Contrasting brain patterns of writing-related DTI parameters, fMRI connectivity, and DTI-fMRI connectivity correlations in children with and without dysgraphia or dyslexia.

Based on comprehensive testing and educational history, children in grades 4-9 (on average 12 years) were diagnosed with dysgraphia (persisting handwriting impairment) or dyslexia (persisting word spelling/reading impairment) or as typical writers and readers (controls). The dysgraphia group (n = 14) and dyslexia group (n = 17) were each compared to the control group (n = 9) and to each other in separate analyses. Four brain region seed points (left occipital temporal gyrus, supramarginal gyrus, precuneus, and inferior frontal gyrus) were used in these analyses which were shown in a metaanalysis to be related to written word production on four indicators of white matter integrity and fMRI functional connectivity for four tasks (self-guided mind wandering during resting state, writing letter that follows a visually displayed letter in alphabet, writing missing letter to create a correctly spelled real word, and planning for composing after scanning on topic specified by researcher). For those DTI indicators on which the dysgraphic group or dyslexic group differed from the control group (fractional anisotropy, relative anisotropy, axial diffusivity but not radial diffusivity), correlations were computed between the DTI parameter and fMRI functional connectivity for the two writing tasks (alphabet and spelling) by seed points. Analyses, controlled for multiple comparisons, showed that (a) the control group exhibited more white matter integrity than either the dysgraphic or dyslexic group; (b) the dysgraphic and dyslexic groups showed more functional connectivity than the control group but differed in patterns of functional connectivity for task and seed point; and (c) the dysgraphic and dyslexic groups showed different patterns of significant DTI-fMRI connectivity correlations for specific seed points and written language tasks. Thus, dysgraphia and dyslexia differ in white matter integrity, fMRI functional connectivity, and white matter-gray matter correlations. Of clinical relevance, brain differences were observed in dysgraphia and dyslexia on written language tasks yoked to their defining behavioral impairments in handwriting and/or in word spelling and on the cognitive mind wandering rest condition and composition planning.

Analysis of speech-related variance in rapid event-related fMRI using a time-aware acquisition system.

Speech production introduces signal changes in fMRI data that can mimic or mask the task-induced BOLD response. Rapid event-related designs with variable ISIs address these concerns by minimizing the correlation of task and speech-related signal changes without sacrificing efficiency; however, the increase in residual variance due to speech still decreases statistical power and must be explicitly addressed primarily through post-processing techniques. We investigated the timing, magnitude, and location of speech-related variance in an overt picture naming fMRI study with a rapid event-related design, using a data acquisition system that time-stamped image acquisitions, speech, and a pneumatic belt signal on the same clock. Using a spectral subtraction algorithm to remove scanner gradient noise from recorded speech, we related the timing of speech, stimulus presentation, chest wall movement, and image acquisition. We explored the relationship of an extended speech event time course and respiration on signal variance by performing a series of voxelwise regression analyses. Our results demonstrate that these effects are spatially heterogeneous, but their anatomic locations converge across subjects. Affected locations included basal areas (orbitofrontal, mesial temporal, brainstem), areas adjacent to CSF spaces, and lateral frontal areas. If left unmodeled, speech-related variance can result in regional detection bias that affects some areas critically implicated in language function. The results establish the feasibility of detecting and mitigating speech-related variance in rapid event-related fMRI experiments with single word utterances. They further demonstrate the utility of precise timing information about speech and respiration for this purpose.

Hemorrhagic stroke associated with the Iowa amyloid precursor protein mutation.

The authors searched for mutations in the beta-amyloid precursor protein in a Spanish family with a hereditary syndrome of hemorrhagic stroke, dementia, leukoencephalopathy, and occipital calcifications. DNA from two affected members demonstrated the Iowa amyloid precursor protein mutation previously identified as a cause of severe amyloid angiopathy without hemorrhagic stroke. These data point to other genetic or environmental factors that may determine the occurrence of symptomatic hemorrhage in amyloid angiopathy.

