Data-driven classification of cognitively normal and mild cognitive impairment subtypes predicts progression in the NACC dataset.

INTRODUCTION: Data-driven neuropsychological methods can identify mild cognitive impairment (MCI) subtypes with stronger associations to dementia risk factors than conventional diagnostic methods. METHODS: Cluster analysis used neuropsychological data from participants without dementia (mean age = 71.6 years) in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (n = 26,255) and the "normal cognition" subsample (n = 16,005). Survival analyses examined MCI or dementia progression. RESULTS: Five clusters were identified: "Optimal" cognitively normal (oCN; 13.2%), "Typical" CN (tCN; 28.0%), Amnestic MCI (aMCI; 25.3%), Mixed MCI-Mild (mMCI-Mild; 20.4%), and Mixed MCI-Severe (mMCI-Severe; 13.0%). Progression to dementia differed across clusters (oCN < tCN < aMCI < mMCI-Mild < mMCI-Severe). Cluster analysis identified more MCI cases than consensus diagnosis. In the "normal cognition" subsample, five clusters emerged: High-All Domains (High-All; 16.7%), Low-Attention/Working Memory (Low-WM; 22.1%), Low-Memory (36.3%), Amnestic MCI (16.7%), and Non-amnestic MCI (naMCI; 8.3%), with differing progression rates (High-All < Low-WM = Low-Memory < aMCI < naMCI). DISCUSSION: Our data-driven methods outperformed consensus diagnosis by providing more precise information about progression risk and revealing heterogeneity in cognition and progression risk within the NACC "normal cognition" group.

Evidence of Impaired Remote Experience-near Semantic Memory in Medial Temporal Lobe Amnesia.

Neuropsychological research suggests that "experience-near" semantic memory, meaning knowledge attached to a spatiotemporal or event context, is commonly impaired in individuals who have medial temporal lobe amnesia. It is not known if this impairment extends to remotely acquired experience-near knowledge, which is a question relevant to understanding hippocampal/medial temporal lobe functioning. In the present study, we administered a novel semantic memory task designed to target knowledge associated with remote, "dormant" concepts, in addition to knowledge associated with active concepts, to four individuals with medial temporal lobe amnesia and eight matched controls. We found that the individuals with medial temporal lobe amnesia generated significantly fewer experience-near semantic memories for both remote concepts and active concepts. In comparison, the generation of abstract or "experience-far" knowledge was largely spared in the individuals with medial temporal lobe amnesia, regardless of whether the targets for retrieval were remote or active concepts. We interpret these findings as evidence that the medial temporal lobes may have a sustained role in the retrieval of semantic memories associated with spatiotemporal and event contexts, which are cognitive features often ascribed to episodic memory. These results align with recent theoretical models proposing that the hippocampus/medial temporal lobes support cognitive processes that are involved in, but not exclusive to, episodic memory.

The role of the striatum in visuomotor integration during handwriting: an fMRI study.

This study investigates the role of the dorsal/sensorimotor striatum in visuomotor integration (i.e., the transformation of internal visual information about letter shapes into motor output) during handwriting. Twenty healthy participants underwent fMRI scanning with tasks consisting of self-paced handwriting of alphabetically ordered single letters and simple dots, with both tasks performed without visual feedback. Functional connectivity (FC) from these two tasks was compared to demonstrate the difference between coordinated activity arising during handwriting and the activity during a simpler motor condition. Our study focused upon the writing-specific cortico-striatal network of preselected regions of interest consisting of the visual word form area (VWFA), anterior intraparietal sulcus/superior parietal lobule, striatum, premotor cortex/Exner's area, and primary and supplementary motor regions. We observed systematically increased task-induced cortico-striatal and cortico-cortical FC. This increased synchronization of neural activity between the VWFA, i.e., the visual cortical area containing information about letter shapes, and the frontoparietal motor regions is mediated by the striatum. These findings suggest the involvement of the striatum in integrating stored letter-shape information with motor planning and execution during handwriting.

