MR Diffusion Tensor Imaging: A Window into White Matter Integrity of the Working Brain

As Norman Geschwind asserted in 1965, syndromes resulting from white matter lesions could produce deficits in higher-order functions and “disconnexion” or the interruption of connection between gray matter regions could be as disruptive as trauma to those regions per se. The advent of in vivo diffusion tensor imaging, which allows quantitative characterization of white matter fiber integrity in health and disease, has served to strengthen Geschwind’s proposal. Here we present an overview of the principles of diffusion tensor imaging (DTI) and its contribution to progress in our current understanding of normal and pathological brain function.     

The Significance of a Non-Reductionist Ontology for the Discipline of Mathematics: A Historical and Systematic Analysis

An overview of the history of the concept of matter highlights the fact that alternative modes of explanation were successively employed. With the discovery of irrational numbers the initial conviction of the Pythagorean School collapsed and was replaced by an exploration of space as a principle of understanding. This legacy dominated the medieval period and had an after-effect well into modernity—for both Descartes and Kant still characterized matter in spatial terms. However, even before Galileo the mechanistic world view slowly entered the scene—the world as chaos, particles in motion. Elevating movement to become the guiding principle in our understanding of matter dominated the main tendency of modern physics until the (end of the) 19th century. The discovery of irreversible processes (radio-activity for example) directed 20th century physics towards an exploration of the meaning of energy-operation. It turned out that even within 20th century physics long-standing legacies prevailed, because an account of the nature of matter continued to be torn apart by atomistic and holistic views—confronted by the problem of constancy and change (radical transformability versus persistence). Concrete, material reality exceeds the scope of any single mode of explanation—an insight that also serves a better understanding of the wave-particle duality.     

Perinatal white matter injury: the changing spectrum of pathology and emerging insights into pathogenetic mechanisms

Perinatal brain injury in survivors of premature birth has a unique and unexplained predilection for periventricular cerebral white matter. Periventricular white-matter injury (PWMI) is now the most common cause of brain injury in preterm infants and the leading cause of chronic neurological morbidity. The spectrum of chronic PWMI includes focal cystic necrotic lesions (periventricular leukomalacia; PVL) and diffuses myelination disturbances. Recent neuroimaging studies support that the incidence of PVL is declining, whereas focal or diffuse noncystic injury is emerging as the predominant lesion. Factors that predispose to PVL during prematurity include hypoxia, ischemia, and maternal-fetal infection. In a significant number of infants, PWMI appears to be initiated by perturbations in cerebral blood flow that reflect anatomic and physiological immaturity of the vasculature. Ischemic cerebral white matter is susceptible to pronounced free radical-mediated injury that particularly targets immature stages of the oligodendrocyte lineage. Emerging experimental data supports that pronounced ischemia in the periventricular white matter is necessary, but not sufficient to generate PWMI. The developmental predilection for PWMI to occur during prematurity appears to be related to both the timing of appearance and regional distribution of susceptible oligodendrocyte progenitors. Injury to oligodendrocyte progenitors may contribute to the pathogenesis of PWMI by disrupting the maturation of myelin-forming oligodendrocytes. Chemical mediators that may contribute to white-matter injury include reactive oxygen species glutamate, cytokines, and adenosine. As our understanding of the pathogenesis of PWMI improves, it is anticipated that new strategies for directly preventing brain injury in premature infants will develop.     

Mister Bixby,Monsieur Bernard,and Some Other 19th Century Scientist–Philosophers on Knowledge-Based Actions

Summary  Following Mr. Bixby and some other 19th century scientist– philosophers such as Claude Bernard, relevant scientific actions should, as a matter of primary importance, be explained with reference to the competence and not to the intentions of those involved. The background is a reliabilist virtue approach – a widespread tendency in 19th century epistemology and philosophy of science. Bixby’s approach includes a critique of some constructivist arguments and establishes a mutually supportive connection to conceptions of scientific progress.     

