Automated discrimination of brain pathological state attending to complex structural brain network properties: the shiverer mutant mouse case

Neuroimaging classification procedures between normal and pathological subjects are sparse and highly dependent of an expert''s clinical criterion. Here, we aimed to investigate whether possible brain structural network differences in the shiverer mouse mutant, a relevant animal model of myelin related diseases, can reflect intrinsic individual brain properties that allow the automatic discrimination between the shiverer and normal subjects. Common structural networks properties between shiverer (C3Fe.SWV Mbp^shi/Mbp^shi, n = 6) and background control (C3HeB.FeJ, n = 6) mice are estimated and compared by means of three diffusion weighted MRI (DW-MRI) fiber tractography algorithms and a graph framework. Firstly, we found that brain networks of control group are significantly more clustered, modularized, efficient and optimized than those of the shiverer group, which presented significantly increased characteristic path length. These results are in line with previous structural/functional complex brain networks analysis that have revealed topologic differences and brain network randomization associated to specific states of human brain pathology. In addition, by means of network measures spatial representations and discrimination analysis, we show that it is possible to classify with high accuracy to which group each subject belongs, providing also a probability value of being a normal or shiverer subject as an individual anatomical classifier. The obtained correct predictions (e.g., around 91.6–100%) and clear spatial subdivisions between control and shiverer mice, suggest that there might exist specific network subspaces corresponding to specific brain disorders, supporting also the point of view that complex brain network analyses constitutes promising tools in the future creation of interpretable imaging biomarkers.     

Single unit approaches to human vision and memory

Research on the visual system focuses on using electrophysiology, pharmacology and other invasive tools in animal models. Non-invasive tools such as scalp electroencephalography and imaging allow examining humans but show a much lower spatial and/or temporal resolution. Under special clinical conditions, it is possible to monitor single-unit activity in humans when invasive procedures are required due to particular pathological conditions including epilepsy and Parkinson's disease. We review our knowledge about the visual system and visual memories in the human brain at the single neuron level. The properties of the human brain seem to be broadly compatible with the knowledge derived from animal models. The possibility of examining high-resolution brain activity in conscious human subjects allows investigators to ask novel questions that are challenging to address in animal models.     

Research on the relation of EEG signal chaos characteristics with high-level intelligence activity of human brain

Using phase space reconstruct technique from one-dimensional and multi-dimensional time series and the quantitative criterion rule of system chaos, and combining the neural network; analyses, computations and sort are conducted on electroencephalogram (EEG) signals of five kinds of human consciousness activities (relaxation, mental arithmetic of multiplication, mental composition of a letter, visualizing a 3-dimensional object being revolved about an axis, and visualizing numbers being written or erased on a blackboard). Through comparative studies on the determinacy, the phase graph, the power spectra, the approximate entropy, the correlation dimension and the Lyapunov exponent of EEG signals of 5 kinds of consciousness activities, the following conclusions are shown: (1) The statistic results of the deterministic computation indicate that chaos characteristic may lie in human consciousness activities, and central tendency measure (CTM) is consistent with phase graph, so it can be used as a division way of EEG attractor. (2) The analyses of power spectra show that ideology of single subject is almost identical but the frequency channels of different consciousness activities have slight difference. (3) The approximate entropy between different subjects exist discrepancy. Under the same conditions, the larger the approximate entropy of subject is, the better the subject's innovation is. (4) The results of the correlation dimension and the Lyapunov exponent indicate that activities of human brain exist in attractors with fractional dimensions. (5) Nonlinear quantitative criterion rule, which unites the neural network, can classify different kinds of consciousness activities well. In this paper, the results of classification indicate that the consciousness activity of arithmetic has better differentiation degree than that of abstract.     

Moving minds: Ethical aspects of neural motor prostheses

Modern brain technology is a highly dynamic and innovative field of research with great potential for medical applications. Recent advances in recording neural signals from the brain by brain-machine interfacing presage new therapeutic options for paralyzed people by means of neural motor prostheses. This paper examines foreseeable ethical questions related to the research on brainmachine interfaces and their possible future applications. It identifies four major topics that need to be considered: first, the questions of personality and its possible alterations; second, responsibility and its possible constraints; third, therapeutic applications and their possible exceedance; and fourth, questions of research ethics that arise when progressing from animal experimentation to application to human subjects. This paper, in identifying and addressing the ethical questions raised by brain-machine interfaces, presents concerns that need to be considered if possible prosthetics based on modern brain technology are to be used cautiously and responsibly.     

Toward a cross-species neuroscientific understanding of the affective mind: do animals have emotional feelings?