Face Recognition.

PURPOSE OF REVIEW: Functional imaging studies, intracranial recordings, and lesion-deficit correlations in neurological patients have produced unique insights into the cognitive mechanisms and neural substrates of face recognition. In this review, we highlight recent advances in the field and integrate data from these complementary lines of research to propose a functional neuroanatomical model of face identity recognition. RECENT FINDINGS: Rather than being localized to a single specialized cortical region, face recognition is supported by a distributed neural network. Core components of the network include face-selective visual areas in the ventral occipito-temporal cortex, whereas the extended network is comprised of anterior temporal lobe structures involved in the retrieval of multimodal identity-specific knowledge about familiar individuals, the amygdala responsible for generating emotional responses to faces, and prefrontal regions that provide top-down executive control of the recognition process. Damage to different network components results in neuropsychological disorders of face identity processing manifested either as impaired recognition of familiar faces (prosopagnosia, person recognition disorders) or as false recognition/misidentification of unfamiliar faces. Face identity recognition requires the coordinated activity of a large-scale neural network. Neurological damage can compromise the structural/functional integrity of specific network nodes or their connections and give rise to face recognition disorders with distinct clinical features and underlying cognitive mechanisms determined primarily by the location of the lesion.

The neural substrates of improved phonological processing following successful treatment in a case of phonological alexia and agraphia.

Phonological deficits are common in aphasia after left-hemisphere stroke, and can have significant functional consequences for spoken and written language. While many individuals improve through treatment, the neural substrates supporting improvements are poorly understood. We measured brain activation during pseudoword reading in an individual through two treatment phases. Improvements were associated with greater activation in residual left dorsal language regions and bilateral regions supporting attention and effort. Gains were maintained, while activation returned to pre-treatment levels. This case demonstrates the neural support for improved phonology after damage to critical regions and that improvements may be maintained without markedly increased effort.

The nature and treatment of phonological text agraphia.

Phonological alexia and agraphia are written language disorders characterised by disproportionate difficulty reading and spelling nonwords in comparison to real words. In phonological alexia, it has been shown that, despite relatively accurate reading of words in isolation, text-level reading deficits are often marked and persistent. Specifically, some individuals demonstrate difficulty reading functors and affixes in sentences, a profile referred to as phonological text alexia. In this paper, we demonstrate an analogous manifestation of the phonological impairment on text-level writing and suggest the term "phonological text agraphia". We examined four individuals with phonological alexia/agraphia who also showed disproportionate difficulty writing well-formed sentences in comparison to their grammatical competence in spoken utterances. Implementation of a phonological treatment protocol resulted in significantly improved sublexical phonology skills as well as improvements in grammatical accuracy of written narratives. These findings support the notion of a common phonological impairment underlying nonword reading/spelling deficits and sentence-level difficulties.

Oscillatory reactivity to effortful cognitive processing in the subthalamic nucleus and internal pallidum: a depth electrode EEG study.

This study investigates how complex motor-cognitive activities are processed in the subthalamic nucleus (STN) and internal globus pallidum (GPi), as adverse neuropsychiatric effects may accompany deep brain stimulation (DBS), mainly in Parkinson's disease (PD) and STN-DBS. Dystonia patients with GPi-DBS electrodes (n = 5) and PD subjects (n = 5) with STN-DBS electrodes performed two tasks: (1) copying letters; and (2) writing any letter other than that appearing on the monitor. The cognitive load of the second task was greater than that of the first. Intracranial local field potentials (LFPs) were analysed. A beta power decrease was the main correlate of the enhanced cognitive load during the second task in both structures, with a lateralization to the left side, mainly in the GPi. A gamma power increase linked with the increased cognitive activity was observed only in the STN. Differences were also observed in the theta and alpha bandpasses. Beta ERD reactivity seems to be essential during the processing of complex motor-cognitive tasks, increases with enhanced cognitive effort, and was observed in both the STN and GPi. Oscillatory reactivity to effortful cognitive processing in other frequency bands was less consistent, with differences between the studied nuclei. Lateralization of activity related to cognitive factors was observed mainly in the GPi.

