (≥25 mmHg), is ongoing and has now recruited 88 % of the required sample size [4]. However, the role of primary DC for evacuation of acute subdural hematomas (ASDH) has not been the subject of any randomized trials to date. As a result, there exists significant variation in the surgical technique employed for the primary evacuation of an ASDH [5]. The well-written paper by Honeybul et al. [3] includes “72 patients who had a unilateral DC following evacuation of an intracranial mass lesion”. The type of mass lesions of this cohort is not defined. To the best of our knowledge, our study is the first to utilize prognostic scores in a cohort of consecutive patients with ASDH in an attempt to compare craniotomy with DC. Our paper is a retrospective cohort comparison study (non-randomized) and by definition does not comprise level I evidence [6]. Importantly, this is the first study to show that unadjusted 6-month outcomes were similar between the craniotomy and DC groups even though the patients who underwent DC were more severely injured. In addition, the standardized morbidity ratio of the DC group is lower than in the craniotomy group, even though the 95 % confidence intervals overlap. While more detailed analyses would certainly improve the statistical sophistication of our results, we felt that this was unlikely to provide a definitive answer to the question posed. Despite the limitations posed by the study design and sample size, our findings lend support to the hypothesis that primary DC may be more effective than craniotomy for selected patients with ASDH. The only way to definitely accept or refute this hypothesis is to perform a multicenter, pragmatic, parallel-group randomized trial in order to compare the clinical and cost-effectiveness of DC versus simple craniotomy for the management of head-injured patients undergoing evacuation of an ASDH. The Brain Trauma Foundation has already identified DC versus craniotomy as the top key issue for future investigation likely to improve the care of patients with ASDH [1]. We are glad that the authors agree that a randomized trial is needed and would welcome their participation in the planned RESCUE-ASDH trial (Randomised Evaluation of Surgery with Craniectomy for patients Undergoing Evacuation of Acute Sub-Dural Haematoma). A. G. Kolias (*) : L. M. Li :M. R. Guilfoyle : I. Timofeev : E. A. Corteen : J. D. Pickard : P. J. Kirkpatrick : P. J. Hutchinson Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke’s Hospital & University of Cambridge, Box 167, Level 3, A Block, Hills Road, Cambridge CB2 0QQ, UK e-mail: angeloskolias@gmail.com

Serum insulin-like growth factor-I levels are associated with improved white matter recovery after traumatic brain injury

Traumatic brain injury (TBI) is a common disabling condition with limited treatment options. Diffusion tensor imaging measures recovery of axonal injury in white matter (WM) tracts after TBI. Growth hormone deficiency (GHD) after TBI may impair axonal and neuropsychological recovery, and serum insulin‐like growth factor‐I (IGF‐I) may mediate this effect. We conducted a longitudinal study to determine the effects of baseline serum IGF‐I concentrations on WM tract and neuropsychological recovery after TBI.

Serum IGF-I levels are associated with improved white matter recovery after TBI

Traumatic brain injury (TBI) is a common disabling condition with limited treatment options. Diffusion tensor imaging measures recovery of axonal injury in white matter (WM) tracts after TBI. Growth hormone deficiency (GHD) after TBI may impair axonal and neuropsychological recovery, and serum insulin‐like growth factor‐I (IGF‐I) may mediate this effect. We conducted a longitudinal study to determine the effects of baseline serum IGF‐I concentrations on WM tract and neuropsychological recovery after TBI.