Neurosciences

We have developed a toolbox and graphic user interface, EEGLAB, running under the cross-platform MATLAB environment (The Mathworks, Inc.) for processing collections of single-trial and/or averaged EEG data of any number of channels. Available functions include EEG data, channel and event information importing, data visualization (scrolling, scalp map and dipole model plotting, plus multi-trial ERP-image plots), preprocessing (including artifact rejection, filtering, epoch selection, and averaging), Independent Component Analysis (ICA) and time/frequency decompositions including channel and component cross-coherence supported by bootstrap statistical methods based on data resampling. EEGLAB functions are organized into three layers. Top-layer functions allow users to interact with the data through the graphic interface without needing to use MATLAB syntax. Menu options allow users to tune the behavior of EEGLAB to available memory. Middle-layer functions allow users to customize data processing using command history and interactive 'pop' functions. Experienced MATLAB users can use EEGLAB data structures and stand-alone signal processing functions to write custom and/or batch analysis scripts. Extensive function help and tutorial information are included. A 'plug-in' facility allows easy incorporation of new EEG modules into the main menu. EEGLAB is freely available (http://www.sccn.ucsd.edu/eeglab/) under the GNU public license for noncommercial use and open source development, together with sample data, user tutorial and extensive documentation.

Eighty-three brains obtained at autopsy from nondemented and demented individuals were examined for extracellular amyloid deposits and intraneuronal neurofibrillary changes. The distribution pattern and packing density of amyloid deposits turned out to be of limited significance for differentiation of neuropathological stages. Neurofibrillary changes occurred in the form of neuritic plaques, neurofibritlary tangles and neuropil threads. The distribution of neuritic plaques varied widely not only within architectonic units but also from one individual to another. Neurofibrillary tangles and neuropil threads, in contrast, exhibited a characteristic distribution pattern permitting the differentiation of six stages. The first two stages were characterized by an either mild or severe alteration of the transentorhinal layer Pre-c~ (transentorhinal stages I-II). The two forms of limbic stages (stages III-IV) were marked by a conspicuous affection of layer Pre-(x in both transentorhinal region and proper entorhinal cortex. In addition, there was mild involvement of the first Ammon's horn sector. The hallmark of the two isocortical stages (stages V-VI) was the destruction of virtually all isocortical association areas. The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations.