Bidirectional iterative parcellation of diffusion weighted imaging data: separating cortical regions connected by the arcuate fasciculus and extreme capsule.

This paper introduces a Bidirectional Iterative Parcellation (BIP) procedure designed to identify the location and size of connected cortical regions (parcellations) at both ends of a white matter tract in diffusion weighted images. The procedure applies the FSL option "probabilistic tracking with classification targets" in a bidirectional and iterative manner. To assess the utility of BIP, we applied the procedure to the problem of parcellating a limited set of well-established gray matter seed regions associated with the dorsal (arcuate fasciculus/superior longitudinal fasciculus) and ventral (extreme capsule fiber system) white matter tracts in the language networks of 97 participants. These left hemisphere seed regions and the two white matter tracts, along with their right hemisphere homologues, provided an excellent test case for BIP because the resulting parcellations overlap and their connectivity via the arcuate fasciculi and extreme capsule fiber systems are well studied. The procedure yielded both confirmatory and novel findings. Specifically, BIP confirmed that each tract connects within the seed regions in unique, but expected ways. Novel findings included increasingly left-lateralized parcellations associated with the arcuate fasciculus/superior longitudinal fasciculus as a function of age and education. These results demonstrate that BIP is an easily implemented technique that successfully confirmed cortical connectivity patterns predicted in the literature, and has the potential to provide new insights regarding the architecture of the brain.

Dysfunctional visual word form processing in progressive alexia.

Progressive alexia is an acquired reading deficit caused by degeneration of brain regions that are essential for written word processing. Functional imaging studies have shown that early processing of the visual word form depends on a hierarchical posterior-to-anterior processing stream in occipito-temporal cortex, whereby successive areas code increasingly larger and more complex perceptual attributes of the letter string. A region located in the left lateral occipito-temporal sulcus and adjacent fusiform gyrus shows maximal selectivity for words and has been dubbed the 'visual word form area'. We studied two patients with progressive alexia in order to determine whether their reading deficits were associated with structural and/or functional abnormalities in this visual word form system. Voxel-based morphometry showed left-lateralized occipito-temporal atrophy in both patients, very mild in one, but moderate to severe in the other. The two patients, along with 10 control subjects, were scanned with functional magnetic resonance imaging as they viewed rapidly presented words, false font strings, or a fixation crosshair. This paradigm was optimized to reliably map brain regions involved in orthographic processing in individual subjects. All 10 control subjects showed a posterior-to-anterior gradient of selectivity for words, and all 10 showed a functionally defined visual word form area in the left hemisphere that was activated for words relative to false font strings. In contrast, neither of the two patients with progressive alexia showed any evidence for a selectivity gradient or for word-specific activation of the visual word form area. The patient with mild atrophy showed normal responses to both words and false font strings in the posterior part of the visual word form system, but a failure to develop selectivity for words in the more anterior part of the system. In contrast, the patient with moderate to severe atrophy showed minimal activation of any part of the visual word form system for either words or false font strings. Our results suggest that progressive alexia is associated with a dysfunctional visual word form system, with or without substantial cortical atrophy. Furthermore, these findings demonstrate that functional MRI has the potential to reveal the neural bases of cognitive deficits in neurodegenerative patients at very early stages, in some cases before the development of extensive atrophy.

Efficient visual object and word recognition relies on high spatial frequency coding in the left posterior fusiform gyrus: evidence from a case-series of patients with ventral occipito-temporal cortex damage.

