Lesion-symptom mapping has become a cornerstone of neuroscience research seeking to localize cognitive function in the brain by examining the sequelae of brain lesions. Recently, multivariate lesion-symptom mapping methods have emerged, such as support vector regression, which simultaneously consider many voxels at once when determining whether damaged regions contribute to behavioral deficits (Zhang, Kimberg, Coslett, Schwartz, & Wang, ). Such multivariate approaches are capable of identifying complex dependences that traditional mass-univariate approach cannot. Here, we provide a new toolbox for support vector regression lesion-symptom mapping (SVR-LSM) that provides a graphical interface and enhances the flexibility and rigor of analyses that can be conducted using this method. Specifically, the toolbox provides cluster-level family-wise error correction via permutation testing, the capacity to incorporate arbitrary nuisance models for behavioral data and lesion data and makes available a range of lesion volume correction methods including a new approach that regresses lesion volume out of each voxel in the lesion maps. We demonstrate these new tools in a cohort of chronic left-hemisphere stroke survivors and examine the difference between results achieved with various lesion volume control methods. A strong bias was found toward brain wide lesion-deficit associations in both SVR-LSM and traditional mass-univariate voxel-based lesion symptom mapping when lesion volume was not adequately controlled. This bias was corrected using three different regression approaches; among these, regressing lesion volume out of both the behavioral score and the lesion maps provided the greatest sensitivity in analyses.

Individuals with primary progressive aphasia (PPA) suffer a gradual decline in communication ability as a result of neurodegenerative disease. Language treatment shows promise as a means of addressing these difficulties but much remains to be learned with regard to the potential value of treatment across variants and stages of the disorder. We present two cases, one with semantic variant of PPA and the other with logopenic PPA, each of whom underwent treatment that was unique in its focus on training self-cueing strategies to engage residual language skills. Despite differing language profiles and levels of aphasia severity, each individual benefited from treatment and showed maintenance of gains as well as generalization to untrained lexical items. These cases highlight the potential for treatment to capitalize on spared cognitive and neural systems in individuals with PPA, improving current language function as well as potentially preserving targeted skills in the face of disease progression.

Neuroimaging and neuropsychological studies have implicated the anterior temporal lobe (ATL) in sentence-level processing, with syntactic structure-building and/or combinatorial semantic processing suggested as possible roles. A potential challenge to the view that the ATL is involved in syntactic aspects of sentence processing comes from the clinical syndrome of semantic variant primary progressive aphasia (semantic PPA, also known as semantic dementia). In semantic PPA, bilateral neurodegeneration of the anterior temporal lobes is associated with profound lexical semantic deficits, yet syntax is strikingly spared. The goal of this study was to investigate the neural correlates of syntactic processing in semantic PPA, in order to determine which regions normally involved in syntactic processing are damaged in semantic PPA, and whether spared syntactic processing depends on preserved functionality of intact regions, preserved functionality of atrophic regions, or compensatory functional reorganization. We scanned 20 individuals with semantic PPA and 24 age-matched controls using structural and functional MRI. Participants performed a sentence comprehension task that emphasized syntactic processing and minimized lexical semantic demands. We found that in controls, left inferior frontal and left posterior temporal regions were modulated by syntactic processing, while anterior temporal regions were not significantly modulated. In the semantic PPA group, atrophy was most severe in the anterior temporal lobes, but extended to the posterior temporal regions involved in syntactic processing. Functional activity for syntactic processing was broadly similar in patients and controls; in particular, whole-brain analyses revealed no significant differences between patients and controls in the regions modulated by syntactic processing. The atrophic left anterior temporal lobe did show abnormal functionality in semantic PPA patients, however this took the unexpected form of a failure to deactivate. Taken together, our findings indicate that spared syntactic processing in semantic PPA depends on preserved functionality of structurally intact left frontal regions and moderately atrophic left posterior temporal regions, but no functional reorganization was apparent as a consequence of anterior temporal atrophy and dysfunction. These results suggest that the role of the anterior temporal lobe in sentence processing is less likely to relate to syntactic structure-building, and more likely to relate to higher level processes such as combinatorial semantic processing.