Do we need to consider mental processes in our analysis of brain functions in other animals? Obviously we do, if such BrainMind functions exist in the animals we wish to understand. If so, how do we proceed, while still retaining materialistic-mechanistic perspectives? This essay outlines the historical forces that led to emotional feelings in animals being marginalized in behavioristic scientific discussions of why animals behave the way they do, and why mental constructs are generally disregarded in modern neuroscientific analyses. The roots of this problem go back to Cartesian dualism and the attempt of 19th century physician-scientists to ground a new type of medical curriculum on a completely materialistic approach to body functions. Thereby all vitalistic principles were discarded from the lexicon of science, and subjective experience in animals was put in that category and discarded as an invalid approach to animal behavior. This led to forms of rigid operationalism during the era of behaviorism and subsequently ruthless reductionism in brain research, leaving little room for mentalistic concepts such as emotional feelings in animal research. However, modern studies of the brain clearly indicate that artificially induced arousals of emotional networks, as with localized electrical and chemical brain stimulation, can serve as "rewards" and "punishments" in various learning tasks. This strongly indicates that animal brains elaborate various experienced states, with those having affective contents being easiest to study rigorously. However, in approaching emotional feelings empirically we must pay special attention to the difficulties and vagaries of human language and evolutionary levels of control in the brain. We need distinct nomenclatures from primary (unconditioned phenomenal experiences) to tertiary (reflective) levels of mind. The scientific pursuit of affective brain processes in other mammals can now reveal general BrainMind principles that also apply to human feelings, as with neurochemical predictions from preclinical animal models to self-reports of corresponding human experiences. In short, brain research has now repeatedly verified the existence of affective experience-various reward and punishment functions-during artificial arousal of emotional networks in our fellow animals. The implications for new conceptual schema for understanding human/primate affective feelings and how such knowledge can impact scientific advances in biological psychiatry are also addressed.     

Multisensory interplay reveals crossmodal influences on 'sensory-specific' brain regions, neural responses, and judgments

Although much traditional sensory research has studied each sensory modality in isolation, there has been a recent explosion of interest in causal interplay between different senses. Various techniques have now identified numerous multisensory convergence zones in the brain. Some convergence may arise surprisingly close to low-level sensory-specific cortex, and some direct connections may exist even between primary sensory cortices. A variety of multisensory phenomena have now been reported in which sensory-specific brain responses and perceptual judgments concerning one sense can be affected by relations with other senses. We survey recent progress in this multisensory field, foregrounding human studies against the background of invasive animal work and highlighting possible underlying mechanisms. These include rapid feedforward integration, possible thalamic influences, and/or feedback from multisensory regions to sensory-specific brain areas. Multisensory interplay is more prevalent than classic modular approaches assumed, and new methods are now available to determine the underlying circuits.     

Le sujet cérébral: une esquisse historique et conceptuelle

Since the middle of the 20th century, numerous discourses and practices, both within and outside scientific and philosophical disciplines, have manifested the development of the notion of the human being as acerebral subject. The brain appears to be the only organ of the body that we need, and that has to be exclusively ours, in order for each individual to be himself or herself. Sincepersonhood is the quality or condition of being an individual person,brainhood is thus the quality or condition of being a brain. This property defines the cerebral subject. The anthropology ofbrainhood may seem a natural consequence of progress in the neurosciences. However, it is rooted in 17th-century developments in the philosophies of matter and personal identity. The neurosciences confirm and reinforce this perspective. The author outlines the historical narrative concerning the development of the cerebral subject as well as some contemporary issues arising from the neurosciences.     

Maternal infection and immune involvement in autism

Recent studies have highlighted a connection between infection during pregnancy and the increased risk of autism in the offspring. Parallel studies of cerebral spinal fluid, blood and postmortem brains reveal an ongoing, hyper-responsive inflammatory-like state in many young as well as adult autism subjects. There are also indications of gastrointestinal problems in at least a subset of autistic children. Work on the maternal infection risk factor using animal models indicates that aspects of brain and peripheral immune dysregulation can begin during fetal development and continue through adulthood. The offspring of infected or immune-activated dams also display cardinal behavioral features of autism, as well as neuropathology consistent with that seen in human autism. These rodent models are proving useful for the study of pathogenesis and gene-environment interactions as well as for the exploration of potential therapeutic strategies.     

