Neuroimaging Methodologies Research Articles

Cognitive phenotypes, brain morphometry and the detection of cognitive decline in preclinical AD.

Identifying a preclinical phase of Alzheimer’s Disease (PCAD) that is distinct from cognitive changes in healthy aging continues to be a major research focus. Combining neuropsychological and neuroimaging methodologies should improve our ability to differentiate healthy from pathological aging, although studies that utilize both methods often result in equivocal findings, possibly due to variability in cognitive test performance that may be capturing distinct phenotypes. One method of capturing this cognitive variability is to utilize contrasting neuropsychological tests to identify subgroups representative of distinct cognitive phenotypes, and determine whether differences in brain morphometry support these classifications. We review several approaches to defining cognitive subgroups, and we consider the possibility that cognitive asymmetry might provide one means of identifying both functional and structural changes associated with aging and dementia.

Cognitive Phenotypes, Brain Morphometry and the Detection of Cognitive Decline in Preclinical AD

Identifying a preclinical phase of Alzheimer’s Disease (PCAD) that is distinct from cognitive changes in healthy aging continues to be a major research focus. Combining neuropsychological and neuroimaging methodologies should improve our ability to differentiate healthy from pathological aging, although studies that utilize both methods often result in equivocal findings, possibly due to variability in cognitive test performance that may be capturing distinct phenotypes. One method of capturing this cognitive variability is to utilize contrasting neuropsychological tests to identify subgroups representative of distinct cognitive phenotypes, and determine whether differences in brain morphometry support these classifications. We review several approaches to defining cognitive subgroups, and we consider the possibility that cognitive asymmetry might provide one means of identifying both functional and structural changes associated with aging and dementia.

P02-07 Neurobiological substrate of Autism Spectrum Disorder - Cerebral blood flow distribution of 11C-butanol as assessed by PET/CT

Background:Functional studies in Autism Spectrum Disorder (ASD) have shown localised focal hypoperfusion and abnormalities in the anatomo-functional connectivity of limbic-striatal “social” brain. However, no common regional abnormalities have been found across studies.The aim of this study was to investigate the cerebral blood flow (CBF) at rest in subjects with ASD as compared to a group of healthy controls.Methods:In this preliminary investigation six normal intelligence patients with ASD and 5 age and sex matched healthy controls (HC) were examined using PET/CT camera and, as CBF tracer, 11C-butanol, a radiopharmaceutical produced on-site. The combination of these two methodologies reduced the whole examination time to less than 10 minutes. Statistical Parametric Mapping was implemented to analyse the data.Results:As compared to HC, ASD showed a highly significant CBF increase (height threshold p=0.001, p< 0.0001 at voxel-level), bilaterally, in large portions of the cerebellum, of the visual associative cortex and of the posterior parietal lobe.Conclusions:This preliminary study was performed by the state-of-the-art neuroimaging methodologies that reduced considerably the examination time and resulted in less stress and more reliable investigations. The occipital and parietal associative cortex as well as the cerebellum showed an increased CBF in ASD, underscoring their involvement in the disease and raising methodological and diagnostic issues to be considered when exploring the neuroanatomy of ASD.

Immunopathogenesis of multiple sclerosis

Multiple sclerosis (MS) is a suspected autoimmune disease in which myelin-specific CD4+ and CD8+ T cells enter the central nervous system (CNS) and initiate an inflammatory response directed against myelin and other components of the CNS. Acute MS exacerbations are believed be the result of active inflammation, and progression of disability is generally believed to reflect accumulation of damage to the CNS, particularly axonal damage. Over the last several years, the pathophysiology of MS is being appreciated to be much more complex, and it appears that the development of the MS plaque involves a large number of cell populations, including CD8+ T lymphocytes, B cells, and Th17 cells (a population of helper T cells that secrete the inflammatory cytokine IL-17). The axonal transection and degeneration that is thought to represent the basis for progressive MS is now recognized to begin early in the disease process and to continue in the progressive forms of the disease. Molecules important for limiting aberrant neural connections in the CNS have been identified, which suppress axonal sprouting and regeneration of transected axons within the CNS. Pathways have also been identified that prevent remyelination of the MS lesion by oligodendrocyte precursors. Novel neuroimaging methodologies and potential biomarkers are being developed to monitor various aspects of the disease process in MS. As we identify the pathways responsible for the clinical phenomena of MS, we will be able to develop new therapeutic strategies for this disabling illness of young adults.