In recent years, many new cortical areas have been identified in the macaque monkey. The number of identified connections between areas has increased even more dramatically. We report here on (1) a summary of the layout of cortical areas associated with vision and with other modalities, (2) a computerized database for storing and representing large amounts of information on connectivity patterns, and (3) the application of these data to the analysis of hierarchical organization of the cerebral cortex. Our analysis concentrates on the visual system, which includes 25 neocortical areas that are predominantly or exclusively visual in function, plus an additional 7 areas that we regard as visual-association areas on the basis of their extensive visual inputs. A total of 305 connections among these 32 visual and visual-association areas have been reported. This represents 31 % of the possible number of pathways if each area were connected with all others. The actual degree of connectivity is likely to be closer to 40%. The great majority of pathways involve reciprocal connections between areas. There are also extensive connections with cortical areas outside the visual system proper, including the somatosensory cortex, as well as neocortical, transitional, and archicortical regions in the temporal and frontal lobes. In the somatosensory/motor system, there are 62 identified pathways linking 13 cortical areas, suggesting an overall connectivity of about 40%. Based on the laminar patterns of connections between areas, we propose a hierarchy of visual areas and of somatosensory/motor areas that is more comprehensive than those suggested in other recent studies. The current version of the visual hierarchy includes 10 levels of cortical processing. Altogether, it contains 14 levels if one includes the retina and lateral geniculate nucleus at the bottom as well as the entorhinal cortex and hippocampus at the top. Within this hierarchy, there are multiple, intertwined processing streams, which, at a low level, are related to the compartmental organization of areas VI and V2 and, at a high level, are related to the distinction between processing centers in the temporal and parietal lobes. However, there are some pathways and relationships (about 10% of the total) whose descriptions do not fit cleanly into this hierarchical scheme for one reason or another. In most instances, though, it is unclear whether these represent genuine exceptions to a strict hierarchy rather than inaccuracies or uncertainties in the reported assignment. Cerebral Cortex Jan/Feb 1991;1:1-47; 1047-3211/91/»2.00 by guest on August 8, 2016 http://cercor.oxfordjournals.org/ Downloaded from 15 16--16 Rgora 1. A 2-0 map of cerebral cortex in macaque monkey, prepared by the method of Van Essen and Marred (1980). Rne tofid Ones represent the contours of layer 4 from a ssriss of 16 horizontal sections taken at 2-mra interval! through the cortex. Hwien along the margins of the map correspond to the different section tevets indicated in the lateral [upper feft) and medial (inter kfi\ views of the hemisphere. St&fog indicates cortex lying within various tufa, an) the fundus of each sulcus is indicated by nasty dashed lines. SoV foes along the perimeter of the map nlicate regions where artificisl cuts have been made to reduce distortions. Dssted Snes along the perimeter represent the margins of the cortex, where it adjoins various noncortxal structures: the corpus calbsum/indoseum gnseum ((op), olfactory tubercle and amygdatar nuda [ritfo), and dentate gyrus of the htppocampus (Aonomj. the scale on the map has been adjusted to correct to the estimated 16% shrinkage that occurs during rctotogkal processing (d. Van Essen and MaunseB, 1980: Van Downloaded from MEDIAL PREFRONTAL 1 cm. . The scale appfies arty ID the map; the brain drawings are smater by 20% (cf. . The specific studies used in estimating the border of the various nonvisual areas are as foBowc Somstosensory areas 3a. 3b, 1, 2, 5, 7b, 3L Ri (retroHisutar), PB (postaudhory), fy (msufar granular), and Id (msufar dytgranularj were based on Jones and Burton (1976), Jones et aL (197B), Robinson end Burton |1980). Friedman a a). (1986). Huerta et aL (1987), and Andersen et aL (1990). Note that, in this scheme, areas 1 and 2 intervene between SI and area 3b. bi other primates, inducting the marmoset and the owl monkey, Sll appears to directly adjoin area 3b, and it has been suggested diet more derated mapping will reveal the same manuanau in the macaque (Cuai et aL, 1989: Krubitzer and Kaas, 1990). Auditory areas Al (primary auditory), Rl (rostrotateraf), CM (caudomecfial). tnd L (lateral) were based on Merenieh and Brugge (1973L The postaudhory area (ft) is described as a somatoseraory area by Robinson and Burton (1980) and as an auditory area by Friedman et at (1986). We have included it as pan of the auditory arm in our analysis, but obviously this issue merits further investigation. Areas of the hippocampal comptai (HC), including the entorhinal conei (ER), areas 35 and 36. presuboifum, prosutriculum, subkulum, and fields CA1 and CA3, were based on Amaral et aL (1987), Insausi et aL (1987), and Saunters et aL {1988). Olfactory areas, including the pirifarra cortex (P1R) and paianiygdatoid conn (PAC), were based on Insausti e) aL (1987). Orbhofromal areas 11, 12, and 13. prnsrxortai (Pro), periaUocortei (Pall), lateral prefromal area 45. dorsal preframa) areas 9 and 10, and medial prefmntal areas 14. 25, and 32 were based on Barfaas and Pandys 11989) and fnsaustj et aL (1987). Motor areas 4 (primary motor) and 6 (premotor and arcuate premnor, or 6s and 6i), supptsmemary motor area ISAM], and medial eye field \MEF, or supplementary eye fields, SEF) were based on Brodmam (1905). Mateffi et al. (1986), tnsaustj et aL (1987). Schlag and Sd%fley (1987), Hutchins et aL (1988). and Mam et aL (1988). Finally, dngutata and other linti areas 23. 24. 29 (retrosptenial). 30 (PGrn or 7m), and prostrate [PS, divided by an artificial cut into dorsal (d) and ventral (v) sectors] were based on msaustj et al. (1987) and Sarites (1970). A few regions in the posterior ortutofraraal, lateral prefromal, and anterior sytvian cortices have not been dosety stnfied and are left unspecifiad here.

Sporadic Parkinson's disease involves multiple neuronal systems and results from changes developing in a few susceptible types of nerve cells. Essential for neuropathological diagnosis are ␣-synuclein-immunopositive Lewy neurites and Lewy bodies. The pathological process targets specific induction sites: lesions initially occur in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus. Thereafter, less vulnerable nuclear grays and cortical areas gradually become affected. The disease process in the brain stem pursues an ascending course with little interindividual variation. The pathology in the anterior olfactory nucleus makes fewer incursions into related areas than that developing in the brain stem. Cortical involvement ensues, beginning with the anteromedial temporal mesocortex. From there, the neocortex succumbs, commencing with high order sensory association and prefrontal areas. First order sensory association/premotor areas and primary sensory/motor fields then follow suit. This study traces the course of the pathology in incidental and symptomatic Parkinson cases proposing a staging procedure based upon the readily recognizable topographical extent of the lesions.