A Fourier transform infrared microspectroscopic imaging investigation into an animal model exhibiting glioblastoma multiforme

Glioblastoma multiforme (GBM) is a highly malignant human brain tumour for which no cure is available at present. Numerous clinical studies as well as animal experiments are under way with the goal being to understand tumour biology and develop potential therapeutic approaches. C6 cell glioma in the adult rat is a frequently used and well accepted animal model for the malignant human glial tumour. By combining standard analytical methods such as histology and immunohistochemistry with Fourier Transform Infrared (FTIR) microspectroscopic imaging and multivariate statistical approaches, we are developing a novel approach to tumour diagnosis which allows us to obtain information about the structure and composition of tumour tissues that could not be obtained easily with either method alone. We have used a “Stingray” FTIR imaging spectrometer to analyse and compare the compositions of coronal brain tissue sections of a tumour-bearing animal and those from a healthy animal. We have found that the tumour tissue has a characteristic chemical signature, which distinguishes it from tumour-free brain tissue. The physical-chemical differences, determined by image and spectral comparison are consistent with changes in total protein absorbance, phosphodiester absorbance and physical dispersive artefacts. The results indicate that FTIR imaging analysis could become a valuable analytic method in brain tumour research and possibly in the diagnosis of human brain tumours.     

A Fourier transform infrared microspectroscopic imaging investigation into an animal model exhibiting glioblastoma multiforme

Glioblastoma multiforme (GBM) is a highly malignant human brain tumour for which no cure is available at present. Numerous clinical studies as well as animal experiments are under way with the goal being to understand tumour biology and develop potential therapeutic approaches. C6 cell glioma in the adult rat is a frequently used and well accepted animal model for the malignant human glial tumour. By combining standard analytical methods such as histology and immunohistochemistry with Fourier Transform Infrared (FTIR) microspectroscopic imaging and multivariate statistical approaches, we are developing a novel approach to tumour diagnosis which allows us to obtain information about the structure and composition of tumour tissues that could not be obtained easily with either method alone. We have used a "Stingray" FTIR imaging spectrometer to analyse and compare the compositions of coronal brain tissue sections of a tumour-bearing animal and those from a healthy animal. We have found that the tumour tissue has a characteristic chemical signature, which distinguishes it from tumour-free brain tissue. The physical-chemical differences, determined by image and spectral comparison are consistent with changes in total protein absorbance, phosphodiester absorbance and physical dispersive artefacts. The results indicate that FTIR imaging analysis could become a valuable analytic method in brain tumour research and possibly in the diagnosis of human brain tumours.     

Undermatching in humans to amount of reinforcement

Human subjects were exposed to a concurrent-chain procedure in which amount of reinforcement in the terminal links was varied. The experimental procedure was designed to resemble as closely as possible animal operant procedures: verbal instructions were eliminated, the key-press operant response was shaped, and a “consummatory” response was required to receive reward. In addition to varying amount of reward, three different pairs of initial-link values in the concurrent chain were studied. The human subjects showed undermatching to amount of reinforcement (as do animal subjects). Moreover, the degree of undermatching tended to increase as the values of the initial links increased, consistent with Fantino's delay reduction hypothesis (1977) that choice for a larger reward decreases as the length of the initial link increases.     

Deconstructing the Animal Image: Toward an Anthropology of Animals

Abstract

Natural science tends to reduce animals to parts, ignoring such characteristics as “inwardness,” ideas, and culture. The social sciences, such as sociology and anthropology, generally confine themselves to human subjects. Even those who study human-animal interactions tend to view animals as passive objects that are acted upon or thought and felt about. Scholars in the humanities assume that sociality and culture do not exist outside the human realm. The author calls for the development of a true anthropology of animals that studies and elucidates, to the extent possible, the animal Other.     

A probabilistic atlas and reference system for the human brain: International Consortium for Brain Mapping (ICBM).

Motivated by the vast amount of information that is rapidly accumulating about the human brain in digital form, we embarked upon a program in 1992 to develop a four-dimensional probabilistic atlas and reference system for the human brain. Through an International Consortium for Brain Mapping (ICBM) a dataset is being collected that includes 7000 subjects between the ages of eighteen and ninety years and including 342 mono- and dizygotic twins. Data on each subject includes detailed demographic, clinical, behavioural and imaging information. DNA has been collected for genotyping from 5800 subjects. A component of the programme uses post-mortem tissue to determine the probabilistic distribution of microscopic cyto- and chemoarchitectural regions in the human brain. This, combined with macroscopic information about structure and function derived from subjects in vivo, provides the first large scale opportunity to gain meaningful insights into the concordance or discordance in micro- and macroscopic structure and function. The philosophy, strategy, algorithm development, data acquisition techniques and validation methods are described in this report along with database structures. Examples of results are described for the normal adult human brain as well as examples in patients with Alzheimer's disease and multiple sclerosis. The ability to quantify the variance of the human brain as a function of age in a large population of subjects for whom data is also available about their genetic composition and behaviour will allow for the first assessment of cerebral genotype-phenotype-behavioural correlations in humans to take place in a population this large. This approach and its application should provide new insights and opportunities for investigators interested in basic neuroscience, clinical diagnostics and the evaluation of neuropsychiatric disorders in patients.     