Recent visual neuroscience investigations suggest that ventral occipito-temporal cortex is retinotopically organized, with high acuity foveal input projecting primarily to the posterior fusiform gyrus (pFG), making this region crucial for coding high spatial frequency information. Because high spatial frequencies are critical for fine-grained visual discrimination, we hypothesized that damage to the left pFG should have an adverse effect not only on efficient reading, as observed in pure alexia, but also on the processing of complex non-orthographic visual stimuli. Consistent with this hypothesis, we obtained evidence that a large case series (n = 20) of patients with lesions centered on left pFG: 1) Exhibited reduced sensitivity to high spatial frequencies; 2) demonstrated prolonged response latencies both in reading (pure alexia) and object naming; and 3) were especially sensitive to visual complexity and similarity when discriminating between novel visual patterns. These results suggest that the patients' dual reading and non-orthographic recognition impairments have a common underlying mechanism and reflect the loss of high spatial frequency visual information normally coded in the left pFG.

Written language impairments in primary progressive aphasia: a reflection of damage to central semantic and phonological processes.

Connectionist theories of language propose that written language deficits arise as a result of damage to semantic and phonological systems that also support spoken language production and comprehension, a view referred to as the "primary systems" hypothesis. The objective of the current study was to evaluate the primary systems account in a mixed group of individuals with primary progressive aphasia (PPA) by investigating the relation between measures of nonorthographic semantic and phonological processing and written language performance and by examining whether common patterns of cortical atrophy underlie impairments in spoken versus written language domains. Individuals with PPA and healthy controls were administered a language battery, including assessments of semantics, phonology, reading, and spelling. Voxel-based morphometry was used to examine the relation between gray matter volumes and language measures within brain regions previously implicated in semantic and phonological processing. In accordance with the primary systems account, our findings indicate that spoken language performance is strongly predictive of reading/spelling profile in individuals with PPA and suggest that common networks of critical left hemisphere regions support central semantic and phonological processes recruited for spoken and written language.

Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect.

BACKGROUND: The APOE epsilon4 allele is associated with the risk of late-onset Alzheimer's disease. The age at which memory decline diverges among persons who are homozygous for the APOE epsilon4 allele, those who are heterozygous for the allele, and noncarriers is unknown. METHODS: Using local advertisements, we recruited cognitively normal subjects between the ages of 21 and 97 years, who were grouped according to their APOE epsilon4 status. We then followed the subjects with longitudinal neuropsychological testing. Anyone in whom mild cognitive impairment or dementia developed during follow-up was excluded. We compared the rates of decline in predetermined cognitive measures between carriers and noncarriers of the APOE epsilon4 allele, using a mixed model for longitudinal change with age. RESULTS: We analyzed 815 subjects: 317 APOE epsilon4 carriers (79 who were homozygous for the APOE epsilon4 allele and 238 who were heterozygous) and 498 noncarriers. Carriers, as compared with noncarriers, were generally younger (mean age, 58.0 vs. 61.4 years; P<0.001) and were followed for a longer period (5.3 vs. 4.7 years, P=0.01), with an equivalent duration of formal education (15.4 years) and proportion of women (69%). Longitudinal decline in memory in carriers began before the age of 60 years and showed greater acceleration than in noncarriers (P=0.03), with a possible allele-dose effect (P=0.008). We observed similar although weaker effects on measures of visuospatial awareness and general mental status. CONCLUSIONS: Age-related memory decline in APOE epsilon4 carriers diverges from that of noncarriers before the age of 60 years, despite ongoing normal clinical status.

Common predictors of spoken and written language performance in aphasia, alexia, and agraphia.