Reading involves the rapid extraction of sound and meaning from print through a cooperative division of labor between phonological and lexical-semantic processes. Whereas lesion studies of patients with stereotyped acquired reading deficits contributed to the notion of a dissociation between phonological and lexical-semantic reading, the neuroanatomical basis for effects of lexicality (word vs pseudoword), orthographic regularity (regular vs irregular spelling-sound correspondences), and concreteness (concrete vs abstract meaning)on reading is underspecified, particularly outside the context of strong behavioral dissociations. Support vector regression lesionsymptom mapping (LSM) of 73 left hemisphere stroke survivors (male and female human subjects) not preselected for stereotyped dissociations revealed the differential contributions of specific cortical regions to reading pseudowords (ventral precentral gyrus), regular words (planum temporale, supramarginal gyrus, ventral precentral and postcentral gyrus, and insula), and concrete words (pars orbitalis and pars triangularis). Consistent with the primary systems view of reading being parasitic on language-general circuitry, our multivariate LSM analyses revealed that phonological decoding depends on perisylvian areas subserving sound-motor integration and that semantic effects on reading depend on frontal cortex subserving control over concrete semantic representations that aid phonological access from print. As the first study to localize the differential cortical contributions to reading pseudowords, regular words, and concrete words in stroke survivors with variable reading abilities, our results provide important information on the neurobiological basis of reading and highlight the insights attainable through multivariate, process-based approaches to alexia. Whereas fMRI evidence for neuroanatomical dissociations between phonological and lexical-semantic reading is abundant, evidence from modern lesion studies establishing the differential contributions of specific brain regions to specific reading processes is lacking. Our application of multivariate lesion-symptom mapping revealed that effects of lexicality, orthographic regularity, and concreteness on reading differentially depend on areas subserving auditory-motor integration and semantic control. Phonological decoding of print relies on a dorsal perisylvian network supporting auditory and articulatory representations, with unfamiliar words relying especially on articulatory mapping. In tandem with this dorsal decoding system, anterior inferior frontal gyrus may coordinate control over concrete semantic representations that support mapping of print to sound, which is a novel potential mechanism for semantic influences on reading.

Phonological encoding depends on left-lateralized regions in the supramarginal gyrus and the ventral precentral gyrus. Localization of these phonological regions in individual participantsincluding individuals with language impairments-is important in several research and clinical contexts. To localize these regions, we developed two paradigms that load on phonological encoding: a rhyme judgment task and a syllable counting task. Both paradigms relied on an adaptive staircase design to ensure that each individual performed each task at a similarly challenging level. The goal of this study was to assess the validity and reliability of the two paradigms, in terms of their ability to consistently produce left-lateralized activations of the supramarginal gyrus and ventral precentral gyrus in neurologically normal individuals with presumptively normal language localization. Sixteen participants were scanned with fMRI as they performed the rhyme judgment paradigm, the syllable counting paradigm, and an adaptive semantic paradigm that we have described previously. We found that the rhyme and syllable paradigms both yielded left-lateralized supramarginal and ventral precentral activations in the majority of participants. The rhyme paradigm produced more lateralized and more reliable activations, and so should be favored in future applications. In contrast, the semantic paradigm did not reveal supramarginal or precentral activations in most participants, suggesting that the recruitment of these regions is indeed driven by phonological encoding, not language processing in general. In sum, the adaptive rhyme judgment paradigm was effective in localizing leftlateralized phonological encoding regions in individual participants, and, in conjunction with the adaptive semantic paradigm, can be used to map individual language networks.

Syntactic processing deficits are highly variable in individuals with primary progressive aphasia. Damage to left inferior frontal cortex has been associated with syntactic deficits in primary progressive aphasia in a number of structural and functional neuroimaging studies. However, a contrasting picture of a broader syntactic network has emerged from neuropsychological studies in other aphasic cohorts, and functional imaging studies in healthy controls. To reconcile these findings, we used functional magnetic resonance imaging to investigate the functional neuroanatomy of syntactic comprehension in 51 individuals with primary progressive aphasia, composed of all clinical variants and a range of degrees of syntactic processing impairment. We used trial-by-trial reaction time as a proxy for syntactic processing load, to determine which regions were modulated by syntactic processing in each patient, and how the set of regions recruited was related to whether syntactic processing was ultimately successful or unsuccessful. Relationships between functional abnormalities and patterns of cortical atrophy were also investigated. We found that the individual degree of syntactic comprehension impairment was predicted by left frontal atrophy, but also by functional disruption of a broader syntactic processing network, comprising left posterior frontal cortex, left posterior temporal cortex, and the left intraparietal sulcus and adjacent regions. These regions were modulated by syntactic processing in healthy controls and in patients with primary progressive aphasia with relatively spared syntax, but they were modulated to a lesser extent or not at all in primary progressive aphasia patients whose syntax was relatively impaired. Our findings suggest that syntactic comprehension deficits in primary progressive aphasia reflect not only structural and functional changes in left frontal cortex, but also disruption of a wider syntactic processing network.

We used fMRI to examine the neural substrates of sublexical phoneme-grapheme conversion during spelling in a group of healthy young adults. Participants performed a writing-to-dictation task involving irregular words (e.g., choir), plausible nonwords (e.g., kroid), and a control task of drawing familiar geometric shapes (e.g., squares). Written production of both irregular words and nonwords engaged a left-hemisphere perisylvian network associated with reading/spelling and phonological processing skills. Effects of lexicality, manifested by increased activation during nonword relative to irregular word spelling, were noted in anterior perisylvian regions (posterior inferior frontal gyrus/operculum/precentral gyrus/insula), and in left ventral occipito-temporal cortex. In addition to enhanced neural responses within domain-specific components of the language network, the increased cognitive demands associated with spelling nonwords engaged domain-general frontoparietal cortical networks involved in selective attention and executive control. These results elucidate the neural substrates of sublexical processing during written language production and complement lesion-deficit correlation studies of phonological 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.