Handbook of research methods in personality psychology

Part 1. Designing a Personality Study. D.P. McAdams, J.L. Pals, The Role of Theory in Personality Assessment. M.B. Donnellan, R.D. Conger, Designing and Implementing Longitudinal Studies. W. Revelle, Experimental Approaches to the Study of Personality. R.F. Krueger, J.L. Tackett, Behavior Genetic Designs. T.S. Conner, L. Feldman Barrett, M.M. Tugade, H. Tennen, Idiographic Personality: The Theory and Practice of Experience Sampling. A.C. Elms, Psychobiography and Case Study Methods. P. Cramer, Mining Archival Data. R.C. Fraley, Using the Internet for Personality Research: What Can Be Done, How to Do It, and Some Concerns. R.C. Fraley, M.J. Marks, The Null Hypothesis Significance-Testing Debate and Its Implications for Personality Research. V. Benet-Martinez, Cross-Cultural Personality Research: Conceptual and Methodological Issues. S. Vazire, S.D. Gosling, A.S. Dickey, S.J. Schapiro, Measuring Personality in Nonhuman Animals. Part 2. Methods for Assessing Personality at Different Levels of Analysis. K.H. Craik, Taxonomies, Trends, and Integrations. D.L. Paulhus, S. Vazire, The Self-Report Method. L.J. Simms, D. Watson, The Construct Validation Approach to Personality Scale Construction. R.R. McCrae, A. Weiss, Observer Ratings of Personality. R.M. Furr, D.C. Funder, Behavior Observation. B.A. Woike, Content Coding of Open-Ended Responses. A.V. Song, D.K. Simonton, Personality Assessment at a Distance. O.C. Schultheiss, J.S. Pang, Measuring Implicit Motives. M.D. Robinson, Lives Lived in Milliseconds: Using Cognitive Methods in Personality Research. J.S. Beer, M.V. Lombardo, Patient and Neuroimaging Methodologies. L.M. Diamond, K. Otter-Henderson, Physiological Measures. R.P. Ebstein, R. Bachner-Melman, S. Israel, L. Nemanov, I. Gritsenko, The Human Genome Project and Personality: What We Can Learn about Our Inner and Outer Selves through Our Genes. Part 3. Analyzing and Interpreting Personality Data. J. Morizot, A.T. Ainsworth, S.P. Reise, Toward Modern Psychometrics: Application of Item Response Theory Models in Personality Research. K. Lee, M.C. Ashton, Factor Analysis in Personality Research. R.H. Hoyle, Applications of Structural Equation Modeling in Personality Research. O.P. John, C.J. Soto, The Importance of Being Valid: Reliability and the Process of Construct Validation. D.J. Ozer, Evaluating Effect Size in Personality Research. J.B. Nezlek, Multilevel Modeling in Personality Research. W. Fleeson, Studying Personality Processes: Explaining Change in Between-persons Longitudinal and Within-Person Multilevel Models. D.K. Mroczek, The Analysis of Longitudinal Data in Personality Research. J.W. Grice, Person-Centered Structural Analyses. S.G. West, L.S. Aiken, W. Wu, A.B. Taylor, Multiple Regression: Applications of the Basics and Beyond in Personality Research. W.F. Chaplin, Moderator and Mediator Models in Personality Research: A Basic Introduction. Y. Shoda, Computational Modeling of Personality as a Dynamical System. B.W. Roberts, N.R. Kuncel, W. Viechtbauer, T. Bogg, Meta-Analysis in Personality Psychology: A Primer. R.W. Robins, J.L. Tracy, J.W. Sherman, What Kinds of Methods Do Personality Psychologists Use? A Survey of Journal Editors and Editorial Board Members.

Neuroimaging Approaches in Mood Disorders: Technique and Clinical Implications

Clinical research in mood disorders increasingly involves advanced neuroimaging techniques. The encompassing aim of this review is to provide the mental health care practitioner with a pragmatic understanding of neuroimaging approaches and their possible clinical application. We conducted a literature search of English-language articles using the search terms, major depressive disorder and bipolar disorder, cross-referenced with available neuroimaging technologies and analytical approaches, The search was supplemented with a manual review of relevant references. We organize the review by reviewing frequently asked questions on the topic of neuroimaging by mental health-care providers. Magnetic resonance (MR) approaches provide information on white and gray matter pathology (segmentation), cellular metabolism (MRS), oxygen consumption (BOLD), and neurocircuitry (DTI). Radionuclide-based neuroimaging methodologies provide quantitative estimates of brain glucose metabolism, regional blood flow, and ligand-receptor/transporter binding. Clinical implications of neuroimaging methodologies are reviewed. Advances in neuroimaging technology have refined models of disease pathophysiology in mood disorders and the mechanistic basis of antidepressant action. Multivariate analysis of functional and structural neuroimaging data, longitudinal analysis in the depressed and remitted states, and inclusion of representative patients with medical and psychiatric comorbidities will enhance the clinical translation of future research findings.