Language performance requires support from central cognitive/linguistic abilities as well as the more peripheral sensorimotor skills to plan and implement spoken and written communication. Both output modalities are vulnerable to impairment following damage to the language-dominant hemisphere, but much of the research to date has focused exclusively on spoken language. In this study we aimed to examine an integrated model of language processing that includes the common cognitive processes that support spoken and written language, as well as modality-specific skills. To do so, we evaluated spoken and written language performance from 87 individuals with acquired language impairment resulting from damage to left perisylvian cortical regions that collectively constitute the dorsal language pathway. Comprehensive behavioral assessment served to characterize the status of central and peripheral components of language processing in relation to neurotypical controls (n = 38). Performance data entered into principal components analyses (with or without control scores) consistently yielded a strong five-factor solution. In line with a primary systems framework, three central cognitive factors emerged: semantics, phonology, and orthography that were distinguished from peripheral processes supporting speech production and allographic skill for handwriting. The central phonology construct reflected performance on phonological awareness and manipulation tasks and showed the greatest deficit of all the derived factors. Importantly, this phonological construct was orthogonal to the speech production factor that reflected repetition of words/non-words. When entered into regression analyses, semantics and phonological skill were common predictors of language performance across spoken and written modalities. The speech production factor was also a strong, distinct predictor of spoken naming and oral reading, in contrast to allographic skills which only predicted written output. As expected, visual orthographic processing contributed more to written than spoken language tasks and reading/spelling performance was strongly reliant on phonological and semantic abilities. Despite the heterogeneity of this cohort regarding aphasia type and severity, the marked impairment of phonological skill was a unifying feature. These findings prompt greater attention to clinical assessment and potential treatment of underlying phonological skill in individuals with left perisylvian damage.

Autobiographical memory unknown: Pervasive autobiographical memory loss encompassing personality trait knowledge in an individual with medial temporal lobe amnesia.

Autobiographical memory consists of distinct memory types varying from highly abstract to episodic. Self trait knowledge, which is considered one of the more abstract types of autobiographical memory, is thought to rely on regions of the autobiographical memory neural network implicated in schema representation, including the ventromedial prefrontal cortex, and critically, not the medial temporal lobes. The current case study introduces an individual who experienced bilateral posterior cerebral artery strokes resulting in extensive medial temporal lobe damage with sparing of the ventromedial prefrontal cortex. Interestingly, in addition to severe retrograde and anterograde episodic and autobiographical fact amnesia, this individual's self trait knowledge was impaired for his current and pre-morbid personality traits. Yet, further assessment revealed that this individual had preserved conceptual knowledge for personality traits, could reliably and accurately rate another person's traits, and could access his own self-concept in a variety of ways. In addition to autobiographical memory loss, he demonstrated impairment on non-personal semantic memory tests, most notably on tests requiring retrieval of unique knowledge. This rare case of amnesia suggests a previously unreported role for the medial temporal lobes in self trait knowledge, which we propose reflects the critical role of this neural region in the storage and retrieval of personal semantics that are experience-near, meaning autobiographical facts grounded in spatiotemporal contexts.

Functional neuroanatomy of reading in Czech: Evidence of a dual-route processing architecture in a shallow orthography.

Introduction: According to the strong version of the orthographic depth hypothesis, in languages with transparent letter-sound mappings (shallow orthographies) the reading of both familiar words and unfamiliar nonwords may be accomplished by a sublexical pathway that relies on serial grapheme-to-phoneme conversion. However, in languages such as English characterized by inconsistent letter-sound relationships (deep orthographies), word reading is mediated by a lexical-semantic pathway that relies on mappings between word-specific orthographic, semantic, and phonological representations, whereas the sublexical pathway is used primarily to read nonwords. Methods: In this study, we used functional magnetic resonance imaging to elucidate neural substrates of reading in Czech, a language characterized by a shallo worthography. Specifically, we contrasted patterns of brain activation and connectivity during word and nonword reading to determine whether similar or different neural mechanisms are involved. Neural correlates were measured as differences in simple whole-brain voxel-wise activation, and differences in visual word form area (VWFA) task-related connectivity were computed on the group level from data of 24 young subject. Trial-to-trial reading reaction times were used as a measure of task difficulty, and these effects were subtracted from the activation and connectivity effects in order to eliminate difference in cognitive effort which is naturally higher for nonwords and may mask the true lexicality effects. Results: We observed pattern of activity well described in the literature mostly derived from data of English speakers - nonword reading (as compared to word reading) activated the sublexical pathway to a greater extent whereas word reading was associated with greater activation of semantic networks. VWFA connectivity analysis also revealed stronger connectivity to a component of the sublexical pathway - left inferior frontal gyrus (IFG), for nonword compared to word reading. Discussion: These converging results suggest that the brain mechanism of skilled reading in shallow orthography languages are similar to those engaged when reading in languages with a deep orthography and are supported by a universal dual-pathway neural architecture.