The International Panel on MS Diagnosis presents revised diagnostic criteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both time and space. Magnetic resonance imaging is integrated with clinical and other paraclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including "monosymptomatic" disease suggestive of MS, disease with a typical relapsingremitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as "clinically definite" and "probable MS" are no longer recommended. The outcome of a diagnostic evaluation is either MS, "possible MS" (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or "not MS."

This paper describes FieldTrip, an open source software package that we developed for the analysis of MEG, EEG, and other electrophysiological data. The software is implemented as a MATLAB toolbox and includes a complete set of consistent and userfriendly high-level functions that allow experimental neuroscientists to analyze experimental data. It includes algorithms for simple and advanced analysis, such as time-frequency analysis using multitapers, source reconstruction using dipoles, distributed sources and beamformers, connectivity analysis, and nonparametric statistical permutation tests at the channel and source level. The implementation as toolbox allows the user to perform elaborate and structured analyses of large data sets using the MATLAB command line and batch scripting. Furthermore, users and developers can easily extend the functionality and implement new algorithms. The modular design facilitates the reuse in other software packages.

Abstract— A method has been developed for the simultaneous measurement of the rates of glucose consumption in the various structural and functional components of the brain in vivo. The method can be applied to most laboratory animals in the conscious state. It is based on the use of 2-deoxy-D-[14C]glucose ([14C]DG) as a tracer for the exchange of glucose between plasma and brain and its phosphorylation by hexokinase in the tissues. [14C]DG is used because the label in its product, [14C]deoxyglucose-6-phosphate, is essentially trapped in the tissue over the time course of the measurement. A model has been designed based on the assumptions of a steady state for glucose consumption, a first order equilibration of the free [14C]DG pool in the tissue with the plasma level, and relative rates of phosphorylation of [14C]DG and glucose determined by their relative concentrations in the precursor pools and their respective kinetic constants for the hexokinase reaction. An operational equation based on this model has been derived in terms of determinable variables. A pulse of [14C]DG is administered intravenously and the arterial plasma [14C]DG and glucose concentrations monitored for a preset time between 30 and 45min. At the prescribed time, the head is removed and frozen in liquid N2-chilled Freon XII, and the brain sectioned for autoradiography. Local tissue concentrations of [14C]DG are determined by quantitative autoradiography. Local cerebral glucose consumption is calculated by the equation on the basis of these measured values.The method has been applied to normal albino rats in the conscious state and under thiopental anesthesia. The results demonstrate that the local rates of glucose consumption in the brain fall into two distinct distributions, one for gray matter and the other for white matter. In the conscious rat the values in the gray matter vary widely from structure to structure (54-197 μmol/100 g/min) with the highest values in structures related to auditory function, e.g. medial geniculate body, superior olive, inferior colliculus, and auditory cortex. The values in white matter are more uniform (i.e. 33–40 μmo1/100 g/min) at levels approximately one-fourth to one-half those of gray matter. Heterogeneous rates of glucose consumption are frequently seen within specific structures, often revealing a pattern of cytoarchitecture. Thiopental anesthesia markedly depresses the rates of glucose utilization throughout the brain, particularly in gray matter, and metabolic rate throughout gray matter becomes more uniform at a lower level.

Here we report that increased pup licking and grooming (LG) and arched-back nursing (ABN) by rat mothers altered the offspring epigenome at a glucocorticoid receptor (GR) gene promoter in the hippocampus. Offspring of mothers that showed high levels of LG and ABN were found to have differences in DNA methylation, as compared to offspring of 'low-LG-ABN' mothers. These differences emerged over the first week of life, were reversed with cross-fostering, persisted into adulthood and were associated with altered histone acetylation and transcription factor (NGFI-A) binding to the GR promoter. Central infusion of a histone deacetylase inhibitor removed the group differences in histone acetylation, DNA methylation, NGFI-A binding, GR expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, suggesting a causal relation among epigenomic state, GR expression and the maternal effect on stress responses in the offspring. Thus we show that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible.