Does the Parietal Cortex Distinguish between “10,” “Ten,” and Ten Dots?

It is well established that the intraparietal sulcus (IPS) plays an important role in the processing and representation of numerical magnitude. Two recent studies by Piazza et al. and Cohen Kadosh et al. published in this issue of Neuron used fMRI adaptation to explore the extent to which parietal number processing is dependent upon or independent of a numbers' surface format. Their results, while slightly different, converge to suggest that the answer may be neither, but rather that it depends on the hemisphere.

Neuroprotection by GDNF-secreting stem cells in a Huntington's disease model: optical neuroimage tracking of brain-grafted cells

The use of stem cells for reconstructive or neuroprotective strategies can benefit from new advances in neuroimaging techniques to track grafted cells. In the present work, we analyze the potential of a neural stem cell (NSC) line, which stably expresses the glial cell line-derived neurotrophic factor (GDNF) and the firefly luciferase gene (GDNF/Luc-NSC), for cell therapy in a Huntington's disease mouse model. Our results show that detection of light photons is an effective method to quantify the proliferation rate and to characterize the migration pathways of transplanted NSCs. Intravenous administration of luciferine, the luciferase substract, into the grafted animals allowed the detection of implanted cells in real time by an optical neuroimaging methodology, overpassing the limits of serial histological analyses. We observed that transplanted GDNF/Luc-NSCs survive after grafting and expand more when transplanted in quinolinate-lesioned nude mouse striata than when transplanted in non-lesioned mice. We also demonstrate that GDNF/Luc-NSCs prevent the degeneration of striatal neurons in the excitotoxic mouse model of Huntington's disease and reduce the amphetamine-induced rotational behavior in mice bearing unilateral lesions.

Extending animal models of fear conditioning to humans

A goal of fear and anxiety research is to understand how to treat the potentially devastating effects of anxiety disorders in humans. Much of this research utilizes classical fear conditioning, a simple paradigm that has been extensively investigated in animals, helping outline a brain circuitry thought to be responsible for the acquisition, expression and extinction of fear. The findings from non-human animal research have more recently been substantiated and extended in humans, using neuropsychological and neuroimaging methodologies. Research across species concur that the neural correlates of fear conditioning include involvement of the amygdala during all stages of fear learning, and prefrontal areas during the extinction phase. This manuscript reviews how animal models of fear are translated to human behavior, and how some fears are more easily acquired in humans (i.e., social–cultural). Finally, using the knowledge provided by a rich animal literature, we attempt to extend these findings to human models targeted to helping facilitate extinction or abolishment of fears, a trademark of anxiety disorders, by discussing efficacy in modulating the brain circuitry involved in fear conditioning via pharmacological treatments or emotion regulation cognitive strategies.

Neuroimaging in late-life depression

Late-life depression may be associated with vasculopathy. Neuroimaging has been a critical tool in exploring the relationship between this form of depression and vascular factors. Magnetic resonance imaging has been the most widely used tool, but there is potential to use other structural imaging techniques as well as functional neuroimaging methodologies. Neuroimaging may potentially be utilized at some point as a biomarker for late-life depression, thus helping with diagnosis and guiding treatment.

INTEGRATING FUNCTIONAL NEUROIMAGING AND HUMAN OPERANT RESEARCH: BRAIN ACTIVATION CORRELATED WITH PRESENTATION OF DISCRIMINATIVE STIMULI

Results of numerous human imaging studies and nonhuman neurophysiological studies on "reward" highlight a role for frontal, striatal, and thalamic regions in operant learning. By integrating operant and functional neuroimaging methodologies, the present investigation examined brain activation to two types of discriminative stimuli correlated with different contingencies. Prior to neuroimaging, 10 adult human subjects completed operant discrimination training in which money was delivered following button pressing (press-money contingency) in the presence of one set of discriminative stimuli, and termination of trials followed not responding (no response-next trial contingency) in the presence of a second set of discriminative stimuli. After operant training, subjects were instructed to memorize a third set of control stimuli unassociated with contingencies. Several hours after training, functional magnetic resonance imaging was performed while subjects viewed discriminative and control stimuli that were presented individually for 1,500 ms per trial, with stimulus presentations occurring, on average, every 6 s. Activation was found in frontal and striatal brain regions to both sets of discriminative stimuli relative to control stimuli. In addition, exploratory analyses highlighted activation differences between discriminative stimuli. The results demonstrate the utility of coupling operant and imaging technologies for investigating the neural substrates of operant learning in humans.