The effects of AbetaPP mutations and APOE polymorphisms on cerebral amyloid angiopathy.

Analysis of causative mutations and genetic risk factors aid in the understanding of important processes of cerebral amyloid angiopathy (CAA) in humans. We identified a mutation at a novel site of the beta-amyloid precursor protein (AbetaPP) gene associated with familial CAA; this mutation causes an aspartate to asparagine substitution at position 23 of the Abeta peptide. Neuropathological analysis of a 68-year-old man with this mutation showed dramatic Abeta deposition in blood vessels, diffiuse parenchymal Abeta deposits, dystrophic neurites and neurofibrillary tangles. The Abeta deposition showed complete co-localization of Abeta40 and Abeta42, compared to the predominant Abeta42 deposition seen in AD. We hypothesize that the loss of an acidic residue at position 23 of Abeta might be important in the process of Abeta aggregation on smooth muscle cells on the cerebrovasculature. We also analyzed how the apolipoprotein E (APOE) gene might influence aggregation of Abeta by examining the physical association of apoE domains with Abeta via immunohistochemistry. We found that the lipid-binding domain of apoE was more strongly associated with Abeta than the receptor-binding domain, and that 40% of all Abeta deposits had no apoE bound to them. We suggest that the initial deposition of Abeta occurs in the absence of apoE, and that the process of Abeta deposit growth or stabilization is apoE-dependent.

Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy.

Several mutations in the amyloid precursor protein (APP) gene have been found to associate with pathologic deposition of the beta-amyloid peptide (Abeta) in neuritic plaques or in the walls of cerebral vessels. We report a mutation at a novel site in APP in a three-generation Iowa family with autosomal dominant dementia beginning in the sixth or seventh decade of life. The proband and an affected brother had progressive aphasic dementia, leukoencephalopathy, and occipital calcifications. Neuropathological examination of the proband revealed severe cerebral amyloid angiopathy, widespread neurofibrillary tangles, and unusually extensive distribution of Abeta40 in plaques. The affected brothers shared a missense mutation in APP, resulting in substitution of asparagine for aspartic acid at position 694. This site corresponds to residue 23 of Abeta, thus differing from familial Alzheimer's disease mutations, which occur outside the Abeta sequence. Restriction enzyme analysis of DNA from 94 unrelated patients with sporadic cerebral amyloid angiopathy-related hemorrhage found no other instances of this mutation. These results suggest a novel site within Abeta that may promote its deposition and toxicity.

A role for left temporal pole in the retrieval of words for unique entities.

Both lesion and functional imaging studies have implicated sectors of high-order association cortices of the left temporal lobe in the retrieval of words for objects belonging to varied conceptual categories. In particular, the cortices located in the left temporal pole have been associated with naming unique persons from faces. Because this neuroanatomical-behavioral association might be related to either the specificity of the task (retrieving a name at unique level) or to the possible preferential processing of faces by anterior temporal cortices, we performed a PET imaging experiment to test the hypothesis that the effect is related to the specificity of the word retrieval task. Normal subjects were asked to name at unique level entities from two conceptual categories: famous landmarks and famous faces. In support of the hypothesis, naming entities in both categories was associated with increases in activity in the left temporal pole. No main effect of category (faces vs. landmarks/buildings) or interaction of task and category was found in the left temporal pole. Retrieving names for unique persons and for names for unique landmarks activate the same brain region. These findings are consistent with the notion that activity in the left temporal pole is linked to the level of specificity of word retrieval rather than the conceptual class to which the stimulus belongs.

Neural correlates of naming actions and of naming spatial relations.