A novel test for the selective identification of anxiolytic and anxiogenic drug effects in the rat is described, using an elevated 4--maze consisting of two open arms and two enclosed arms. The use of this test for detecting such drug effects was validated behaviourally, physiologically, and pharmacologically. Rats made significantly fewer entries into the open arms than into the closed arms, and spent significantly less time in open arms. Confinement to the open arms was associated with the observation of significantly more anxiety-related behaviours, and of significantly greater plasma corticosterone concentrations, than confinement to the closed arms. Neither novelty nor illumination was a significant contributor to the behaviour of the rats on the +-maze. A significant increase in the percentage of time spent on the open arms and the number of entries into the open arms was observed only within clinically effective anxiolytics (chlordiazepoxide, diazepam and, less effectively, phenobarbitone). Compounds that cause anxiety in man significantly reduced the percentage of entries into, and time spent on, the open arms (yohimbine, pentylenetetrazole, caffeine, amphetamine). Neither antidepressants nor major tranquilisers had a specific effect. Exposure to a holeboard immediately before placement on the +-maze showed that behaviour on the maze was not clearly correlated either with exploratory head-dipping or spontaneous locomotor activity.

The Cancer Genome Atlas Network recently cataloged recurrent genomic abnormalities in glioblastoma multiforme (GBM). We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes and integrate multidimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define the Classical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell types show a strong relationship between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefit in the Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies.

Evidence is presented that EEG oscillations in the alpha and theta band reflect cognitive and memory performance in particular. Good Ž . Ž . performance is related to two types of EEG phenomena i a tonic increase in alpha but a decrease in theta power, and ii a large phasic Ž . event-related decrease in alpha but increase in theta, depending on the type of memory demands. Because alpha frequency shows large interindividual differences which are related to age and memory performance, this double dissociation between alpha vs. theta and tonic vs. phasic changes can be observed only if fixed frequency bands are abandoned. It is suggested to adjust the frequency windows of alpha and theta for each subject by using individual alpha frequency as an anchor point. Based on this procedure, a consistent interpretation of a Ž variety of findings is made possible. As an example, in a similar way as brain volume does, upper alpha power increases but theta power . decreases from early childhood to adulthood, whereas the opposite holds true for the late part of the lifespan. Alpha power is lowered and theta power enhanced in subjects with a variety of different neurological disorders. Furthermore, after sustained wakefulness and during the transition from waking to sleeping when the ability to respond to external stimuli ceases, upper alpha power decreases, whereas Ž . theta increases. Event-related changes indicate that the extent of upper alpha desynchronization is positively correlated with semantic long-term memory performance, whereas theta synchronization is positively correlated with the ability to encode new information. The reviewed findings are interpreted on the basis of brain oscillations. It is suggested that the encoding of new information is reflected by Ž . theta oscillations in hippocampo-cortical feedback loops, whereas search and retrieval processes in semantic long-term memory are reflected by upper alpha oscillations in thalamo-cortical feedback loops. q

In this paper, we show how ElectroEncephaloGraphic (EEG) and MagnetoEncephaloGraphic (MEG) data can be analyzed statistically using nonparametric techniques. Nonparametric statistical tests offer complete freedom to the user with respect to the test statistic by means of which the experimental conditions are compared. This freedom provides a straightforward way to solve the multiple comparisons problem (MCP) and it allows to incorporate biophysically motivated constraints in the test statistic, which may drastically increase the sensitivity of the statistical test. The paper is written for two audiences: (1) empirical neuroscientists looking for the most appropriate data analysis method, and (2) methodologists interested in the theoretical concepts behind nonparametric statistical tests. For the empirical neuroscientist, a large part of the paper is written in a tutorial-like fashion, enabling neuroscientists to construct their own statistical test, maximizing the sensitivity to the expected effect. And for the methodologist, it is explained why the nonparametric test is formally correct. This means that we formulate a null hypothesis (identical probability distribution in the different experimental conditions) and show that the nonparametric test controls the false alarm rate under this null hypothesis.

The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some diseasemodifying therapies may be most efficacious.

Pediatric neuroimaging studies 1-5 , up to now exclusively cross sectional, identify linear decreases in cortical gray matter and increases in white matter across ages 4 to 20. In this large-scale longitudinal pediatric neuroimaging study, we confirmed linear increases in white matter, but demonstrated nonlinear changes in cortical gray matter, with a preadolescent increase followed by a postadolescent decrease. These changes in cortical gray matter were regionally specific, with developmental curves for the frontal and parietal lobe peaking at about age 12 and for the temporal lobe at about age 16, whereas cortical gray matter continued to increase in the occipital lobe through age 20.