The world as an inside working memory

O'Regan & Noë's (O&N's) theoretical framework for studying visual perception and awareness is intriguing. This framework, based on sensorimotor contingency, can be examined in recent visual brain theories using neuroimaging methodologies. Here, I consider how a working memory (WM) system explains the sensorimotor account of visual consciousness. I believe WM inside the brain provides at least partial support for O&N's theory.

Multimodality Imaging

Noninvasive “multimodal” in vivo imaging is not just becoming standard practice in the clinic, but is rapidly changing the evolving field of experimental imaging of genetic expression (“molecular imaging”). The development of multimodality methodology based on nuclear medicine (NM), positron emission tomography (PET) imaging, magnetic resonance imaging (MRI), and optical imaging is the single biggest focus in many imaging and cancer centers worldwide and is bringing together researchers and engineers from the far-ranging fields of molecular pharmacology to nanotechnology engineering. The rapid growth of in vivo multimodality imaging arises from the convergence of established fields of in vivo imaging technologies with molecular and cell biology. The cross-pollination of these disciplines has been accelerated in part by the establishment of the National Institutes of Health NCI P20 and P50 awards, for example, and by the sheer potential of the technology. Multimodality imaging is widely considered to involve the incorporation of two or more imaging modalities, usually within the setting of a single examination using, for example, dual- or triple-labeled optical or nuclear medicine “reporter” agents or by performing ultrasound or optical studies within the MR, single-photon emission computed tomography (SPECT), or x-ray computed tomography (CT) environment. Clinically, the best example of multimodality imaging is seen in the rapid evolution of PET-SPECT and PET-CT scanner hybrids. The PET modality has developed into perhaps the most used “multimodal” imaging method. The incorporation of PET into single, hybrid, and multimodality units to provide functional (typically from injected F-18DG studies) and anatomic information is becoming extremely popular,1–2 so much so that, for example, PET/CT hybrids can be found in outpatient screening centers located in shopping malls. The role of any multimodal imaging …

Functional imaging of the sleeping brain: review of findings and implications for the study of insomnia

Despite the growing literature indicating that insomnia is prevalent and a substantial risk factor for medical and psychiatric morbidity, the pathophysiology of both Primary and Secondary Insomnia is poorly understood. Multiple trait and state factors are thought to give rise to and/or moderate illness severity in insomnia, but 'hyperarousal' is widely believed to be the final common pathway of the disorder. To date, very little work has been undertaken using functional imaging to explore the CNS correlates, underpinnings, or consequences of hyperarousal as it occurs in Primary Insomnia. In fact, all but one of the extant studies have been of healthy good sleepers or subjects with Secondary Insomnia. In the present article, we: (1) review the studies that have been undertaken in good sleepers and in patients using functional neuroimaging methodologies, and (2) discuss how these data can inform a research agenda aimed at describing the neuropathophysiology of insomnia.

Educational neuroimaging: a proposed neuropsychological application of near-infrared spectroscopy (nIRS).

To provide a description of an emerging neuroimaging methodology, near-infrared spectroscopy (nIRS), and a potential educational application of the unique aspects of this technology. nIRS is documented for its potential as a personal, portable, brain imaging system that may prove useful for cerebral monitoring in applied settings such as home, school, and work. The basis of nIRS brain imaging is reviewed, with summary descriptions of optical and neurovascular issues as well as a brief comparison to other brain imaging methodologies. Recent developments in nIRS technology are discussed, including ongoing validation efforts and potential applications for neuropsychologists. We describe one potential application of nIRS (i.e., educational neuroimaging) as an illustration of the use of nIRS technology and the potential expansion of the neuropsychologist's role in the educational setting. nIRS holds the potential of opening new clinical questions and opportunities for neuropsychologists, and may provide a low-cost means of repeatable, neurovascular monitoring in nonmedical settings.