Structural brain variation,age, and response time

Response time (RT) generally slows with aging, but the contribution of structural brain changes to this slowing is unknown. We used voxel-based morphometry (VBM) to determine gray matter (GM) and white matter (WM) brain volumes in 9 middle-aged adults (38–58 years old) and 9 seniors (66–82 years old). We correlated brain volumes with RT assessed in both a simple visual stimulus-response task and a visual continuous recognition memory task. No GM correlations with simple RT were significant; there was one WM correlation in the right fusiform gyrus. In the memory task, faster RT was correlated (p<.05, corrected) with less GM in the globus pallidus, the parahippocampus, and the thalamus for both groups. Several Brodmann areas (BA) differed between the groups such that in each area, less GM was correlated with slower RTs in the middle-aged group but with faster RTs in the senior group (BAs 19, 37, 46, 9, 8, 6, 13, 10, 41, and 7). The results suggest that individual differences in specific brain structure volumes should be considered as potential moderating factors in cognitive brain imaging studies.     

Functional topography of early periventricular brain lesions in relation to cytoarchitectonic probabilistic maps

Early periventricular brain lesions can not only cause cerebral palsy, but can also induce a reorganization of language. Here, we asked whether these different functional consequences can be attributed to topographically distinct portions of the periventricular white matter damage. Eight patients with pre- and perinatally acquired left-sided periventricular brain lesions underwent focal transcranial magnetic stimulation to assess the integrity of cortico-spinal hand motor projections, and functional MRI to determine the hemispheric organization of language production. MRI lesion-symptom mapping revealed that two distinct portions of the periventricular lesions were critically involved in the disruption of cortico-spinal hand motor projections on the one hand and in the induction of language reorganization into the contra-lesional right hemisphere on the other hand. Both regions are located in a position compatible with the course of cortico-spinal/cortico-nuclear projections of the primary motor cortex in the periventricular white matter, as determined by the stereotaxic probabilistic cytoarchitectonic atlas developed by the Jülich group.     

Structural brain abnormalities in psychopaths-a review

The biological basis of psychopathy has not yet been fully elucidated. Few studies deal with structural neuroimaging in psychopaths. The aim of this article is to review these studies in order to contribute to our understanding of the biological basis of psychopathy. Data in the literature report a reduction in prefrontal gray matter volume, gray matter loss in the right superior temporal gyrus, amygdala volume loss, a decrease in posterior hippocampal volume, an exaggerated structural hippocampal asymmetry, and an increase in callosal white matter volume in psychopathic individuals. These findings suggest that psychopathy is associated with brain abnormalities in a prefrontal-temporo-limbic circuit-i.e. regions that are involved, among others, in emotional and learning processes. Additionally, data indicate that psychopathic individuals cannot be seen as a homogeneous group. The associations between structural changes and psychopathic characteristics do not enable causal conclusions to be drawn, but point rather to the important role of biological brain abnormalities in psychopathy. To gain a comprehensive understanding of this, psychopathy must be viewed as a multifactorial process involving neurobiological, genetic, epidemiological and sociobiographical factors.     

Finding the g-factor in brain structure using the method of correlated vectors

It is unclear whether brain mechanisms underlying human intelligence are distributed throughout the brain or mainly concentrated in the frontal lobes. Data are inconsistent possibly due, at least in part, to the different ways the construct of intelligence is measured. Here we apply the method of correlated vectors to determine how the general factor of intelligence (g) is related to regional gray matter and white matter volumes. This is a re-analysis of an earlier study showing regional gray matter and white matter volume is correlated to Full Scale IQ (FSIQ). However, it is well-known that FSIQ taps several cognitive abilities and skills in addition to g. The results now show that the g factor accounts for several but not all FSIQ/gray matter correlations distributed throughout the brain and these areas may differ for young and older adults.     

Cerebral White Matter Integrity and Cognitive Aging: Contributions from Diffusion Tensor Imaging

The integrity of cerebral white matter is critical for efficient cognitive functioning, but little is known regarding the role of white matter integrity in age-related differences in cognition. Diffusion tensor imaging (DTI) measures the directional displacement of molecular water and as a result can characterize the properties of white matter that combine to restrict diffusivity in a spatially coherent manner. This review considers DTI studies of aging and their implications for understanding adult age differences in cognitive performance. Decline in white matter integrity contributes to a disconnection among distributed neural systems, with a consistent effect on perceptual speed and executive functioning. The relation between white matter integrity and cognition varies across brain regions, with some evidence suggesting that age-related effects exhibit an anterior–posterior gradient. With continued improvements in spatial resolution and integration with functional brain imaging, DTI holds considerable promise, both for theories of cognitive aging and for translational application.     

