Quantitative imaging of energy expenditure in human brain

Despite the essential role of the brain energy generated from ATP hydrolysis in supporting cortical neuronal activity and brain function, it is challenging to noninvasively image and directly quantify the energy expenditure in the human brain. In this study, we applied an advanced in vivo(31)P MRS imaging approach to obtain regional cerebral metabolic rates of high-energy phosphate reactions catalyzed by ATPase (CMR(ATPase)) and creatine kinase (CMR(CK)), and to determine CMR(ATPase) and CMR(CK) in pure gray mater (GM) and white mater (WM), respectively. It was found that both ATPase and CK rates are three times higher in GM than WM; and CMR(CK) is seven times higher than CMR(ATPase) in GM and WM. Among the total brain ATP consumption in the human cortical GM and WM, 77% of them are used by GM in which approximately 96% is by neurons. A single cortical neuron utilizes approximately 4.7 billion ATPs per second in a resting human brain. This study demonstrates the unique utility of in vivo(31)P MRS imaging modality for direct imaging of brain energy generated from ATP hydrolysis, and provides new insights into the human brain energetics and its role in supporting neuronal activity and brain function.     

In vivo detection of gray and white matter differences in GABA concentration in the human brain

A novel selective multiple quantum filtering-based chemical shift imaging method was developed for acquiring GABA images in the human brain at 3 T. This method allows a concomitant acquisition of an interleaved total creatine image with the same spatial resolution. Using T(1)-based image segmentation and a nonlinear least square regression analysis of GABA-to-total creatine concentration ratios in frontal and parietal lobes of healthy adult volunteers as a function of the tissue gray matter fraction, the mean GABA concentration in gray and white matter was determined to be 1.30+/-0.36 micromol/g and 0.16+/-0.16 micromol/g (mean+/-SD, n=13), respectively. It is expected that this method will become a useful tool for studying GABAergic function in the human brain in vivo.     

A diffusion tensor brain template for rhesus macaques

Diffusion tensor imaging (DTI) is a powerful and noninvasive imaging method for characterizing tissue microstructure and white matter organization in the brain. While it has been applied extensively in research studies of the human brain, DTI studies of non-human primates have been performed only recently. The growing application of DTI in rhesus monkey studies would significantly benefit from a standardized framework to compare findings across different studies. A very common strategy for image analysis is to spatially normalize (co-register) the individual scans to a representative template space. This paper presents the development of a DTI brain template, UWRMAC-DTI271, for adolescent Rhesus Macaque (Macaca mulatta) monkeys. The template was generated from 271 rhesus monkeys, collected as part of a unique brain imaging genetics study. It is the largest number of animals ever used to generate a computational brain template, which enables the generation of a template that has high image quality and accounts for variability in the species. The quality of the template is further ensured with the use of DTI-TK, a well-tested and high-performance DTI spatial normalization method in human studies. We demonstrated its efficacy in monkey studies for the first time by comparing it to other commonly used scalar-methods for DTI normalization. It is anticipated that this template will play an important role in facilitating cross-site voxelwise DTI analyses in Rhesus Macaques. Such analyses are crucial in investigating the role of white matter structure in brain function, development, and other psychopathological disorders for which there are well-validated non-human primate models.     

Homocarnosinosis: lack of serum carnosinase is the defect probably responsible for elevated brain and CSF homocarnosine

Patients afflicted with homocarnosinosis have elevated concentrations of homocarnosine in brain and CSF. It has been reported that they lack brain homocarnosinase. However, we have found that these patients are deficient in serum carnosinase, a dipeptidase which hydrolyzes homocarnosine about 5% as rapidly as it splits carnosine. Homocarnosinase could not be detected in normal human brain extracts after isoelectric focusing or DEAE-cellulose column chromatography. The ability of brain extracts to hydrolyze homocarnosine thus appears to be attributable solely to the serum carnosinase which is present because of serum trapped in the brain sample. Preliminary data indicate that homocarnosinase is probably not present in 13 other human tissues. Normal CSF contained serum carnosinase, whereas the CSF of a homocarnosinosis patient was lacking this enzyme. Thus it appears that the elevated concentrations of homocarnosine in the CSF of homocarnosinosis patients are attributable to serum carnosinase deficiency.     

