Brain injury clinical trials: new agents or new statistics?

Failure of the vast majority of clinical trials evaluating recovery after severe brain injury from stroke or trauma has triggered interest in novel statistical techniques that are more powerful than conventional dichotomized outcomes. A retrospective analysis of data from a large international trial evaluating high-dose steroids for severe traumatic brain injury found that analysis of a wide range of outcome levels by using an ordinal scale with proportional odds regression or a sliding dichotomy was more likely to detect a treatment effect than the single-dichotomy approach. These techniques may soon become commonplace as critical care research increasingly focuses on patient-centered functional outcomes.     

Pain Measurement and Brain Activity: Will Neuroimages Replace Pain Ratings?

Arguments made for the advantages of replacing pain ratings with brain-imaging data include assumptions that pain ratings are less reliable and objective and that brain image data would greatly benefit the measurement of treatment efficacy. None of these assumptions are supported by available evidence. Self-report of pain is predictable and does not necessarily reflect unreliability or error. Because pain is defined as an experience, magnitudes of its dimensions can be estimated by well-established methods, including those used to validate brain imaging of pain. Brain imaging helps to study pain mechanisms and might be used as proxy measures of pain in persons unable to provide verbal reports. Yet eliminating pain ratings or replacing them with neuroimaging data is misguided because brain images only help explain pain if they are used in conjunction with self-report. There is no objective readout mechanism of pain (pain thermometer) that is unaffected by psychological factors. Benefits from including neuroimaging data might include increased understanding of underlying neural mechanisms of treatment efficacy, discovery of new treatment vectors, and support of conclusions derived from self-report. However, neither brain imaging nor self-report data are privileged over the other. The assumption that treatment efficacy is hampered by self-report has not been shown; there is a plethora of treatment studies showing that self-report is sensitive to treatment. Dismissal of patients’ self-reports (pain ratings) by brain-imaging data is potentially harmful. The aim of replacing self-report with brain-imaging data is misguided and has no scientific or philosophical foundation.PerspectiveAlthough brain imaging may offer considerable insight into the neural mechanisms of pain, including relevant causes and correlations, brain images cannot and should not replace self-report. Only the latter assesses the experience of pain, which is not identical to neural activity. Brain imaging may help to explain pain, but replacing self-report with brain-imaging data would be philosophically and scientifically misguided and potentially harmful to pain patients.     

Brain–skull contact boundary conditions in an inverse computational deformation model

Biomechanical models simulating brain motion under loading and boundary conditions in the operating room (OR) are gaining attention as alternatives for brain shift compensation during open cranial neurosurgeries. Although the significance of brain–skull boundary conditions (BCs) in these models has been explored in dynamic simulations, it has not been fully investigated in models representing the quasi-static brain motion that prevails during neurosurgery. In this study, we extend the application of a brain–skull contact BC by incorporating it into an inversion estimation scheme for the deformation field using the steepest gradient descent (SGD) framework. The technique allows parenchymal surface motion normal to the skull while maintaining stress-free BCs at the craniotomy and minimizing the effect of measurement noise. Application of the algorithm in five clinical cases using sparse data generated at the tumor boundary confirms the significance of brain–skull BCs in the model response. Specifically, the results demonstrate that the contact BC enhances model flexibility and achieves improved or comparable performance at the tumor boundary (recovering about 85% of the deformation) relative to that obtained when normal motion of the parenchymal surface is not allowed. It also significantly improves model estimation accuracy at the craniotomy (1.6 mm on average), especially when the normal motion is large. The importance of the method is that model performance significantly improves when brain–skull contact influences the deformation field but does not degrade when the contact is less critical and simpler BCs would suffice. The computational cost of the technique is currently 3.9 min on average, but may be further reduced by applying an iterative solver to the linear systems of equations involved and/or by local refinement of the mesh in regions of interest.     

Brain damage and cardiopulmonary bypass: is there really any association?

Brain damage, in the form of stroke and cognitive deficit associated with heart surgery, has long been attributed unquestioningly to cardiopulmonary bypass (CPB). The aim of this paper is to review the randomised control trials (RCT), systematic reviews and meta-analyses of studies, comparing patients who have undergone on- or off-pump coronary artery bypass grafting (CABG) surgeries that have used stroke or cognition as an outcome to determine whether CPB is associated with brain damage. Although not definitive, the evidence base to date strongly suggests that the incidence of stroke and the effect on cognition, if any, are no different whether CABG surgery is undertaken on- or off-pump. In addition and contrary to long-held beliefs, this review leads to the conclusion that CPB may well not be the cause of the brain damage associated with heart surgery.     

Deep Brain Stimulation in Cluster Headache: Hypothalamus or Midbrain Tegmentum?

