Please cite this article as: Harvey DY, Schnur TT, Distinct loci of lexical and semantic access deficits in aphasia: Evidence from voxel-based lesion-symptom mapping and diffusion tensor imaging, CORTEX (2015), doi: 10.1016/j.cortex.2015.03.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Further, damage to the left inferior frontal gyrus (LIFG), a region implicated in cognitive control, results in increasing semantic interference when items repeat across cycles in both language production and comprehension (Jefferies, Baker, Doran, & Lambon Ralph, 2007). This generates the prediction that the LIFG via white matter connections supports resolution of semantic interference arising from different loci (lexical vs. semantic) in the temporal lobe. However, it remains unclear whether the cognitive and neural mechanisms that resolve semantic interference are the same across tasks. Thus, we examined which gray matter structures (using whole brain and region of interest approaches) and white matter connections (using deterministic tractography) when damaged impact semantic interference and its increase across cycles when repeatedly producing and understanding words in 15 speakers with varying lexical-semantic deficits from left hemisphere stroke. We found that damage to distinct brain regions, the posterior vs. anterior temporal lobe, was associated with semantic interference (collapsed across cycles) in naming and comprehension, respectively. Further, those with LIFG damage compared to those without exhibited marginally larger increases in semantic interference across cycles in naming but not comprehension. Lastly, the inferior fronto-occipital fasciculus, connecting the LIFG with posterior temporal lobe, related to semantic interference in naming, whereas the inferior longitudinal fasciculus, connecting posterior with anterior temporal regions related to semantic interference in comprehension. These neuroanatomical-behavioral findings have

In language production, humans are confronted with considerable word selection demands. Often, we must select a word from among similar, acceptable, and competing alternative words to construct a sentence that conveys an intended meaning. In recent years, the left inferior frontal gyrus (LIFG) has been identified as being critical to this ability. Despite a recent emphasis on network approaches to understanding language, how the LIFG interacts with the brain's complex networks to facilitate controlled language performance remains unknown. Here, we take a novel approach to understanding word selection as a network control process in the brain. Using an anatomical brain network derived from high-resolution diffusion spectrum imaging, we computed network controllability underlying the site of transcranial magnetic stimulation (TMS) in the LIFG between administrations of language tasks that vary in response (cognitive control) demands: open-response tasks (word generation) versus closed response tasks (number naming). We found that a statistic that quantifies the LIFG's theoretically predicted control of communication across modules in the human connectome explains TMS-induced changes in open-response language task performance only. Moreover, we found that a statistic that quantifies the LIFG's theoretically predicted control of difficult-to-reach states explains vulnerability to TMS in the closed-ended (but not open-ended) response task. These findings establish a link among network controllability, cognitive function, and TMS effects. This work illustrates that network control statistics applied to anatomical connectivity data demonstrate relationships with cognitive variability during controlled language tasks and TMS effects.

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Background and Objective While noninvasive brain stimulation techniques show promise for language recovery after stroke, the underlying mechanisms remain unclear. We applied inhibitory repetitive transcranial magnetic stimulation (rTMS) to regions of interest in the right inferior frontal gyrus of patients with chronic poststroke aphasia and examined changes in picture naming performance and cortical activation. Methods Nine patients received 10 days of 1-Hz rTMS (Monday through Friday for 2 weeks). We assessed naming performance before and immediately after stimulation on the first and last days of rTMS therapy, and then again at 2 and 6 months post-rTMS. A subset of six of these patients underwent functional magnetic resonance imaging pre-rTMS (baseline) and at 2 and 6 months post-rTMS. Results Naming accuracy increased from pre- to post-rTMS on both the first and last days of treatment. We also found naming improvements long after rTMS, with the greatest improvements at 6 months post-rTMS. Long-lasting effects were associated with a posterior shift in the recruitment of the right inferior frontal gyrus: from the more anterior Brodmann area 45 to the more posterior Brodmann areas 6, 44, and 46. The number of left hemispheric regions recruited for naming also increased. Conclusions This study found that rTMS to the right hemisphere Broca area homologue confers long-lasting improvements in picture naming performance. The mechanism involves dynamic bilateral neural network changes in language processing, which take place within the right prefrontal cortex and the left hemisphere more generally. Clinical Trial Registration ClinicalTrials.gov (Identifier NCT00608582).

