Whole-brain imaging with single-cell resolution using chemical cocktails and computational analysis

Systems-level identification and analysis of cellular circuits in the brain will require the development of whole-brain imaging with single-cell resolution. To this end, we performed comprehensive chemical screening to develop a whole-brain clearing and imaging method, termed CUBIC (clear, unobstructed brain imaging cocktails and computational analysis). CUBIC is a simple and efficient method involving the immersion of brain samples in chemical mixtures containing aminoalcohols, which enables rapid whole-brain imaging with single-photon excitation microscopy. CUBIC is applicable to multicolor imaging of fluorescent proteins or immunostained samples in adult brains and is scalable from a primate brain to subcellular structures. We also developed a whole-brain cell-nuclear counterstaining protocol and a computational image analysis pipeline that, together with CUBIC reagents, enable the visualization and quantification of neural activities induced by environmental stimulation. CUBIC enables time-course expression profiling of whole adult brains with single-cell resolution.

Current pre-hospital traumatic brain injury management in China

BACKGROUND Traumatic brain injury (TBI) is associated with mo st trauma-related deaths. Secondary brain injury is the leading cause of in-hospital deaths after traumatic brain injury. By early prevention and slowing of the initial pathophysiological mechanism of secondary brain injury, pre- hospital service can signifi cantly reduce case-fata lity rates of TBI. In China, the incidence of TBI is increasing and the proportion of severe TBI is much higher than that in other countries. The objective of this paper is to review the pre-hospital management of TBI in China. DATA SOURCES A literature search was conducted in January 2014 using the China National Knowledge Infrastructure (CNKI). Articles on the assessment and treatment of TBI in pre-hospital settings practiced by Chinese doctors were identified. The information on the assessment and treatment of hypoxemia, hypotension, and brain hern iation was extracted from the identifi ed articles. RESULTS Of the 471 articles identified, 65 met the selecti on criteria. The existing literature indicated that current practices of pre-hospital TBI management in China were sub-optimal and varied considerably across different regions. CONCLUSION Since pre-hospital care is the weakest part of Chinese emergency care, appropriate training programs on pre-hospital TBI management are urgently needed in China.

Practices and knowledge levels of prehospital doctors in traumatic brain injury management in Hubei, China

This thesis is a cross-sectional questionnaire survey of pre-hospital doctors' knowledge and practice of managing traumatic brain injury in two major cities of Hubei province, China. This study provides evidence for future research on improving the quality of pre-hospital management in China.

Characterizing self-reported sleep disturbance after mild traumatic brain injury

Sleep disturbance after mild traumatic brain injury (mTBI) is commonly reported as debilitating and persistent. However, the nature of this disturbance is poorly understood. This study sought to characterize sleep after mTBI compared with a control group. A cross-sectional matched case control design was used. Thirty-three persons with recent mTBI (1–6 months ago) and 33 age, sex, and ethnicity matched controls completed established questionnaires of sleep quality, quantity, timing, and sleep-related daytime impairment. The mTBI participants were compared with an independent sample of close-matched controls (CMCs; n=33) to allow partial internal replication. Compared with controls, persons with mTBI reported significantly greater sleep disturbance, more severe insomnia symptoms, a longer duration of wake after sleep onset, and greater sleep-related impairment (all medium to large effects, Cohen's d>0.5). No differences were found in sleep quantity, timing, sleep onset latency, sleep efficiency, or daytime sleepiness. All findings except a measure of sleep timing (i.e., sleep midpoint) were replicated for CMCs. These results indicate a difference in the magnitude and nature of perceived sleep disturbance after mTBI compared with controls, where persons with mTBI report poorer sleep quality and greater sleep-related impairment. Sleep quantity and timing did not differ between the groups. These preliminary findings should guide the provision of clearer advice to patients about the aspects of their sleep that may change after mTBI and could inform treatment selection.

Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P<5 × 10−8) loci, some including known iron-related genes (​HFE, ​SLC40A1, ​TF, ​TFR2, ​TFRC, ​TMPRSS6) and others novel (​ABO, ​ARNTL, ​FADS2, ​NAT2, ​TEX14). SNPs at ​ARNTL, ​TF, and ​TFR2 affect iron markers in ​HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease.