Sex differences in the IQ-white matter microstructure relationship: A DTI study

Sex differences in the relationship between general intelligence and brain structure are a topic of increasing research interest. Early studies focused mainly on gray and white matter differences using voxel-based morphometry, while more recent studies investigated neural fiber tracts using diffusion tensor imaging (DTI) to analyze the white matter microstructure. In this study we used tract-based spatial statistics (TBSS) on DTI to test how intelligence is associated with brain diffusion indices and to see whether this relationship differs between men and women. 63 Men and women divided into groups of lower and higher intelligence were selected. Whole-brain DTI scans were analyzed using TBSS calculating maps of fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). The results reveal that the white matter microstructure differs between individuals as a function of intelligence and sex. In men, higher intelligence was related to higher FA and lower RD in the corpus callosum. In women, in contrast, intelligence was not related to the white matter microstructure. The higher values of FA and lower values of RD suggest that intelligence is associated with higher myelination and/or a higher number of axons particularly in men. This microstructural difference in the corpus callosum may increase cognitive functioning by reducing inter-hemispheric transfer time and thus account for more efficient brain functioning in men.     

The cortical language circuit: from auditory perception to sentence comprehension

Over the years, a large body of work on the brain basis of language comprehension has accumulated, paving the way for the formulation of a comprehensive model. The model proposed here describes the functional neuroanatomy of the different processing steps from auditory perception to comprehension as located in different gray matter brain regions. It also specifies the information flow between these regions, taking into account white matter fiber tract connections. Bottom-up, input-driven processes proceeding from the auditory cortex to the anterior superior temporal cortex and from there to the prefrontal cortex, as well as top-down, controlled and predictive processes from the prefrontal cortex back to the temporal cortex are proposed to constitute the cortical language circuit.     

Between-individual variability and interpretation of associations between neurophysiological and behavioral measures in aging populations: comment on Salthouse (2011)

Salthouse (2011) argued that (a) variance between individuals on cognitive test scores remains constant between 20 and 90 years of age and (b) widely recognized problems of deducing functional relationships from patterns of correlations between measurements become especially severe for neuropsychological indices, especially for gross indices of age-related brain changes (e.g., losses of brain volume or increases in white matter lesions). I argue that between-individual variability on cognitive tests does increase with age and provides useful information on causes of age-related cognitive decline. I suggest that problems of inference from correlations are just as difficult for behavioral as for neurophysiological indices and that inclusion, in analyses, of even gross measures of brain status such as loss of volume and white matter lesions can correct misinterpretations that occur when only behavioral data are examined.     

Effect of socioeconomic status (SES) disparity on neural development in female African‐American infants at age 1 month

There is increasing interest in both the cumulative and long‐term impact of early life adversity on brain structure and function, especially as the brain is both highly vulnerable and highly adaptive during childhood. Relationships between SES and neural development have been shown in children older than age 2 years. Less is known regarding the impact of SES on neural development in children before age 2. This paper examines the effect of SES, indexed by income‐to‐needs (ITN) and maternal education, on cortical gray, deep gray, and white matter volumes in term, healthy, appropriate for gestational age, African‐American, female infants. At 5 weeks postnatal age, unsedated infants underwent MRI (3.0T Siemens Verio scanner, 32‐channel head coil). Images were segmented based on a locally constructed template. Utilizing hierarchical linear regression, SES effects on MRI volumes were examined. In this cohort of healthy African‐American female infants of varying SES, lower SES was associated with smaller cortical gray and deep gray matter volumes. These SES effects on neural outcome at such a young age build on similar studies of older children, suggesting that the biological embedding of adversity may occur very early in development.     

Correlation between gray/white matter volume and cognition in healthy elderly people

This study applied volumetric analysis and voxel-based morphometry (VBM) of brain magnetic resonance (MR) images to assess whether correlations exist between global and regional gray/white matter volume and the cognitive functions of semantic memory and short-term memory, which are relatively well preserved with aging, using MR image data from 109 community-dwelling healthy elderly individuals. We used the Information and Digit Span subtests of the Wechsler Adult Intelligent Scale-Revised as measures of semantic memory and short-term memory, respectively. We found significant positive correlations between the gray matter ratio, the percentage of gray matter volume in the intracranial volume, and performance on the Digit Span subtest, and between the regional gray matter volumes of the bilateral anterior temporal lobes and performance on the Information subtest. No significant correlations between performance on the cognitive tests and white matter volume were found. Our results suggest that individual variability in specific cognitive functions that are relatively well preserved with aging is accounted for by the variability of gray matter volume in healthy elderly subjects.     