Largely intact memory for spatial locations during navigation in an individual with dense amnesia.

Spatial navigation and event memory (termed episodic memory) are thought to be heavily intertwined, both in terms of their cognitive processes and underlying neural systems. Some theoretical models posit that both memory for places during navigation and episodic memory depend on highly overlapping brain systems. Here, we assessed this relationship by testing navigation in an individual with severe retrograde and anterograde amnesia; the amnesia stemmed from bilateral lesions in the medial temporal lobes from two separate strokes. The individual with amnesia and age-matched controls were tested on their memories for the locations of previously seen objects relative to distal mountain cues in an immersive virtual environment involving free ambulation. All participants were tested from both repeated and novel start locations and when a single distal mountain cue was unknowingly moved to determine if they relied on a single (beacon) cue to a greater extent than the collection of all distal cues. Compared to age-matched controls, the individual with amnesia showed no significant deficits in navigation from either the repeated or novel start points, although both the individual with amnesia and controls performed well above chance at placing objects near their correct locations. The individual with amnesia also relied on a combination of distal cues in a manner comparable to age-matched controls. Despite largely intact memory for locations using distal cues, the individual with amnesia walked longer paths, rotated more, and took longer to complete trials. Our findings suggest that memory for places during navigation and episodic memory may involve partially dissociable brain circuits and that other brain regions outside of the medial temporal lobe partially support some aspects of navigation. At the same time, the fact that the individual with amnesia walked more circuitous paths and had dense amnesia for autobiographic events supports the idea that the hippocampus may be important for binding information as part of a larger role in memory.

Structural Changes in Thalamic Nuclei Across Prodromal and Clinical Alzheimer's Disease.

BACKGROUND: Increasing evidence suggests that thalamic nuclei may atrophy in Alzheimer's disease (AD). We hypothesized that there will be significant atrophy of limbic thalamic nuclei associated with declining memory and cognition across the AD continuum. OBJECTIVE: The objective of this work was to characterize volume differences in thalamic nuclei in subjects with early and late mild cognitive impairment (MCI) as well as AD when compared to healthy control (HC) subjects using a novel MRI-based thalamic segmentation technique (THOMAS). METHODS: MPRAGE data from the ADNI database were used in this study (n = 540). Healthy control (n = 125), early MCI (n = 212), late MCI (n = 114), and AD subjects (n = 89) were selected, and their MRI data were parcellated to determine the volumes of 11 thalamic nuclei for each subject. Volumes across the different clinical subgroups were compared using ANCOVA. RESULTS: There were significant differences in thalamic nuclei volumes between HC, late MCI, and AD subjects. The anteroventral, mediodorsal, pulvinar, medial geniculate, and centromedian nuclei were significantly smaller in subjects with late MCI and AD when compared to HC subjects. Furthermore, the mediodorsal, pulvinar, and medial geniculate nuclei were significantly smaller in early MCI when compared to HC subjects. CONCLUSION: This work highlights nucleus specific atrophy within the thalamus in subjects with early and late MCI and AD. This is consistent with the hypothesis that memory and cognitive changes in AD are mediated by damage to a large-scale integrated neural network that extends beyond the medial temporal lobes.

Articulatory network reorganization in Parkinson's disease as assessed by multimodal MRI and acoustic measures.