The relationship between stress, HPA axis functioning and brain structure in first episode psychosis over the first 12 weeks of treatment

Stress and abnormal hypothalamic-pituitary-adrenal axis functioning have been implicated in the early phase of psychosis and may partly explain reported changes in brain structure. This study used magnetic resonance imaging to investigate whether biological measures of stress were related to brain structure at baseline and to structural changes over the first 12 weeks of treatment in first episode patients (n=22) compared with matched healthy controls (n=22). At baseline, no significant group differences in biological measures of stress, cortical thickness or hippocampal volume were observed, but a significantly stronger relationship between baseline levels of cortisol and smaller white matter volumes of the cuneus and anterior cingulate was found in patients compared with controls. Over the first 12 weeks of treatment, patients showed a significant reduction in thickness of the posterior cingulate compared with controls. Patients also showed a significant positive relationship between baseline cortisol and increases in hippocampal volume over time, suggestive of brain swelling in association with psychotic exacerbation, while no such relationship was observed in controls. The current findings provide some support for the involvement of stress mechanisms in the pathophysiology of early psychosis, but the changes are subtle and warrant further investigation.

Stroke: A brain attack!

Brain cells control everything we do - from speaking to walking to breathing. The brain needs a steady supply of blood and oxygen to function properly. Without this vital steady supply of blood, brain cells don't get enough nutrients and oxygen to do their job, and a stroke or 'brain attack' occurs. The human brain is divided into regions that control various motor (movement) and sensory (the senses) functions. Damage from stroke to a specific region may affect the functions it controls. This causes symptoms such as paralysis (loss of movement), difficulty speaking, or loss of coordination. The left side of the brain controls motor and sensory functions on the right side of the body. The left side is also responsible for scientific functions, understanding written and spoken language, number skills and reasoning. The right side of the brain controls motor and sensory functions on the left side of the body. It also controls artistic functions, such as music, art awareness, and insight. If an artery inside the brain or leading to the brain becomes temporarily blocked, the flow of blood to an area of the brain slows or stops. The lack of blood can cause temporary symptoms such as weakness, numbness, problems with speech, dizziness, or loss of vision.

Building a "brain attack" team to administer thrombolytic therapy for acute ischemic stroke

Before tissue plasminogen activator (tPA) was licensed for use in Canada, in February 1999, the Calgary Regional Stroke Program spearheaded the development and organization of local resources to use thrombolytic therapy in patients who had experienced acute ischemic stroke. In 1996 special permission was obtained from the Calgary Regional Health Authority to use intravenously administered tPA for acute ischemic stroke, and ethical and scientific review boards approved the protocols. After 3 years our efforts have resulted in improved patient outcomes, shorter times from symptom onset to treatment and acceptable adverse event rates. Areas for continued improvement include the door-to-needle time and broader education of the public about the symptoms of acute ischemic stroke.

Probabilistic orthographic cues to grammatical category in the brain

What helps us determine whether a word is a noun or a verb, without conscious awareness? We report on cues in the way individual English words are spelled, and, for the first time, identify their neural correlates via functional magnetic resonance imaging (fMRI). We used a lexical decision task with trisyllabic nouns and verbs containing orthographic cues that are either consistent or inconsistent with the spelling patterns of words from that grammatical category. Significant linear increases in response times and error rates were observed as orthography became less consistent, paralleled by significant linear decreases in blood oxygen level dependent (BOLD) signal in the left supramarginal gyrus of the left inferior parietal lobule, a brain region implicated in visual word recognition. A similar pattern was observed in the left superior parietal lobule. These findings align with an emergentist view of grammatical category processing which results from sensitivity to multiple probabilistic cues.

Quantifying the heritability of task-related brain activation and performance during the N-back working memory task: A twin fMRI study

Working memory-related brain activation has been widely studied, and impaired activation patterns have been reported for several psychiatric disorders. We investigated whether variation in N-back working memory brain activation is genetically influenced in 60 pairs of twins, (29 monozygotic (MZ), 31 dizygotic (DZ); mean age 24.4 ± 1.7S.D.). Task-related brain response (BOLD percent signal difference of 2 minus 0-back) was measured in three regions of interest. Although statistical power was low due to the small sample size, for middle frontal gyrus, angular gyrus, and supramarginal gyrus, the MZ correlations were, in general, approximately twice those of the DZ pairs, with non-significant heritability estimates (14-30%) in the low-moderate range. Task performance was strongly influenced by genes (57-73%) and highly correlated with cognitive ability (0.44-0.55). This study, which will be expanded over the next 3 years, provides the first support that individual variation in working memory-related brain activation is to some extent influenced by genes.

