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Lesion analysis is a classic approach to study brain functions. Because brain function is a result of coherent activations of a collection of functionally related voxels, lesion-symptom relations are generally contributed by multiple voxels simultaneously. Although voxel-based lesion symptom mapping (VLSM) has made substantial contributions to the understanding of brain-behavior relationships, a better understanding of the brain-behavior relationship contributed by multiple brain regions needs a multivariate lesion symptom mapping (MLSM). The purpose of this paper was to develop an MLSM using a machine learning-based multivariate regression algorithm: support vector regression (SVR). In the proposed SVR-LSM, the symptom relation to the entire lesion map as opposed to each isolated voxel is modeled using a non-linear function, so the intervoxel correlations are intrinsically considered, resulting in a potentially more sensitive way to examine lesion-symptom relationships. To explore the relative merits of VLSM and SVR-LSM we used both approaches in the analysis of a synthetic dataset. SVR-LSM showed much higher sensitivity and specificity for detecting the synthetic lesion-behavior relations than VLSM. When applied to lesion data and language measures from patients with brain damages, SVR-LSM reproduced the essential pattern of previous findings identified by VLSM and showed higher sensitivity than VLSM for identifying the lesion-behavior relations. Our data also showed the possibility of using lesion data to predict continuous behavior scores.

Abstract& Previous data from single-case and small group studies have suggested distinctions among structural, conceptual, and online sensorimotor representations of the human body. We developed a battery of tasks to further examine the prevalence and anatomic substrates of these body representations. The battery was administered to 70 stroke patients. Fifty-one percent of the patients were impaired relative to controls on at least one body representation measure. Further, principal components analysis of the patient data as well as direct comparisons of patient and control performance suggested a triple dissociation between measures of the 3 putative body representations. Consistent with previous distinctions between the ''what'' and ''how'' pathways, lesions of the left temporal lobe were most consistently associated with impaired performance on tasks assessing knowledge of the shape or lexical-semantic information about the body, whereas lesions of the dorsolateral frontal and parietal regions resulted in impaired performance on tasks requiring on-line coding of body posture. &

SES AND NEUROANATOMY IN READING DISABILITY 2 Although reading disability (RD) and socioeconomic status (SES) are independently associated with variation in reading ability and brain structure/function, the joint influence of SES and RD on neuroanatomy and/or response to intervention is unknown. Sixty-five children with RD (ages 6 to 9) with diverse SES were assigned to an intensive, 6-week summer reading intervention (n = 40) or to a waiting-list control group (n = 25). Before and after, all children completed standardized reading assessments and magnetic resonance imaging (MRI) to measure cortical thickness. At baseline, higher SES correlated with greater vocabulary and greater cortical thickness in bilateral perisylvian and supramarginal regions-especially in left pars opercularis. Within the intervention group, lower SES was associated with both greater reading improvement and greater cortical thickening across broad, bilateral occipitotemporal and temporoparietal regions following the intervention. Additionally, treatment responders (n = 20), compared to treatment non-responders (n = 19), exhibited significantly greater cortical thickening within similar regions. The waiting control and non-responder groups exhibited developmentally-typical, non-significant cortical thinning during this time period. These findings indicate that effective summer reading intervention is coupled with cortical growth, and is especially beneficial for children with RD who come from lower-SES home environments. (Word count: 197)

Objective-Frontotemporal lobar degeneration (FTLD) is characterized by impairments in social, behavioral, and/or language function, but postmortem studies indicate that multiple neuropathological entities lead to FTLD. This study assessed whether specific clinical features predict the underlying pathology.Methods-A clinicopathological correlation was performed on 90 consecutive patients with a pathological diagnosis of frontotemporal dementia and was compared with an additional 24 cases accrued during the same time period with a clinical diagnosis of FTLD, but with pathology not typically associated with frontotemporal dementia.Results-Postmortem examination showed multiple pathologies including tauopathies (46%), FTLD with ubiquitin-positive inclusions (29%), and Alzheimer's disease (17%). The pathological groups manifested some distinct demographic, clinical, and neuropsychological features, although these attributes showed only a statistical association with the underlying pathology. FTLD with ubiquitin-positive inclusions was more likely to present with both social and language dysfunction, and motor neuron disease was more likely to emerge in these patients. Tauopathies were more commonly associated with an extrapyramidal disorder. Alzheimer's disease was associated with relatively greater deficits in memory and executive function.Interpretation-Clinical and neuropsychological features contribute to delineating the spectrum of pathology underlying a patient diagnosed with FTLD, but biomarkers are needed that, together with the clinical phenotype, can predict the underlying neuropathology.Frontotemporal lobar degeneration (FTLD) is characterized clinically by progressive changes in social, behavioral, and/or language function. 1-3 In the frontal or social/dysexecutive variant Address correspondence to Dr Grossman, Department of Neurology, University of Pennsylvania School of Medicine, 3600 Spruce Street, 3 West Gates, Philadelphia, PA 19104-4283. E-mail: mgrossma@mail.med.upenn NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of FTLD, there is an early change in social comportment and personality often associated with disinhibition, apathy, and lack of insight. In contrast, the aphasic variant of FTLD is further classified as either progressive nonfluent aphasia, characterized by effortful speech and phonemic errors, 4 or semantic dementia, manifested by severe problems with naming and understanding word and object meaning. 5 In both the social/dysexecutive and aphasic variants, there is relative preservation of memory, especially in early stages. In addition, some patients with FTLD manifest a motor disorder such as parkinsonism or motor neuron disease (MND). 6,7Multiple neuropathological abnormalities are associated with FTLD, 3,8 and this pathological heterogeneity is reflected in a recent classification scheme from an frontotemporal dementia (FTD) work group that was the first to incorporate both immunohistochemical and biochemical data in the diagnostic algorithm (Fig 1...

