Through Thick and Thin: Baseline Cortical Volume and Thickness Predict Performance and Response to Transcranial Direct Current Stimulation in Primary Progressive Aphasia.

Objectives: We hypothesized that measures of cortical thickness and volume in language areas would correlate with response to treatment with high-definition transcranial direct current stimulation (HD-tDCS) in persons with primary progressive aphasia (PPA). Materials and Methods: In a blinded, within-group crossover study, PPA patients (N = 12) underwent a 2-week intervention HD-tDCS paired with constraint-induced language therapy (CILT). Multi-level linear regression (backward-fitted models) were performed to assess cortical measures as predictors of tDCS-induced naming improvements, measured by the Western Aphasia Battery-naming subtest, from baseline to immediately after and 6 weeks post-intervention. Results: Greater baseline thickness of the pars opercularis significantly predicted naming gains (p = 0.03) immediately following intervention, while greater thickness of the middle temporal gyrus (MTG) and lower thickness of the superior temporal gyrus (STG) significantly predicted 6-week naming gains (p's < 0.02). Thickness did not predict naming gains in sham. Volume did not predict immediate gains for active stimulation. Greater volume of the pars triangularis and MTG, but lower STG volume significantly predicted 6-week naming gains in active stimulation. Greater pars orbitalis and MTG volume, and lower STG volume predicted immediate naming gains in sham (p's < 0.05). Volume did not predict 6-week naming gains in sham. Conclusion: Cortical thickness and volume were predictive of tDCS-induced naming improvement in PPA patients. The finding that frontal thickness predicted immediate active tDCS-induced naming gains while temporal areas predicted naming changes at 6-week suggests that a broader network of regions may be important for long-term maintenance of treatment gains. The finding that volume predicted immediate naming performance in the sham condition may reflect the benefits of behavioral speech language therapy and neural correlates of its short-lived treatment gains. Collectively, thickness and volume were predictive of treatment gains in the active condition but not sham, suggesting that pairing HD-tDCS with CILT may be important for maintaining treatment effects.

Brain-Derived Neurotrophic Factor Gene Polymorphism Predicts Response to Continuous Theta Burst Stimulation in Chronic Stroke Patients.

OBJECTIVES: The efficacy of repetitive transcranial magnetic stimulation (rTMS) in clinically relevant neuroplasticity research depends on the degree to which stimulation induces robust, reliable effects. The high degree of interindividual and intraindividual variability observed in response to rTMS protocols, such as continuous theta burst stimulation (cTBS), therefore represents an obstacle to its utilization as treatment for neurological disorders. Brain-derived neurotrophic factor (BDNF) is a protein involved in human synaptic and neural plasticity, and a common polymorphism in the BDNF gene (Val66Met) may influence the capacity for neuroplastic changes that underlie the effects of cTBS and other rTMS protocols. While evidence from healthy individuals suggests that Val66Met polymorphism carriers may show diminished or facilitative effects of rTMS compared to their homozygous Val66Val counterparts, this has yet to be demonstrated in the patient populations where neuromodulatory therapies are most relevant. MATERIALS AND METHODS: We examined the effects of BDNF Val66Met polymorphism on cTBS aftereffects in stroke patients. We compared approximately 30 log-transformed motor-evoked potentials (LnMEPs) obtained per time point: at baseline and at 0, 10, 20, and 30 min after cTBS-600, from 18 patients with chronic stroke using single TMS pulses. We used linear mixed-effects regression with trial-level data nested by subject for higher statistical power. RESULTS: We found a significant interaction between BDNF genotype and pre-/post-cTBS LnMEPs. Val66Val carriers showed decrease in cortical excitability, whereas Val66Met carriers exhibited a modest increase in cortical excitability for 20 min poststimulation, followed by inhibition 30 min after cTBS-600. CONCLUSIONS: Our findings strongly suggest that BDNF genotype differentially affects neuroplastic responses to TMS in individuals with chronic stroke. This provides novel insight into potential sources of variability in cTBS response in patients, which has important implications for optimizing the utility of this neuromodulation approach. Incorporating BDNF polymorphism genetic screening to stratify patients prior to use of cTBS as a neuromodulatory technique in therapy or research may optimize response rates.

Genetic and Neurophysiological Biomarkers of Neuroplasticity Inform Post-Stroke Language Recovery.