INTRODUCTION: Hypokinetic dysarthria (HD) is common in Parkinson's disease (PD). Our objective was to evaluate articulatory networks and their reorganization due to PD pathology in individuals without overt speech impairment using a multimodal MRI protocol and acoustic analysis of speech. METHODS: A total of 34 PD patients with no subjective HD complaints and 25 age-matched healthy controls (HC) underwent speech task recordings, structural MRI, and reading task-induced and resting-state fMRI. Grey matter probability maps, task-induced activations, and resting-state functional connectivity within the regions engaged in speech production (ROIs) were assessed and compared between groups. Correlation with acoustic parameters was also performed. RESULTS: PD patients as compared Tto HC displayed temporal decreases in speech loudness which were related to BOLD signal increases in the right-sided regions of the dorsal language pathway/articulatory network. Among those regions, activation of the right anterior cingulate was increased in PD as compared to HC. We also found bilateral posterior superior temporal gyrus (STG) GM loss in PD as compared to HC that was strongly associated with diadochokinetic (DDK) irregularity in the PD group. Task-induced activations of the left STG were increased in PD as compared to HC and were related to the DDK rate control. CONCLUSIONS: The results provide insight into the neural correlates of speech production control and distinct articulatory network reorganization in PD apparent already in patients without subjective speech impairment.

Cost function masking during normalization of brains with focal lesions: still a necessity?

Although normalization of brain images is critical to the analysis of structural damage across individuals, loss of tissue due to focal lesions presents challenges to the available normalization algorithms. Until recently, cost function masking, as advocated by Brett and colleagues (2001), was the accepted method to overcome difficulties encountered when normalizing damaged brains; however, development of the unified segmentation approach for normalization in SPM5 (Ashburner & Friston, 2005) offered an alternative. Crinion et al. (2007) demonstrated this approach produced normalization results without cost function masking that appeared to be robust to lesion effects when tested using the same simulated lesions studied by Brett et al. (2001). The present study sought to confirm the validity of this approach in brains with focal damage due to vascular events. To do so, we examined outcomes of normalization using unified segmentation with and without cost function masking in 49 brain images with chronic stroke. Lesion masks were created using two approaches (precise and rough drawings of lesion boundaries), and normalization was implemented with both smoothed and unsmoothed versions of the masks. We found that failure to employ cost function masking produced less accurate results in real and simulated lesions, compared to masked normalization, both in terms of deformation field displacement and voxelwise intensity differences. Additionally, unmasked normalization led to significant underestimation of lesion volume relative to all four masking conditions, especially in patients with large lesions. Taken together, these findings suggest cost function masking is still necessary when normalizing brain images with chronic infarcts.

Phonological dyslexia and dysgraphia: cognitive mechanisms and neural substrates.

To examine the validity of different theoretical assumptions about the neuropsychological mechanisms and lesion correlates of phonological dyslexia and dysgraphia, we studied written and spoken language performance in a large cohort of patients with focal damage to perisylvian cortical regions implicated in phonological processing. Despite considerable variation in accuracy for both words and non-words, the majority of participants demonstrated the increased lexicality effects in reading and spelling that are considered the hallmark features of phonological dyslexia and dysgraphia. Increased lexicality effects were also documented in spoken language tasks such as oral repetition, and patients performed poorly on a battery of phonological tests that did not involve an orthographic component. Furthermore, a composite measure of general phonological ability was strongly predictive of both reading and spelling accuracy, and we obtained evidence that the continuum of severity that characterized the written language disorder of our patients was attributable to an underlying continuum of phonological impairment. Although patients demonstrated qualitatively similar deficits across measures of written and spoken language processing, there were quantitative differences in levels of performance reflecting task difficulty effects. Spelling was more severely affected than reading by the reduction in phonological capacity and this differential vulnerability accounted for occasional disparities between patterns of impairment on the two written language tasks. Our findings suggest that phonological dyslexia and dysgraphia in patients with perisylvian lesions are manifestations of a central or modality-independent phonological deficit rather than the result of damage to cognitive components dedicated to reading or spelling. Our results also provide empirical support for shared-components models of written language processing, according to which the same central cognitive systems support both reading and spelling. Lesion-deficit correlations indicated that phonological dyslexia and dysgraphia may be produced by damage to a variety of perisylvian cortical regions, consistent with distributed network models of phonological processing.