Brain, mind and limitations of a scientific theory of human consciousness

In biological terms, human consciousness appears as a feature associated with the functioning of the human brain. The corresponding activities of the neural network occur strictly in accord with physical laws; however, this fact does not necessarily imply that there can be a comprehensive scientific theory of consciousness, despite all the progress in neurobiology, neuropsychology and neurocomputation. Predictions of the extent to which such a theory may become possible vary widely in the scientific community. There are basic reasons-not only practical but also epistemological-why the brain-mind relation may never be fully "decodable" by general finite procedures. In particular self-referential features of consciousness, such as self-representations involved in strategic thought and dispositions, may not be resolvable in all their essential aspects by brain analysis. Assuming that such limitations exist, objective analysis by the methods of natural science cannot, in principle, fully encompass subjective, mental experience.     

Performing Behavioral Tasks in Subjects with Intracranial Electrodes

Patients having stereo-electroencephalography (SEEG) electrode, subdural grid or depth electrode implants have a multitude of electrodes implanted in different areas of their brain for the localization of their seizure focus and eloquent areas. After implantation, the patient must remain in the hospital until the pathological area of brain is found and possibly resected. During this time, these patients offer a unique opportunity to the research community because any number of behavioral paradigms can be performed to uncover the neural correlates that guide behavior. Here we present a method for recording brain activity from intracranial implants as subjects perform a behavioral task designed to assess decision-making and reward encoding. All electrophysiological data from the intracranial electrodes are recorded during the behavioral task, allowing for the examination of the many brain areas involved in a single function at time scales relevant to behavior. Moreover, and unlike animal studies, human patients can learn a wide variety of behavioral tasks quickly, allowing for the ability to perform more than one task in the same subject or for performing controls. Despite the many advantages of this technique for understanding human brain function, there are also methodological limitations that we discuss, including environmental factors, analgesic effects, time constraints and recordings from diseased tissue. This method may be easily implemented by any institution that performs intracranial assessments; providing the opportunity to directly examine human brain function during behavior.     

Variance in the production of homovanillic acid and 3-methoxy-4-hydroxyphenethyleneglycol by the awake primate brain

Previous experimental results, using a new technique whereby the production rates of the neurotransmitter metabolites homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) by the awake primate brain are determined, have shown a wide variance in metabolite production among both animal and human subjects. These data suggested that either individual subjects differ in the activity of brain dopamine (DA) or norepinephrine (NE) neurons and/or that the activities of these neurons fluctuate over time. For these reasons a series of experiments were performed in which measures of HVA and MHPG production were obtained at three time points in the same animal (monkeys) over a three hour period. It was found that the group mean values for the production of HVA and MHPG by brain were similar for each of the three time points. However, it was also found that marked variations in HVA and MHPG production occur within a single animal over a three hour period. The coefficients of variation for individual animals for HVA ranged from 9.3 to 31.9% and for MHPG from 10.1 to 62.3%. These variations were not correlated with grossly observable changes in behavioral states. Using an analysis of variance it was found that the variance in MHPG production was significantly greater than that for HVA (F = 6.2, p < 0.05) suggesting that brain NE systems are more liable and/or show greater change than do brain DA systems. These data are interpreted as indicating that in the awake, resting primate brain fluctuations in the activities of DA and NE neurons occur, i.e. there is not a steady, invariant production of metabolites but rather they are produced in pulses of varying lengths. This interpretation of the data is generally consistent with electrophysiological studies which indicate that catecholamine neurons fire in bursts which are then followed by silent periods. Finally, in terms of practical application of the V-A difference technique, these data indicate that replicable group mean estimates of brain HVA and MHPG production can be obtained by averaging values from a single time point whereas accurate information about an individual animal will require multiple samplings.Recent reports from this laboratory have described a method whereby a direct measure of the rates of production of neurotransmitter metabolites such as homovanillic acid (HVA), 3-methoxy-4-hydroxyphenethyleneglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) by the awake primate brain can be determined (1, 2, 3, 4). Since the quantities of HVA, MHPG, and probably 5-HIAA in the brain vary as a function of the activity of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) neurons (1, 5, 6, 7, 8), it is likely that these measures of neurotransmitter metabolite production reflect the functional state of brain DA, NE, and 5-HT neuronal systems. The experimental results thus far obtained with this technique have shown a wide variance in the rates of neurotransmitter metabolite production across both animal and human subjects even though the subjects were not in clearly different behavioral or emotional states (1, 2, 4, 9). These data suggested that either individual subjects differ markedly in the activities of brain DA, NE, and 5-HT neurotransmitter systems and/or that the activity of these systems fluctuates markedly over time. For these reasons, experiments were undertaken in which repeated measures of HVA and MHPG production by brain within the same animal were determined over a three hour period. The results of these experiments, which are reported here, indicate that there are marked changes in brain metabolite production which occur within animals. The implications of these findings for our understanding of the functioning of brain neurotransmitter systems and for the practical applications of this technique are discussed.     