Advances in Functional Neuroimaging Methodology for the Study of Brain Systems Underlying Human Neuropsychological Function and Dysfunction

Functional neuroimaging allows the non-invasive identification of distributed patterns of human brain activity associated with perceptual, congnitive, emotional and behavioral processes, in health and disease. Work in this field is methodologically intensive, requiring an interdisciplinary team of scientists to develop and apply rapidly advancing techniques. Here we focus upon the principles and methods of functional imaging, from hypothesis generation and study design, to subject recruitment and clinical characterization, neuropsychological paradigm development, image acquisition, image processing and statistical analysis, and data interpretation. The strengths and limitations of the various techniques are discussed, with an emphasis on positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), which have proven to be powerful tools for human brain mapping. The integration of these techniques with electroencephalography (EEG) and magnetoencephalography (MEG), which provide greater temporal information, is outlined. An understanding of such methodological issues is a necessary prerequisite to the development of new imaging methods with improved capabilities, to the careful application of existing methods to neuropsychological problems, and to the critical examination of planned or published studies.

Neuroimaging in Alzheimer's disease: relevance for treatment.

Neuroimaging methodologies have shown some of their greatest promise in studies of Alzheimer's disease (AD). Imaging outcome measures are now entering the arena of investigational trials for AD, to elucidate treatment mechanisms, optimize drug dosing, and perhaps serve as surrogate efficacy measures. Drugs that enhance central cholinergic neurotransmission have been extensively examined for their effects on regional cerebral blood flow, regional cerebral glucose metabolism, or levels of N-acetyl-aspartate in AD patients. Putative disease-modifying agents will be studied by structural magnetic resonance imaging for their ability to reduce rates of hippocampal or whole brain atrophy. When anti-amyloid therapies reach widespread clinical testing, their effects may be monitored by specific imaging probes for amyloid-beta peptide-containing senile plaques. Neuroimaging studies of AD patients and asymptomatic subjects who carry the apolipoprotein E e4 allele suggest that these individuals may be particularly suitable for testing candidate prevention therapies for AD.

Statistical limitations in functional neuroimaging. II. Signal detection and statistical inference.

The field of functional neuroimaging (FNI) methodology has developed into a mature but evolving area of knowledge and its applications have been extensive. A general problem in the analysis of FNI data is finding a signal embedded in noise. This is sometimes called signal detection. Signal detection theory focuses in general on issues relating to the optimization of conditions for separating the signal from noise. When methods from probability theory and mathematical statistics are directly applied in this procedure it is also called statistical inference. In this paper we briefly discuss some aspects of signal detection theory relevant to FNI and, in addition, some common approaches to statistical inference used in FNI. Low-pass filtering in relation to functional-anatomical variability and some effects of filtering on signal detection of interest to FNI are discussed. Also, some general aspects of hypothesis testing and statistical inference are discussed. This includes the need for characterizing the signal in data when the null hypothesis is rejected, the problem of multiple comparisons that is central to FNI data analysis, omnibus tests and some issues related to statistical power in the context of FNI. In turn, random field, scale space, non-parametric and Monte Carlo approaches are reviewed, representing the most common approaches to statistical inference used in FNI. Complementary to these issues an overview and discussion of non-inferential descriptive methods, common statistical models and the problem of model selection is given in a companion paper. In general, model selection is an important prelude to subsequent statistical inference. The emphasis in both papers is on the assumptions and inherent limitations of the methods presented. Most of the methods described here generally serve their purposes well when the inherent assumptions and limitations are taken into account. Significant differences in results between different methods are most apparent in extreme parameter ranges, for example at low effective degrees of freedom or at small spatial autocorrelation. In such situations or in situations when assumptions and approximations are seriously violated it is of central importance to choose the most suitable method in order to obtain valid results.

Recent advances in genetic research on schizophrenia.

Evidence for genetic factors in schizophrenia is reviewed with regard to family, twin and adoption studies, and recent advances in molecular genetic technology are applied to explore possible gene loci susceptible to schizophrenia. Application of neuropsychological and neuroimaging methodologies are also reviewed with an aim to develop criteria for defining phenotypes for genetic studies.

Magnetic Resonance Imaging of Human Intracortical Structure in vivo

Current neuroimaging methodologies have lacked the resolution needed to visualize cortical organization at the microscopic level. As a consequence, when neurological diseases disrupt the internal structure of the cerebral cortex, the changes can only be visualized postmortem, by histological examination. This imposes severe limitations in the in vivo diagnosis and investigation of those conditions. Here, we report on a magnetic resonance technique that permitted the visualization of some features of cerebral cortex in 14 living human subjects and in 2 fixed brains. The key finding was a periodic pattern of low- and high-signal slabs, oriented perpendicularly to the pial surface, that seem to correspond, respectively, to columnar modules and myelin septa. The key parameters of the new protocol included modifications in pulse sequence, field of view, number of repetitions, and plane of sectioning.