Ina [(15)O] water PET experiment, 10 normal subjects retrieved words denoting actions (performed with or without an implement), and another 10 normal subjects retrieved words denoting the spatial relations between objects. Our objective was to test the following hypothesis: that the salient neural activity associated with naming actions and spatial relations occurs in left frontal operculum and left parietal association cortices, but not in the left inferotemporal cortices (IT) or in the right parietal association cortices. There were two control tasks, one requiring a decision on the orientation of unknown faces (a standard control task in our laboratory) and another requiring the retrieval of words denoting the concrete entities used in the action and spatial relations tasks. In accordance with the hypothesis, both naming actions and spatial relations (using the face orientation task as control activated the left frontal operculum; naming actions also activated the left parietal lobe. However, sectors of the left posterior IT were also engaged in both naming actions and spatial relations. When the naming of concrete entities was subtracted from the naming of actions performed with such entities, area MT in the posterior temporo-occipital region was activated bilaterally. On the other hand, when naming of the concrete entities was subtracted from the naming of spatial relations, left parietal activation was found, and when two tasks of naming spatial relations were contrasted to each other bilateral parietal activation was seen, right when abstract stimuli were used and left when concrete objects were used. The activity in posterior IT is thought to be related to object processing and possibly name retrieval at a subconscious level.

Real-time multiple linear regression for fMRI supported by time-aware acquisition and processing.

Real-time parametric statistical analysis of functional MRI (fMRI) data would potentially enlarge the scope of experimentation and facilitate its application to clinical populations. A system is described that addresses the need for rapid analysis of fMRI data and lays the foundation for dealing with problems that impede the application of fMRI to clinical populations. The system, I/OWA (Input/Output time-aWare Architecture), combines a general architecture for sampling and time-stamping relevant information channels in fMRI (image acquisition, stimulation, subject responses, cardiac and respiratory monitors, etc.) and an efficient approach to manipulating these data, featuring incremental subsecond multiple linear regression. The advantages of the system are the simplification of event timing and efficient and unified data formatting. Substantial parametric analysis can be performed and displayed in real-time. Immediate (replay) and delayed off-line analysis can also be performed with the same interface. The capabilities of the system are demonstrated in normal subjects using a polar visual angle phase mapping paradigm. The system provides a time-accounting infrastructure that readily supports standard and innovative approaches to fMRI. Magn Reson Med 45:289-298, 2001.

Validation of partial tissue segmentation of single-channel magnetic resonance images of the brain.

We describe and evaluate a practical, automated algorithm based on local statistical mixture modeling for segmenting single-channel, T1-weighted volumetric magnetic resonance images of the brain into gray matter, white matter, and cerebrospinal fluid. We employed a stereological sampling method to assess, prospectively, the performance of the method with respect to human experts on 10 normal T1-weighted brain scans acquired with a three-dimensional gradient echo pulse sequence. The overall kappa statistic for the concordance of the algorithm with the human experts was 0.806, while that among raters, excluding the algorithm, was 0.802. The algorithm had better agreement with the modal expert decision (kappa = 0.878). The algorithm could not be distinguished from the experts by this measure. We also validated the algorithm on a simulated MR scan of a digital brain phantom with known tissue composition. Global gray matter and white matter errors were 1% and <1%, respectively, and correlation coefficients with the underlying tissue model were 0.95 for gray matter, 0.98 for white matter, and 0.95 for cerebrospinal fluid. In both approaches to validation, we evaluated both local and global performance of the algorithm. Human experts generated slightly higher global gray matter proportion estimates on the test brain scans relative to the algorithm (3.7%) and on the simulated MR scan relative to the true tissue model (4.4%). The algorithm underestimated gray in some subcortical nuclei which contain admixed gray and white matter. We demonstrate the reliability of the method on individual 1 NEX data sets of the test subjects, and its insensitivity to the precise values of initial model parameters. The output of this algorithm is suitable for quantifying cerebral cortical tissue, using a commonly performed commercial pulse sequence.

Subcortical and cortical brain activity during the feeling of self-generated emotions.