Genetic effects on the cerebellar role in working memory: Same brain, different genes?

Over the past several years, evidence has accumulated showing that the cerebellum plays a significant role in cognitive function. Here we show, in a large genetically informative twin sample (n= 430; aged 16-30. years), that the cerebellum is strongly, and reliably (n=30 rescans), activated during an n-back working memory task, particularly lobules I-IV, VIIa Crus I and II, IX and the vermis. Monozygotic twin correlations for cerebellar activation were generally much larger than dizygotic twin correlations, consistent with genetic influences. Structural equation models showed that up to 65% of the variance in cerebellar activation during working memory is genetic (averaging 34% across significant voxels), most prominently in the lobules VI, and VIIa Crus I, with the remaining variance explained by unique/unshared environmental factors. Heritability estimates for brain activation in the cerebellum agree with those found for working memory activation in the cerebral cortex, even though cerebellar cyto-architecture differs substantially. Phenotypic correlations between BOLD percent signal change in cerebrum and cerebellum were low, and bivariate modeling indicated that genetic influences on the cerebellum are at least partly specific to the cerebellum. Activation on the voxel-level correlated very weakly with cerebellar gray matter volume, suggesting specific genetic influences on the BOLD signal. Heritable signals identified here should facilitate discovery of genetic polymorphisms influencing cerebellar function through genome-wide association studies, to elucidate the genetic liability to brain disorders affecting the cerebellum.

Heritability of working memory brain activation

Although key to understanding individual variation in task-related brain activation, the genetic contribution to these individual differences remains largely unknown. Here we report voxel-by-voxel genetic model fitting in a large sample of 319 healthy, young adult, human identical and fraternal twins (mean ± SD age, 23.6 ±1.8 years) who performed an n-back working memory task during functional magnetic resonance imaging (fMRI) at a high magnetic field (4 tesla). Patterns of task-related brain response (BOLD signal difference of 2-back minus 0-back) were significantly heritable, with the highest estimates (40 - 65%) in the inferior, middle, and superior frontal gyri, left supplementary motor area, precentral and postcentral gyri, middle cingulate cortex, superior medial gyrus, angular gyrus, superior parietal lobule, including precuneus, and superior occipital gyri. Furthermore, high test-retest reliability for a subsample of 40 twins indicates that nongenetic variance in the fMRI brain response is largely due to unique environmental influences rather than measurement error. Individual variations in activation of the working memory network are therefore significantly influenced by genetic factors. By establishing the heritability of cognitive brain function in a large sample that affords good statistical power, and using voxel-by-voxel analyses, this study provides the necessary evidence for task-related brain activation to be considered as an endophenotype for psychiatric or neurological disorders, and represents a substantial new contribution to the field of neuroimaging genetics. These genetic brain maps should facilitate discovery of gene variants influencing cognitive brain function through genome-wide association studies, potentially opening up new avenues in the treatment of brain disorders.

A tensor-based morphometry study of genetic influences on brain structure using a new fluid registration method

We incorporated a new Riemannian fluid registration algorithm into a general MRI analysis method called tensor-based morphometry to map the heritability of brain morphology in MR images from 23 monozygotic and 23 dizygotic twin pairs. All 92 3D scans were fluidly registered to a common template. Voxelwise Jacobian determinants were computed from the deformation fields to assess local volumetric differences across subjects. Heritability maps were computed from the intraclass correlations and their significance was assessed using voxelwise permutation tests. Lobar volume heritability was also studied using the ACE genetic model. The performance of this Riemannian algorithm was compared to a more standard fluid registration algorithm: 3D maps from both registration techniques displayed similar heritability patterns throughout the brain. Power improvements were quantified by comparing the cumulative distribution functions of the p-values generated from both competing methods. The Riemannian algorithm outperformed the standard fluid registration.