Motor evoked potentials

Noninvasive electrical stimulation of the human brain first was attempted in the 1950s. In the early 1980s, the first clinical application method of transcranial electrical stimulation was developed. Investigators in the mid-1980s showed that it was possible to stimulate the nerve and the brain using external magnetic stimulation (transcranial magnetic stimulation [TMS]), with little or no pain. TMS now is used commonly in clinical neurology to study central motor conduction time. Depending on the stimulation techniques and parameters, TMS can excite or inhibit brain activity, allowing functional mapping of cortical regions and creation of transient functional lesions. It now is used widely as a research tool to study aspects of human brain physiology, including motor function and the pathophysiology of various brain disorders.     

A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier

The blood-brain barrier (BBB) protects the brain from toxic substances within the peripheral circulation. It maintains brain homeostasis and is a hurdle for drug delivery to the CNS to treat neurodegenerative diseases, including Alzheimer’s disease and brain tumors. The drug efflux transporter P-glycoprotein (P-gp) is highly expressed on brain endothelial cells and blocks the entry of most drugs delivered to the brain. Here, we show that activation of the A2A adenosine receptor (AR) with an FDA-approved A2A AR agonist (Lexiscan) rapidly and potently decreased P-gp expression and function in a time-dependent and reversible manner. We demonstrate that downmodulation of P-gp expression and function coincided with chemotherapeutic drug accumulation in brains of WT mice and in primary mouse and human brain endothelial cells, which serve as in vitro BBB models. Lexiscan also potently downregulated the expression of BCRP1, an efflux transporter that is highly expressed in the CNS vasculature and other tissues. Finally, we determined that multiple pathways, including MMP9 cleavage and ubiquitinylation, mediated P-gp downmodulation. Based on these data, we propose that A2A AR activation on BBB endothelial cells offers a therapeutic window that can be fine-tuned for drug delivery to the brain and has potential as a CNS drug-delivery technology.     

Skull stripping based on region growing for magnetic resonance brain images

In this paper, we propose a new skull stripping method for T1-weighted magnetic resonance (MR) brain images. Skull stripping has played an important role in neuroimage research because it is a basic preliminary step in many clinical applications. The process of skull stripping can be challenging due to the complexity of the human brain, variable parameters of MR scanners, individual characteristics, etc. In this paper, we aim to develop a computationally efficient and robust method. In the proposed algorithm, after eliminating the background voxels with histogram analysis, two seed regions of the brain and non-brain regions were automatically identified using a mask produced by morphological operations. Then we expanded these seed regions with a 2D region growing algorithm based on general brain anatomy information. The proposed algorithm was validated using 56 volumes of human brain data and simulated phantom data with manually segmented masks. It was compared with two popular automated skull stripping methods: the brain surface extractor (BSE) and the brain extraction tool (BET). The experimental results showed that the proposed algorithm produced accurate and stable results against data sets acquired from various MR scanners and effectively addressed difficult problems such as low contrast and large anatomical connections between the brain and surrounding tissues. The proposed method was also robust against noise, RF, and intensity inhomogeneities.     

Quantitative proton magnetic resonance spectroscopy and spectroscopic imaging of the brain: a didactic review

This article presents background information related to methodology for estimating brain metabolite concentration from magnetic resonance spectroscopy (MRS) and magnetic resonance spectroscopic imaging measurements of living human brain tissue. It reviews progress related to this methodology, with emphasis placed on progress reported during the past 10 years. It is written for a target audience composed of radiologists and magnetic resonance imaging technologists. It describes in general terms the relationship between MRS signal amplitude and concentration. It then presents an overview of the many practical problems associated with deriving concentration solely from absolute measured signal amplitudes and demonstrates how a various signal calibration approaches can be successfully used. The concept of integrated signal amplitude is presented with examples that are helpful for qualitative reading of MRS data as well as for understanding the methodology used for quantitative measurements. The problems associated with the accurate measurement of individual signal amplitudes in brain spectra having overlapping signals from other metabolites and overlapping nuisance signals from water and lipid are presented. Current approaches to obtaining accurate amplitude estimates with least-squares fitting software are summarized.     