In a series of [15O]PET experiments aimed at investigating the neural basis of emotion and feeling, 41 normal subjects recalled and re-experienced personal life episodes marked by sadness, happiness, anger or fear. We tested the hypothesis that the process of feeling emotions requires the participation of brain regions, such as the somatosensory cortices and the upper brainstem nuclei, that are involved in the mapping and/or regulation of internal organism states. Such areas were indeed engaged, underscoring the close relationship between emotion and homeostasis. The findings also lend support to the idea that the subjective process of feeling emotions is partly grounded in dynamic neural maps, which represent several aspects of the organism's continuously changing internal state.

Lesion segmentation and manual warping to a reference brain: intra- and interobserver reliability.

The study of subjects with acquired brain damage has been an invaluable tool for exploring human brain function, and the description of lesion locations within and across subjects is an important component of this method. Such descriptions usually involve the separation of lesioned from nonlesioned tissue (lesion segmentation) and the description of the lesion location in terms of a standard anatomical reference space (lesion warping). The objectives of this study were to determine the sources and magnitude of variability involved in lesion segmentation and warping using the MAP-3 approach. Each of two observers segmented the lesion volume in ten brain-damaged subjects twice, so as to permit pairwise comparisons of both intra- and interobserver agreement. The segmented volumes were then warped to a reference brain using both a manual (MAP-3) and an automated (AIR-3) technique. Observer agreement between segmented and warped volumes was analyzed using four measures: volume size, distance between the volume surfaces, percentage of nonoverlapping voxels, and percentage of highly discrepant voxels. The techniques for segmentation and warping produced high agreement within and between observers. For example, in most instances, the warped volume surfaces created by different observers were separated by less than 3 mm. The performance of the automated warping technique compared favorably to the manual technique in most subjects, although important exceptions were found. Overall, these results establish benchmark parameters for expert and automated lesion transfer, and indicate that a high degree of confidence can be placed in the detailed anatomical interpretation of focal brain damage based upon the MAP-3 technique.

Premotor and prefrontal correlates of category-related lexical retrieval.

It has been shown that the retrieval of words denoting visually presented concrete entities engages neural systems in the left temporal lobe and that the precise pattern of activation within the temporal lobe depends in part on the conceptual category to which the entity belongs. Here, we used [15O]water positron emission tomography to test the hypothesis that the pattern of activation associated with word retrieval in left frontal lobe would also be related to conceptual category. The design entailed the performance of three tasks requiring the retrieval of words denoting animals, tools, and unique persons. The visual stimuli were presented at different rates, to produce equal performance success across categories, a feature which also had the effect of equalizing the proportion of scan time spent in mental search. All three word retrieval tasks activated the left inferior frontal gyrus, but they differed in their recruitment of two other premotor and prefrontal areas. Activity in a portion of the middle frontal gyrus, corresponding to Brodmann area 46, bore a linear relation to response latency and may index the extent of mental search. This region was most active when subjects named persons. Activity in the anterior bank of the precentral gyrus, along the inferior and middle frontal gyri, was most marked for naming tools. This region overlaps the area activated when subjects generate words for actions. We suggest that it is engaged by the retrieval of words denoting actions or objects with characteristic actions. The data presented here provide additional support for the notion that "nonclassical" language areas in extrasylvian frontal and temporal regions mediate word retrieval and that the pattern of their engagement relates to conceptual category.

Autosomal dominant dementia with widespread neurofibrillary tangles.