Postmodern Personhood: A Matter of Consciousness

The concept of person is integral to bioethical discourse because persons are the proper subject of the moral domain. Nevertheless, the concept of person has played no role in the prevailing formulation of human death because of a purported lack of consensus concerning the essential attributes of a person. Beginning with John Locke's fundamental proposition that person is a 'forensic term', I argue that in Western society we do have a consensus on at least one necessary condition for personhood, and that is the capacity for conscious experience. When we consider the whole brain formulation of death, and the most prominent defense of it by the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, we can readily identify the flaws that grow out of the failure to define human death as the permanent loss of the capacity for conscious experience. Most fundamental among these flaws is a definition of human death that reduces persons to the capacity of the brain to regulate purely physiological functioning. Such a formulation would, in theory, apply to any member of the animal kingdom. I suggest that an appropriate concept of death should capture what it is about a particular living being that is so essential to it that the permanent loss of that thing constitutes death. What is essential to being a human being is living the life of a person, which derives from the capacity for conscious experience.     

Postmodern personhood: a matter of consciousness

The concept of person is integral to bioethical discourse because persons are the proper subject of the moral domain. Nevertheless, the concept of person has played no role in the prevailing formulation of human death because of a purported lack of consensus concerning the essential attributes of a person. Beginning with John Locke's fundamental proposition that person is a 'forensic term', I argue that in Western society we do have a consensus on at least one necessary condition for personhood, and that is the capacity for conscious experience. When we consider the whole brain formulation of death, and the most prominent defense of it by the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, we can readily identify the flaws that grow out of the failure to define human death as the permanent loss of the capacity for conscious experience. Most fundamental among these flaws is a definition of human death that reduces persons to the capacity of the brain to regulate purely physiological functioning. Such a formulation would, in theory, apply to any member of the animal kingdom. I suggest that an appropriate concept of death should capture what it is about a particular living being that is so essential to it that the permanent loss of that thing constitutes death. What is essential to being a human being is living the life of a person, which derives from the capacity for conscious experience.     

Gomesin, a peptide produced by the spider Acanthoscurria gomesiana, is a potent anticryptococcal agent that acts in synergism with fluconazole

Gomesin is an 18-residue cysteine-rich antimicrobial peptide produced by hemocytes of the spider Acanthoscurria gomesiana. In the present study, the antifungal properties of gomesin against Cryptococcus neoformans, the etiologic agent of cryptococcosis, were evaluated. Gomesin bound to the cell surface of cryptococci, which resulted in cell death associated with membrane permeabilization. Antifungal concentrations of gomesin were not toxic for human brain cells. Supplementation of cryptococcal cultures with the peptide (1 microM) caused a decrease in capsule expression and rendered fungal cells more susceptible to killing by human brain phagocytes. The possible use of gomesin in combination with fluconazole, a standard antifungal drug, was also evaluated. In association with fluconazole, gomesin concentrations with low antimicrobial activity (0.1-1 microM) inhibited fungal growth and enhanced the antimicrobial activity of brain phagocytes. These results reveal the potential of gomesin to promote inhibition of cryptococcal growth directly or by enhancing the effectiveness of host defenses.     

Biogenic monoamines of the brain and spinal cord pia mater in vertebrates

Fluorimetric studies have been made on the content of adrenalin, noradrenaline, serotonin, dopamine, and tryptamine in the pial matter of the brain and spinal cord of fishes, birds and mammals including man. Using histochemical method with glyoxylic acid, biogenic monoamines were revealed in the adrenergic nerve fibers and monoaminocytes. Their total content in the pial matter of the brain is approximately the same in all vertebrates, being significantly lower in man. Higher concentration of adrenergic axons and lower amount of monoaminocytes in human subjects reveal the key role of the nervous influences in regulation of hemodynamics of the brain.