Three-dimensional electrical impedance tomography of human brain activity

Regional cerebral blood flow and blood volume changes that occur during human brain activity will change the local impedance of that cortical area, as blood has a lower impedance than that of brain. Theoretically, such impedance changes could be measured from scalp electrodes and reconstructed into images of the internal impedance of the head. Electrical Impedance Tomography (EIT) is a newly developed technique by which impedance measurements from the surface of an object are reconstructed into impedance images. It is fast, portable, inexpensive, and noninvasive, but has a relatively low spatial resolution. EIT images were recorded with scalp electrodes and an EIT system, specially optimized for recording brain function, in 39 adult human subjects during visual, somatosensory, or motor activity. Reproducible impedance changes of about 0.5% occurred in 51/52 recordings, which lasted from 6 s after the stimulus onset to 41 s after stimulus cessation. When these changes were reconstructed into impedance images, using a novel 3-D reconstruction algorithm, 19 data sets demonstrated significant impedance changes in the appropriate cortical region. This demonstrates, for the first time, that significant impedance changes, which could form the basis for a novel neuroimaging technology, may be recorded in human subjects with scalp electrodes. The final images contained spatial noise and strategies to reduce this in future work are presented.     

In vivo sequestration of Plasmodium falciparum-infected human erythrocytes: a severe combined immunodeficiency mouse model for cerebral malaria

Cerebral malaria is a fatal complication of infection by Plasmodium falciparum in man. The neurological symptoms that characterize this form of malarial disease are accompanied by the adhesion of infected erythrocytes to the vasculature of the brain. To study this phenomenon in vivo, an acute phase severe combined immunodeficiency (SCID) mouse model was developed in which sequestration of P. falciparum-infected human erythrocytes took place. During acute cerebral malaria in humans, the expression of intercellular adhesion molecule-1 (ICAM-1) is induced in vascular endothelium by inflammatory reactions. Acute phase ICAM-1 expression can also be obtained in SCID mice. The endothelium of the midbrain region was the most responsive to such inflammatory stimulus. It is noteworthy that the reticular formation in the midbrain controls the level of consciousness, and loss of consciousness is a symptom of cerebral malaria. We found that infected human erythrocytes were retained 24 times more than normal erythrocytes in ICAM-1-positive mouse brain. Sequestration to the brain was reduced by anti-ICAM-1 antibodies. These in vivo results were confirmed by the binding of P. falciparum-infected erythrocytes to the ICAM-1-positive endothelium in tissue sections of mouse brain. We conclude that the SCID mouse serves as a versatile in vivo model that allows the study of P. falciparum- infected erythrocyte adhesion as it occurs in human cerebral malaria. Upregulation of ICAM-1 expression in the region of the midbrain correlates with increased retention of malaria-infected erythrocytes and with the symptoms of cerebral malaria.     

Studies on acute disseminated encephalomyelitis produced experimentally in rhesus monkeys

The factor in brain tissue which induces acute disseminated encephalomyelitis, when injected into rhesus monkeys as an emulsion with adjuvants, has been found in human, monkey, rabbit, and chicken brain but is absent from frog and fish brain. It is unaffected by fixation of the brain in formalin, by boiling, and by treatment with ultrasound. It is present in the spinal cord of 3 day old rabbits but does not appear in the rabbit cerebrum until about the 12th day of life; in this respect it parallels the laying down of myelin. Attempts to produce the encephalomyelitis passively with large quantities of serum or of cell exudates, and suspensions of cells from spleen and lymph node from monkeys with encephalomyelitis, were unsuccessful.     

Antibody-independent complement activation by myelin via the classical complement pathway

Murine or rabbit whole brain homogenates were shown to activate human complement via the classical pathway by an antibody-independent reaction. This activity required Ca++ ions. Anticomplementary activity in fractionated murine brain was found to reside in the myelin fraction and in purified myelin. It was absent, however, both from highly purified myelin basic protein (MBP) and from the MBP-free residue. Because purified MBP is a monomer and this protein exists in brain tissue largely as a dimer, the ability of the cross-linked form of MBP to activate complement was investigated. MBP, dimerized with difluorodinitrobenzene, was highly anticomplementary. The murine brain, inactive when taken from the newborn mouse, was shown to first acquire the capacity to activate complement at 7 d after birth. This finding is consistent with the report that the synthesis of myelin protein has been shown to be initiated in murine brain 8 d after birth. Complement activation by MBP could play an important role in the pathological changes observed in neurological disorders.     