Several familial dementing conditions with atypical features have been characterized, but only rarely is the neuropathology dominated solely by neurofibrillary lesions. We present a Midwestern American pedigree spanning four generations in which 15 individuals were affected by early-onset dementia with long disease duration, with an autosomal dominant inheritance pattern, and with tau-rich neurofibrillary pathology found in the brain post mortem. The average age at presentation was 55 years with gradual onset and progression of memory loss and personality change. After 30 years' disease duration, the proband's neuropathologic examination demonstrated abundant intraneuronal neurofibrillary tangles (NFTs) involving the hippocampus, pallidum, subthalamic nucleus, substantia nigra, pons, and medulla. Only sparse neocortical tangles were present and amyloid plaques were absent. The tangles were recognized by antibodies specific for phosphorylation-independent (Tau-2, T46, 133, and Alz-50) and phosphorylation-dependent epitopes (AT8, T3P, PHF-1, 12E8, AT6, AT18, AT30) in tau proteins. Electron microscopy of NFTs in the dentate gyrus and midbrain demonstrated paired helical filaments. Although the clinical phenotype resembles Alzheimer's disease, and the neuropathologic phenotype resembles progressive supranuclear palsy, an alternative consideration is that this familial disorder may be a new or distinct disease entity.

Brainvox: an interactive, multimodal visualization and analysis system for neuroanatomical imaging.

A study of cognition emerging from a neurobiological perspective, as opposed to one emerging from a purely computational or psychological perspective, begins with observations of the human brain in normal and pathological states and is furthered by the investigation of hypotheses which are articulated using neuroanatomical nomenclature. Brainvox is an interactive three-dimensional brain imaging software package designed to permit such research through the support of the description and quantification of brain pathology in magnetic resonance images and of the experimental investigation of human cognition in lesion and functional imaging studies. Important general features of Brainvox, for these purposes, are: (1) adaptation of volume rendering for brain lesions and for corendered datasets; (2) shared memory architecture, which enables the user to identify and label anatomical structures, while inspecting the brain in multiple views simultaneously; (3) modular program design, including interlocking command-line utilities, which make Brainvox extensible and empower users without programming expertise to implement new analysis techniques through Unix shell scripting; and (4) full integration of three-dimensional tools for visualization with tools for analysis. Specific features include a new object templating technique (MAP-3) for studies of groups of brain-lesioned subjects, a complete and extensible suite of command-line processing utilities, a three-dimensional optimal graph-searching tool, and a method for planning PET slices and matching MR and PET slices (MP_FIT).

A neural basis for lexical retrieval.

Two parallel studies using positron emission tomography, one conducted in neurological patients with brain lesions, the other in normal individuals, indicate that the normal process of retrieving words that denote concrete entities depends in part on multiple regions of the left cerebral hemisphere, located outside the classic language areas. Moreover, anatomically separable regions tends to process words for distinct kinds of items.

Reliability of PET activation across statistical methods, subject groups, and sample sizes.

Four pixel-based methods for estimating regional activation in positron emission tomography (PET) images were implemented so as to allow the comparison of their performances in the same dataset. Change distribution analysis, Worsley's method, a pixelwise general linear model, a nonparametric method, and several methods derived from them were investigated. Important technical factors, including the degree of smoothing, stereotactic transform, coregistration algorithm, search volume, and the volumetric alpha level, were held constant. The dataset, which was obtained with a verb generation paradigm, was large enough to permit assessment of concordance between independent samples of conventional size, as well assessment of within-cohort replicability. (Eighteen normal subjects performed four GENERATE-READ pairs each.) Same-task (noise) images were also analyzed.In noise datasets, type I errors (false positives) occurred at the nominal rate (in 5% of datasets). Detected regions of activation were highly likely to be internally replicated (93%). The detected activations were a superset of activations previously reported using the same paradigm. The methods were chiefly distinguished by type II error rates and by the stability of the location of activation clusters. Those methods dependent on local variance estimates were less powerful with small sample sizes and less stable with respect to the attributed location of task-induced changes. The use of pooled variance (Worsley's method) reduced these problems, but variance was not stationary. Overall, the power of all analyses was modest with samples of conventional size (nine subjects x one or two task-pairs). Modeling of the sources of variance, particularly improvement of anatomical standardization, is likely to improve the power of pixel-based analyses.