Naming pictures and matching words to pictures belonging to the same semantic category impairs performance relative to when stimuli come from different semantic categories (i.e., semantic interference). Despite similar semantic interference phenomena in both picture naming and word-picture matching tasks, the locus of interference has been attributed to different levels of the language system – lexical in naming and semantic in word-picture matching. Although both tasks involve access to shared semantic representations, the extent to which interference originates and/or has its locus at a shared level remains unclear, as these effects are often investigated in isolation. We manipulated semantic context in cyclical picture naming and word-picture matching tasks, and tested whether factors tapping semantic-level (generalization of interference to novel category items) and lexical-level processes (interactions with lexical frequency) affected the magnitude of interference, while also assessing whether interference occurs at a shared processing level(s) (transfer of interference across tasks). We found that semantic interference in naming was sensitive to both semantic- and lexical-level processes (i.e., larger interference for novel vs. old and low- vs. high-frequency stimuli), consistent with a semantically mediated lexical locus. Interference in word-picture matching exhibited stable interference for old and novel stimuli and did not interact with lexical frequency. Further, interference transferred from word-picture matching to naming. Together, these experiments provide evidence to suggest that semantic interference in both tasks originates at a shared processing stage (presumably at the semantic level), but that it exerts its effect at different loci when naming pictures vs. matching words to pictures.

Background: Fatigue and cognitive dysfunction are two common symptoms experienced by patients with multiple sclerosis (MS). The relationship between subjective and objective fatigue (fatigability) in MS is poorly understood. Cognitive control tasks might be more conducive to fatigability and more likely to show associations between subjective and objective cognitive fatigue in MS. Objective: To study the association between objective fatigability, as induced by a cognitive control task called the Blocked Cyclic Naming Task (BCNT), subjective fatigue and baseline cognitive functioning in patients with MS. Methods: Twenty-one patients with MS completed baseline questions about their disease, the Montreal Cognitive Assessment (MoCA) battery and self-reported questionnaires on trait fatigue, sleep and depression. Disability was captured using the expanded disability status scale (EDSS). Participants then performed the BCNT and were asked about their level of state momentary fatigue before and after the BCNT. The BCNT consists of several blocks of either related or unrelated pictures that participants name as quickly as possible. The pictures cycled 4 times in each block and the difference in the response times (RTs) between related and unrelated blocks was captured. Data were analyzed using repeated measures analysis of variance and Pearson correlations. Results: MS participants’ performance declined for the related, but not unrelated blocks. The difference in RTs between related and unrelated conditions increased with repetition across cycles (p < 0.001). Participants also showed objective fatigability with less repetition priming (p = 0.02) in the 4th quarter and with greater differences between related and unrelated conditions in the later part of the task. Objective fatigability was strongly associated with participants’ assessment of their level of momentary state fatigue (r =0.612, p =0.007). Conclusion: Using the appropriate tools, this study showed an association between subjective and objective cognitive fatigue in people with MS. The BCNT and cognitive control are useful tools in assessing patients with MS and should be explored in future, larger studies in this population.

Background: Repetitive transcranial magnetic stimulation (rTMS) has been used experimentally to facilitate naming abilities in individuals with chronic post-stroke aphasia. However, little is known about how rTMS confers clinical improvement, hampering its therapeutic value. The present study investigated the characteristics of naming failure that improve following administration of continuous theta burst stimulation (cTBS)-an inhibitory form of rTMS-to the right pars triangularis (rPTr) in persons with chronic aphasia.

Fluent speech production is a critical aspect of language processing and is central to aphasia diagnosis and treatment. Multiple cognitive processes and neural subsystems must be coordinated to produce fluent narrative speech. To refine the understanding of these systems, measures that minimize the influence of other cognitive processes were defined for articulatory deficits and grammatical deficits. Articulatory deficits were measured by the proportion of phonetic errors (articulatory and prosodic) in a word repetition task in 115 participants with aphasia following left hemisphere stroke. Grammatical deficits were assessed in 46 participants based on two measures-proportion of closed class words and proportion of words in sentences-generated during semistructured narrative speech production (telling the Cinderella story). These measures were used to identify brain regions critical for articulatory and grammatical aspects of speech production using a multivariate lesion-symptom mapping approach based on support vector regression. Phonetic error proportion was associated with damage to the postcentral gyrus and the inferior parietal lobule (particularly the supramarginal gyrus). Proportion of closed class words in narrative speech did not have consistent lesion correlates. Proportion of words in sentences was strongly associated with frontal lobe damage, particularly the inferior and middle frontal gyri. Grammatical sentence structuring relies on frontal regions, particularly the inferior and middle frontal gyri, whereas phonetic-articulatory planning and execution relies on parietal regions, particularly the postcentral and supramarginal gyri. These results clarify and extend current understanding of the functional components of the frontoparietal speech production system.