Detection and statistical analysis of human cortical sulci

Many studies dealing with the human brain use the spatial coordinate system of brain anatomy to localize functional regions. Unfortunately, brain anatomy, and especially cortical sulci, is characterized by a high interindividual variability. Specific tools called anatomical atlases must then be considered to make the interpretation of anatomical examinations easier. The work described here first aims at building a numerical atlas of the main cortical sulci. Our system is based on a database containing a collection of anatomical MRI of healthy volunteer brains. Their sulci have been manually drawn and labeled for both hemispheres. Sulci are represented as 3D superficial curves. After a nonlinear registration process, a statistical atlas of the cortical topography of a particular MRI is built from the database. It is an a priori model of cortical sulci, including three major components: an average curve represents the average shape and position of each sulcus; a search area accounts for its spatial variation domain; a set of quantitative parameters describes the variability of sulci geometry and topology. This atlas is completely individualized and adapted to the features of the brain under examination. The atlas is represented by a graph, the nodes of which represent sulci and the edges the relations between sulci. It can also be considered a statistical model that describes the cortical topography as well as its variability.     

Brain death and death of human individual

The revised Organ Transplant Law of Japan, enforced from July, 2010, has made "brain death", as well as "cardiac death", death of human individual and procurement of an organ from a brain dead body is now possible by a surviving family's consent. However, brain death issue is a still serious topic, and arguments are going around on whether it is morally justifiable to accept brain death, and if so, in what sense. The author argues that death of human being occurs when "vital triangle," consisted of brain, heart and lung, is severed out.     

Topographically specific functional connectivity between visual field maps in the human brain

Neural activity in mammalian brains exhibits large spontaneous fluctuations whose structure reveals the intrinsic functional connectivity of the brain on many spatial and temporal scales. Between remote brain regions, spontaneous activity is organized into large-scale functional networks. To date, it has remained unclear whether the intrinsic functional connectivity between brain regions scales down to the fine detail of anatomical connections, for example the fine-grained topographic connectivity structure in visual cortex. Here, we show that fMRI signal fluctuations reveal a detailed retinotopically organized functional connectivity structure between the visual field maps of remote areas of the human visual cortex. The structured coherent fluctuations were even preserved in complete darkness when all visual input was removed. While the topographic connectivity structure was clearly visible in within hemisphere connections, the between hemisphere connectivity structure differs for representations along the vertical and horizontal meridian respectively. These results suggest a tight link between spontaneous neural activity and the fine-grained topographic connectivity pattern of the human brain. Thus, intrinsic functional connectivity reflects the detailed connectivity structure of the cortex at a fine spatial scale. It might thus be a valuable tool to complement anatomical studies of the human connectome, which is one of the keys to understand the functioning of the human brain.     

The evolving landscape of human cortical connectivity: facts and inferences

Human cognitive brain mapping is at a crossroads. On the one hand, it can access a rich data set of synaptic connectivity in the cerebral cortex of the monkey, an animal that lacks many of the complicated behaviors of interest. On the other hand, it is rapidly amassing an even richer data set on the functional map of the human cerebral cortex, but with relatively little hard data on underlying structural connectivity. This second point tends to be blurred in the current literature because of the multiple ways in which the term 'connection' is used in the context of the human brain. In some instances the term is used at a conceptual level, to designate a pathway that should be there if the behavior is to be performed. In other instances, it refers to the computational demonstration of a functional relationship, the structural basis of which is not necessarily known. A third usage is based on connections that are known to exist in the monkey and that are inferred to also exist in the human. The fourth and most direct usage involves connections structurally proven to exist in the human. These four usages have been invoked interchangeably to propose connectivistic mechanisms of human cognitive function. To enlarge the currently limited data set on structural connectivity is of considerable importance for conducting biologically more valid explorations of large-scale neurocognitive networks. This challenging goal will require histological laboratory investigations of the human brain to resume their former prominence and to play an increasingly more substantial role in brain mapping research.     