Astrocytes and developmental white matter disorders

There is an increasing awareness that the astrocytes in the immature periventricular white matter are vulnerable to ischemia and respond to inflammation. Here we provide a synopsis of the articles that have evaluated the causes and consequences of developmental brain injuries to white matter astrocytes as well as the consequences of several genetic mutations that result in abnormal astrocyte development. Emerging data suggest that the astrocytes are not simply responding to the injury but are likely victims as well as culprits. Given the important roles that astrocytes play in maintaining ionic, neurotransmitter, and metabolic homeostasis in the brain, a more thorough understanding of the mechanisms that lead to their incapacitation, demise, or reactions as well as a better understanding of the stimuli that regulate their neuroprotective and regenerative properties will enable these cells to be manipulated to preserve the integrity of white matter and to potentially provide therapeutics to enhance neonatal regeneration and recovery from brain injury.     

Executive functions and the frontal lobes: a conceptual view

Several problems in understanding executive functions and their relationships to the frontal lobes are discussed. Data are then presented from several of our studies to support the following statements: (1) the examination of patients with focal frontal lobe lesions is a necessary first step in defining the relation of executive functions to the frontal lobes; (2) there is no unitary executive function. Rather, distinct processes related to the frontal lobes can be differentiated which converge on a general concept of control functions; (3) a simple control-automatic distinction is inadequate to explain the complexity of control-automatic processes; (4) the distinction between complex and simple tasks cannot explain the differences in functions between the frontal lobes and other brain regions; and (5) the most important role of the frontal lobes may be for affective responsiveness, social and personality development, and self-awareness and unconsciousness. Received: 31 March 1999 / Accepted: 23 July 1999     

A Contemporary Metaphysical Controversy

I argue that a metaphysical controversy, comparable with the ‘pantheism controversy’ of the late 18th century, is being played out today in the world-wide clash between religion and science, in which one side adheres to a strict materialism and the other admits phenomena of inspiritment as having a place in ontology. Just as the pantheism controversy was resolved, to some degree, via the concept of panentheism, so the solution to the contest between science and religion today might be pointing us in a panentheist direction. Taking into account (a) the empirical evidence of science, (b) the widespread evidence of spirit phenomena from different religions and spirit traditions, and (c) that the experience of spirit phenomena varies according to cultural frame of reference, I conclude that spirit phenomena must emanate from something that is common across cultures. The only thing that could be common across cultures is matter: it must be matter itself then that is imbued with spirit. While this position has affinities with panentheism, I argue that ‘panentheism’ is not in fact an appropriate name for it in the 21st century, as this name excludes the experience of many cultures for whom phenomena of inspiritment are not describable in any kind of theistic terms.     

A genetic analysis of brain volumes and IQ in children

In a population-based sample of 112 nine-year old twin pairs, we investigated the association among total brain volume, gray matter and white matter volume, intelligence as assessed by the Raven IQ test, verbal comprehension, perceptual organization and perceptual speed as assessed by the Wechsler Intelligence Scale for Children-III. Phenotypic correlations between the brain volumes and intelligence traits ranged between .20 and .33. Processing speed and brain volume did not correlate. The relation between brain volume and intelligence was entirely explained by a common set of genes influencing both sets of phenotypes.     

Neuroimaging studies in eating disorders

The understanding of the eating disorders (EDs) anorexia (AN) and bulimia nervosa (BN) has undergone remarkable advancements in the past decade. Most studies that have been done in AN show brain gray and white matter volume loss during the ill state that, at least in part, remit with recovery. Similar patterns occur for brain phospholipids assessed using magnet resonance spectroscopy (MRS). Imaging studies have been used to provide functional information regarding serotonin neuroreceptor dynamics, regional cerebral blood flow, or cerebral glucose metabolism. Such studies have implicated cingulate, frontal, temporal, and parietal regions in AN. Investigators have found that challenges such as food and body image distortions may activate some of these regions, raising the possibility that such studies may shed light on puzzling AN symptoms, such as body image distortions or extremes of appetitive behaviors. Emerging data suggest these disturbances persist after recovery from AN, suggesting the possibility that these are traits that may create a vulnerability to develop an ED. While fewer studies have been done in BN or binge eating disorder, there may be disturbances of serotonin metabolism in similar brain regions. Taken together, these findings give promise for future investigations with the hope of delineating brain pathways that contribute to the etiology of EDs