Functional and structural neuroimaging studies have provided pivotal insights into the pathophysiology of trigeminal autonomic cephalalgias (TACs), particularly cluster headache (CH). Functional imaging studies using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) in TACs have reported activation of the posterior hypothalamus. A structural neuroimaging study using voxel-based morphometry in CH reported increased volume of the hypothalamic gray, although another larger study failed to reproduce this finding. These studies in CH prompted the use of stereotactic stimulation of the target point identified by functional and structural neuroimaging. The precise anatomical localization of the deep brain stimulation (DBS) target places it at the midbrain tegmentum rather than the posterior hypothalamus. A comparison of the PET and fMRI studies in TACs reveals that the diencephalic/mesencephalic activation is more posteroinferior in the PET studies, straddling the hypothalamus and midbrain tegmentum, whereas the activation is centered on the hypothalamus in the higher spatial resolution fMRI studies. To optimize the outcomes from DBS, it is likely that patients will need to be studied individually using functional imaging techniques that have high spatial and temporal resolution to enable targeting of the appropriate locus with stereotactic stimulation.     

Brain lesions in septic shock: a magnetic resonance imaging study

Background Understanding of sepsis-induced brain dysfunction remains poor, and relies mainly on data from animals or post-mortem studies in patients. The current study provided findings from magnetic resonance imaging of the brain in septic shock. Methods Nine patients with septic shock and brain dysfunction [7 women, median age 63 years (interquartile range 61–79 years), SAPS II: 48 (44–56), SOFA: 8 (6–10)] underwent brain magnetic resonance imaging including gradient echo T1-weighted, fluid-attenuated inversion recovery (FLAIR), T2-weighted and diffusion isotropic images, and mapping of apparent diffusion coefficient. Results Brain imaging was normal in two patients, showed multiple ischaemic strokes in two patients, and in the remaining patients showed white matter lesions at the level of the centrum semiovale, predominating around Virchow–Robin spaces, ranging from small multiple areas to diffuse lesions, and characterised by hyperintensity on FLAIR images. The main lesions were also characterised by reduced signal on diffusion isotropic images and increased apparent diffusion coefficient. The lesions of the white matter worsened with increasing duration of shock and were correlated with Glasgow Outcome Score. Conclusion This preliminary study showed that sepsis-induced brain lesions can be documented by magnetic resonance imaging. These lesions predominated in the white matter, suggesting increasedblood–brain barrier permeability, and were associated with poor outcome.     

Deep Brain Stimulation of the Prelimbic Medial Prefrontal Cortex: Quantification of the Effect on Glucose Metabolism in the Rat Brain Using [18 F]FDG MicroPET

Purpose

Prefrontal cortex (PFC) deep brain stimulation (DBS) has been proposed as a therapy for addiction and depression. This study investigates changes in rat cerebral glucose metabolism induced by different DBS frequencies using μPET.

Procedures

One hour DBS of the prelimbic area (PL) of the medial PFC (mPFC) (60 Hz, 130 Hz or sham) in rats (n?=?9) was followed by 2-deoxy-2-[¹⁸?F] fluoro-d-glucose ([¹⁸?F]FDG) μPET.

Results

Sixty Hz DBS elicited significant hypermetabolism in the ipsilateral PL ([¹⁸?F]FDG uptake +5.2?±?2.3 %, p?Conclusions This study suggests the potential of 60 Hz PL mPFC DBS for the treatment of disorders associated with prefrontal hypofunction.     

a Transcranial Doppler Study of Locally Using Dexamethasone after Brain Injury in Rabbits

Since the introduction of transcranial Doppler (TCD) by Aaslid[1], the measurement of the blood flow velocity (BFV) in basal cerebral arteries has been possible, which offers the advantage of being an easily portable and noninvasive method of assessing intracranial hemodynamics. Yet, TCD in the observation of post－traumatic treatment has not been universally applied. It was once thought that a large dose of steroid had an obvious therapeutic effect on brain trauma and cerebral edema. As t…     

What Have We Learned From Brain Functional Connectivity Studies in Migraine Headache?

Over the past 20 years, headache syndromes, especially migraine, have benefited significantly from the knowledge gained through neuroimaging studies. This article is focused on the neuroimaging studies of the functional organization and connectivity of the migraine brain. First, data sources and the study design elements in functional neuroimaging studies of the brain connectivity in migraine headaches are discussed. Then, the article reviews the findings to date and discusses how functional connectivity studies have contributed to a better understanding of the mechanisms of the migraine disease by extending the focus from a single region or structure to a network of regions and structures and the interactions among them. Finally, the potential scenarios for the translation of connectivity knowledge to the benefit for patients are discussed.