Monoclonal immunotherapy with human monoclonal antibody(CLN-IgG) in glioma patients

It is well recognized that malignant gliomas escape an immune response by hiding behind the blood-brain barrier and by producing proteins that suppress systemic immunity. However, if gliomas can be made to be more immunogenic or if a tumor vaccine can be produced, then access to all tumor cells including those that infiltrate into the brain can be achieved through the patient's immune response. Several strategies have been investigated for immunotherapy. Laboratory studies and animal models have shown that these immune cells will attack the tumor cell, reduce the size of implanted tumors, and that the immune memory is sufficient to suppress tumor growth when the animal is rechallenges with a tumor implant. Since the development of hybridoma technology, monoclonal antibodies against human cancer cells have been produced and antigens have been identified. Hagiwara reported the production of a human monoclonal antibody, CLN-IgG, made by fusing UC 729-6, human lymphoblastoid B-cell line, with lymphocytes obtained from a patient with the cervical carcinoma. It has been reported that CLN-IgG recognized the antigen expressed in various histological types of human cancers including malignant gliomas. The effect of human monoclonal antibody(CLN-IgG) on malignant brain tumors was evaluated in patients with malignant glioma. Early phase II study was concluded that this specific immunotherapy with CLN-IgG is safe and effective therapy in patients with malignant glioma. We treated 10 cases of malignant gliomas with CLN-IgG. All patients had received radiotherapy and chemotherapy before this immunotherapy using the human monoclonal antibody. The human monoclonal antibody(CLN-IgG) was administered intravenously once or twice/week during 24 weeks. Six cases of glioblastoma, 1 medulloblastoma and 3 cases of potine glioma histologically unverified, were treated. Five cases of 6 glioblastomas died 4 to 12 months after this treatment, 3 cases of pontine glioma showed good responses, 2 cases showed marked decrease of tumor size and 1 case showed no regrowth of tumor on MRI imaging. For the above reasons, Human monoclonal antibody(CLN-IgG) might be useful as an immunotherapy of malignant gliomas.     

肠道微生物群组在创伤性脑损伤后遗症的作用机制

创伤性脑损伤(TBI)是威胁人类健康的主要问题之一,因其可造成人类认知能力下降、癫痫发作、运动功能受损和人格改变等,而广受人类关注,而颅脑损伤后体内微生物变化及其对脑外伤后遗症的影响机制研究还不透彻.本文回顾颅脑损伤后人体内肠道微生物的变化及其对脑外伤后遗症的影响,包括血脑屏障的通透性增加、脑肠轴的变化等,并探讨可能的...     

Investigation of MCPH1 G37995C and ASPM A44871G polymorphisms and brain size in a healthy cohort

Loss-of-function mutations in MCPH1 and ASPM are responsible for some cases of autosomal recessive primary microcephaly. Recent studies have indicated that certain common variants of these genes have been positively selected for during the evolution of modern humans. It is therefore possible that these variants may predispose to an increase in brain size in the normal human population. We genotyped the MCPH1 G37995C and ASPM A44871G polymorphisms in a cohort of 118 healthy people who had undergone structural magnetic resonance imaging analysis. We did not detect significant association of either MCPH1 G37995C or ASPM A44871G genotype with whole brain volume, cerebral cortical volume or proportion of grey matter in this cohort. Nor did we detect an association of combined MCPH1 37995C and ASPM 44871G allele dosage with these brain measurements. These results were also confirmed in an age-restricted subcohort of 94 individuals. This study suggests that phenotypes other than brain size may have been selected for in ASPM and MCPH1 variants during evolution of modern humans.     

Cortical expression of peroxisome proliferator-activated receptor-alpha after human brain contusion

Recent studies have demonstrated that peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonists can protect the brain against excessive oxidative stress and inflammation in traumatic brain injury (TBI) and stroke through endogenous PPAR-alpha. However, it has not been investigated whether, and to what degree, cerebral expression of PPAR-alpha changes after TBI, especially in the human brain. In this study, 12 contused brain samples were obtained from 11 patients undergoing surgery for TBI 6 - 98 h after trauma. PPAR-alpha binding activity was measured by electrophoretic mobility shift assay, and temporal and cellular expression of PPAR-alpha by immunohistochemistry. The results showed that a persistent upregulation of PPAR-alpha binding activity and protein expression occurred in injured cortex after TBI, which peaked 24 - 72 h post-injury. Expression of PPAR-alpha was mainly located in glial and vascular endothelial cells with a little expression in the neurons. It is concluded that TBI could greatly upregulate the binding activity and protein expression of PPAR-alpha in injured human brain, which might be important in brain pathophysiology after TBI.