The concept of working memory proposes that a dedicated system maintains and stores information in the short term, and that this system underlies human thought processes. Current views of working memory involve a central executive and two storage systems: the phonological loop and the visuospatial sketchpad. Although this basic model was first proposed 30 years ago, it has continued to develop and to stimulate research and debate. The model and the most recent results are reviewed in this article.

The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in ϳ50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors. NEUROLOGY 2005;65:1863-1872 Clinical diagnostic criteria for DLB. Since the publication of Consensus criteria for clinical and pathologic diagnosis of dementia with Lewy bodies (DLB), 1,2 new information indicates that clinical criteria for probable DLB have acceptable specificity, but suboptimal sensitivity. Reasons identified in-clude difficulties in recognition of the core feature fluctuation 5,6 and a low rate of all core features (fluctuation, visual hallucinations, parkinsonism) in the presence of neocortical, neurofibrillary tangle (NFT) pathology. 7-9 The criteria have therefore been modified (table 1) to incorporate additional items indicative of LB pathology. Distinction is made between clinical features or investigations that are suggestive of DLB, i.e., have been demonstrated to be significantly more frequent than in

An individual has a theory of mind if he imputes mental states to himself and others. A system of inferences of this kind is properly viewed as a theory because such states are not directly observable, and the system can be used to make predictions about the behavior of others. As to the mental states the chimpanzee may infer, consider those inferred by our own species, for example, purpose or intention, as well as knowledge, belief, thinking, doubt, guessing, pretending, liking, and so forth. To determine whether or not the chimpanzee infers states of this kind, we showed an adult chimpanzee a series of videotaped scenes of a human actor struggling with a variety of problems. Some problems were simple, involving inaccessible food-bananas vertically or horizontally out of reach, behind a box, and so forth-as in the original Kohler problems; others were more complex, involving an actor unable to extricate himself from a locked cage, shivering because of a malfunctioning heater, or unable to play a phonograph because it was unplugged. With each videotape the chimpanzee was given several photographs, one a solution to the problem, such as a stick for the inaccessible bananas, a key for the locked up actor, a lit wick for the malfunctioning heater. The chimpanzee's consistent choice of the correct photographs can be understood by assuming that the animal recognized the videotape as representing a problem, understood the actor's purpose, and chose alternatives compatible with that purpose.

Chemical transmission at excitatory synapses in the brain is mediated by a diverse family of glutamate receptor ion channels (iGluRs), tetrameric membrane protein assemblies of molecular weight 400-600 kD. Until recently, structural information for intact iGluRs was limited to biochemically tractable homomeric receptors trapped in different conformational states. These provided key insights into the mechanisms of iGluR activation and desensitization. Structures of heteromeric AMPA and NMDA receptors, the major iGluR families in the brain, together with long awaited cryo-EM structures of an AMPA receptor TARP complex, expand this picture and reveal surprising conformational diversity, raising many fundamental and controversial questions.

The National Institute on Aging and the Alzheimer’s Association charged a workgroup with the task of developing criteria for the symptomatic predementia phase of Alzheimer’s disease (AD), referred to in this article as mild cognitive impairment due to AD. The workgroup developed the following two sets of criteria: (1) core clinical criteria that could be used by healthcare providers without

Neurovascular unit A functional unit composed of groups of neurons and their associated astrocytes, interacting with smooth muscle cells and endothelial cells on the microvessels (arterioles) responsible for their blood supply, and capable of regulating the local blood flow. Gliovascular unit A proposed functional unit composed of single astrocytic glial cells and the neurons they surround, interacting with local segments of blood vessels, and capable of regulating blood flow at the arteriolar level and BBB functions at the capillary level.

This report describes the first human study of a novel amyloid-imaging positron emission tomography (PET) tracer, termed Pittsburgh Compound-B (PIB), in 16 patients with diagnosed mild AD and 9 controls. Compared with controls, AD patients typically showed marked retention of PIB in areas of association cortex known to contain large amounts of amyloid deposits in AD. In the AD patient group, PIB retention was increased most prominently in frontal cortex (1.94-fold, p = 0.0001). Large increases also were observed in parietal (1.71-fold, p = 0.0002), temporal (1.52-fold, p = 0.002), and occipital (1.54-fold, p = 0.002) cortex and the striatum (1.76-fold, p = 0.0001). PIB retention was equivalent in AD patients and controls in areas known to be relatively unaffected by amyloid deposition (such as subcortical white matter, pons, and cerebellum). Studies in three young (21 years) and six older healthy controls (69.5 ± 11 years) showed low PIB retention in cortical areas and no significant group differences between young and older controls. In cortical areas, PIB retention correlated inversely with cerebral glucose metabolism determined with 18F-fluorodeoxyglucose. This relationship was most robust in the parietal cortex (r = −0.72; p = 0.0001). The results suggest that PET imaging with the novel tracer, PIB, can provide quantitative information on amyloid deposits in living subjects.