Analysis of error types provides useful information about the stages and processes involved in normal and aphasic word production. In picture naming, semantic errors (horse for goat) generally result from something having gone awry in lexical access such that the right concept was mapped to the wrong word. This study used the new lesion analysis technique known as voxel-based lesion-symptom mapping to investigate the locus of lesions that give rise to semantic naming errors. Semantic errors were obtained from 64 individuals with post-stroke aphasia, who also underwent high-resolution structural brain scans. Whole brain voxel-based lesion-symptom mapping was carried out to determine where lesion status predicted semantic error rate. The strongest associations were found in the left anterior to mid middle temporal gyrus. This area also showed strong and significant effects in further analyses that statistically controlled for deficits in pre-lexical, conceptualization processes that might have contributed to semantic error production. This study is the first to demonstrate a specific and necessary role for the left anterior temporal lobe in mapping concepts to words in production. We hypothesize that this role consists in the conveyance of fine-grained semantic distinctions to the lexical system. Our results line up with evidence from semantic dementia, the convergence zone framework and meta-analyses of neuroimaging studies on word production. At the same time, they cast doubt on the classical linkage of semantic error production to lesions in and around Wernicke's area.

To produce a word, the intended word must be selected from a competing set of other words. In other domains where competition affects the selection process, the left inferior frontal gyrus (LIFG) responds to competition among incompatible representations. The aim of this study was to test whether the LIFG is necessary for resolution of competition in word production. Using a methodological approach applying the same rigorous analytic methods to neuropsychological data as is done with neuroimaging data, we compared brain activation patterns in normal speakers (using fMRI) with the results of lesion-deficit correlations in aphasic speakers who performed the same word production task designed to elicit competition during lexical selection. The degree of activation of the LIFG in normal speakers and damage to the LIFG in aphasic speakers was associated with performance on the production task. These convergent findings provide strong support for the hypothesis that the region of cortex commonly known as Broca's area (i.e., the posterior LIFG) serves to bias competitive interactions during language production. aphasia ͉ language production ͉ left inferior frontal gyrus ͉ lexical competition I n 1861, Paul Broca wrote ''somewhere in these [frontal] lobes, one or several convolutions holds under their dependence one of the elements essential to the complex phenomenon of speech.'' In the ensuing century and a half, investigations of the psychological and neural characterization of the ''phenomenon of speech'' have flourished. Here, we unite the principal method of Broca's day, the assessment of the relation between lesion location and cognitive impairments, with the primary human neuroscientific tool of the modern era, functional magnetic resonance imaging (fMRI), in a rigorous evaluation of one putative element of speech: conflict resolution.The need to resolve conflict during speech production is not self-evident; producing speech can feel spontaneous and easy. However, every word produced is susceptible to error. The analysis of speech errors, both the relatively infrequent ones that are made by normal speakers and those that occur with much greater frequency in patients with acquired language disorders, has been a rich source of information about the speech production process. Such analyses have revealed that word selection during production is a naturally competitive process, determined by the relative degree of support for (i.e., activation of) a set of candidate words (1-3). The question addressed in this article is whether a region of the frontal lobes commonly referred to as Broca's area [i.e., the posterior portion of the left inferior frontal gyrus (LIFG)], an area implicated in controlled memory retrieval (4), multiple aspects of language processing (5-8), and competition among linguistic and nonlinguistic representations (9, 10), is necessary for the resolution of conflict among competing lexical representations during word production. We posed this question of both normal and impaired speakers, using a word...

The authors sought to determine whether errors of action committed by patients with closed head injury (CHI) would conform to predictions derived from frontal lobe theories. In Study 1, 30 CHI patients and 18 normal controls performed routine activities, such as wrapping a present, under conditions of graded complexity. CHI patients committed more errors even on the simplest condition; but, except for a higher proportion of omitted actions, their error profile was very similar to that of controls. Study 2 involved a subset of patients whose performance in Study 1 was within normal limits. When these high functioning patients were asked to perform the routine tasks under still more taxing conditions, they, too, committed errors in excess of the control group. Accounts based on frontal mechanisms have a difficult time explaining the overall pattern of findings. An alternative based on limited-capacity resources is suggested.