Study Design. The Oswestry Disability Index (ODI) has become one of the principal condition-specific outcome measures used in the management of spinal disorders. This review is based on publications using the ODI identified from the authors' personal databases, the Science Citation Index, and hand searches of Spine and current textbooks of spinal disorders.

We present here both linear regressions and multivariate analyses correlating three global neuropsychological tests with a number of structural and neurochemical measurements performed on a prospective series of 15 patients with Alzheimer's disease and 9 neuropathologically normal subjects. The statistical data show only weak correlations between psychometric indices and plaques and tangles, but the density of neocortical synapses measured by a new immunocytochemical/densitometric technique reveals very powerful correlations with all three psychological assays. Multivariate analysis by stepwise regression produced a model including midfrontal and inferior parietal synapse density, plus inferior parietal plaque counts with a correlation coefficient of 0.96 for Mattis's Dementia Rating Scale. Plaque density contributed only 26% of that strength.

| In response to stress, the brain activates several neuropeptide-secreting systems. This eventually leads to the release of adrenal corticosteroid hormones, which subsequently feed back on the brain and bind to two types of nuclear receptor that act as transcriptional regulators. By targeting many genes, corticosteroids function in a binary fashion, and serve as a master switch in the control of neuronal and network responses that underlie behavioural adaptation. In genetically predisposed individuals, an imbalance in this binary control mechanism can introduce a bias towards stress-related brain disease after adverse experiences. New candidate susceptibility genes that serve as markers for the prediction of vulnerable phenotypes are now being identified.

Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid beta peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.

This paper concerns the spatial and intensity transformations that map one image onto another. We present a general technique that facilitates nonlinear spatial (stereotactic) normalization and image realignment. This technique minimizes the sum of squares between two images following nonlinear spatial deformations and transformations of the voxel (intensity) values. The spatial and intensity transformations are obtained simultaneously, and explicitly, using a least squares solution and a series of linearising devices. The approach is completely noninteractive (automatic), nonlinear, and noniterative. It can be applied in any number of dimensions.

This article has an accompanying continuing medical education activity on page e30. Learning Objective: Upon completion of this assessment, successful learners will be able to understand epidemiological factors of the inflammatory bowel diseases. BACKGROUND & AIMS: We conducted a systematic review to determine changes in the worldwide incidence and prevalence of ulcerative colitis (UC) and Crohn's disease (CD) in different regions and with time. METHODS: We performed a systematic literature search of MEDLINE (1950-2010; 8103 citations) and EMBASE (1980-2010; 4975 citations) to identify studies that were population based, included data that could be used to calculate incidence and prevalence, and reported separate data on UC and/or CD in full manuscripts (n ϭ 260). We evaluated data from 167 studies from Europe (1930-2008), 52 studies from Asia and the Middle East (1950-2008), and 27 studies from North America (1920-2004). Maps were used to present worldwide differences in the incidence and prevalence of inflammatory bowel diseases (IBDs); time trends were determined using joinpoint regression. RESULTS: The highest annual incidence of UC was 24.3 per 100,000 person-years in Europe, 6.3 per 100,000 person-years in Asia and the Middle East, and 19.2 per 100,000 person-years in North America. The highest annual incidence of CD was 12.7 per 100,000 person-years in Europe, 5.0 person-years in Asia and the Middle East, and 20.2 per 100,000 person-years in North America. The highest reported prevalence values for IBD were in Europe (UC, 505 per 100,000 persons; CD, 322 per 100,000 persons) and North America (UC, 249 per 100,000 persons; CD, 319 per 100,000 persons). In time-trend analyses, 75% of CD studies and 60% of UC studies had an increasing incidence of statistical significance (P Ͻ .05). CONCLUSIONS: Although there are few epidemiologic data from developing countries, the incidence and prevalence of IBD are increasing with time and in different regions around the world, indicating its emergence as a global disease.