BACKGROUND: There is high variability in post-stroke aphasia severity and predicting recovery remains imprecise. Standard prognostics do not include neurophysiological indicators or genetic biomarkers of neuroplasticity, which may be critical sources of variability. OBJECTIVE: To evaluate whether a common polymorphism (Val66Met) in the gene for brain-derived neurotrophic factor (BDNF) contributes to variability in post-stroke aphasia, and to assess whether BDNF polymorphism interacts with neurophysiological indicators of neuroplasticity (cortical excitability and stimulation-induced neuroplasticity) to improve estimates of aphasia severity. METHODS: Saliva samples and motor-evoked potentials (MEPs) were collected from participants with chronic aphasia subsequent to left-hemisphere stroke. MEPs were collected prior to continuous theta burst stimulation (cTBS; index for cortical excitability) and 10 minutes following cTBS (index for stimulation-induced neuroplasticity) to the right primary motor cortex. Analyses assessed the extent to which BDNF polymorphism interacted with cortical excitability and stimulation-induced neuroplasticity to predict aphasia severity beyond established predictors. RESULTS: Val66Val carriers showed less aphasia severity than Val66Met carriers, after controlling for lesion volume and time post-stroke. Furthermore, Val66Val carriers showed expected effects of age on aphasia severity, and positive associations between severity and both cortical excitability and stimulation-induced neuroplasticity. In contrast, Val66Met carriers showed weaker effects of age and negative associations between cortical excitability, stimulation-induced neuroplasticity and aphasia severity. CONCLUSIONS: Neurophysiological indicators and genetic biomarkers of neuroplasticity improved aphasia severity predictions. Furthermore, BDNF polymorphism interacted with cortical excitability and stimulation-induced neuroplasticity to improve predictions. These findings provide novel insights into mechanisms of variability in stroke recovery and may improve aphasia prognostics.

Noninvasive brain stimulation to augment language therapy for poststroke aphasia.

Behavioral language treatment approaches represent the standard of care for persons with aphasia (PWA), but the benefits of these treatments are variable. Moreover, due to the logistic and financial limitations on the amount of behavioral therapy available to patients, it is often infeasible for PWA to receive behavioral interventions with the level of frequency, intensity, or duration that would provide significant and lasting benefit, underscoring the need for novel, effective treatment approaches. Noninvasive brain stimulation (NIBS) techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), have emerged as promising neurally-based tools to enhance language abilities for PWA following stroke. This chapter first provides an overview of the methods and physiologic basis motivating the use of NIBS to enhance aphasia recovery followed by a selective review of the growing evidence of its potential as a novel therapeutic tool. Subsequent sections discuss some of the principles that may prove most useful in guiding and optimizing the effects of NIBS on aphasia recovery, focusing on how the functional state of the brain at the time of stimulation interacts with the behavioral aftereffects of neuromodulation. We conclude with a discussion of current challenges and future directions for NIBS in aphasia treatment.

Factors predicting long-term recovery from post-stroke aphasia.

Background: It remains widely accepted that spontaneous recovery from aphasia is largely limited to the first related factors. This has direct implications for acute and chronic interventions for aphasia. few months following stroke. A few recent studies challenge this view, revealing that some individuals' language abilities improve even during the chronic stage. Aims: To identify prognostic indicators of long-term aphasia recovery. Methods & Procedures: Eighteen people with aphasia initially evaluated in the chronic stage were retested at least one year later. The Western Aphasia Battery-Revised (WAB-R) Aphasia Quotient (AQ) was used to quantify changes in language impairment. Prognostic factors included those related to the patient (demographic, psychosocial), stroke (lesion volume and location), and treatment (medical, rehabilitative). Outcomes & Results: Twelve participants improved and 6 remained stable or declined. Linear regression analysis revealed that lesion volume predicted long-term language gains, with smaller lesions yielding greater improvements. Individuals who did not improve were more likely to have lesions encompassing critical frontal and temporoparietal cortical regions and interconnecting white matter pathways. Exploratory regression analysis of psychosocial and treatment-related factors revealed a positive relationship between improvement and satisfaction with life participation, and a negative relationship between improvement and perceived impairment severity. Critically, psychosocial and treatment-related factors significantly improved model fit over lesion volume, suggesting that these factors add predictive value to determining long-term aphasia prognosis. Conclusions: Long-term aphasia recovery is multidetermined by a combination of stroke-, psychosocial-, and treatment-related factors. This has direct implications for acute and chronic interventions for aphasia.

Language Tasks and the Network Control Role of the Left Inferior Frontal Gyrus.

Recent work has combined cognitive neuroscience and control theory to make predictions about cognitive control functions. Here, we test a link between whole-brain theories of semantics and the role of the left inferior frontal gyrus (LIFG) in controlled language performance using network control theory (NCT), a branch of systems engineering. Specifically, we examined whether two properties of node controllability, boundary and modal controllability, were linked to semantic selection and retrieval on sentence completion and verb generation tasks. We tested whether the controllability of the left IFG moderated language selection and retrieval costs and the effects of continuous θ burst stimulation (cTBS), an inhibitory form of transcranial magnetic stimulation (TMS) on behavior in 41 human subjects (25 active, 16 sham). We predicted that boundary controllability, a measure of the theoretical ability of a node to integrate and segregate brain networks, would be linked to word selection in the contextually-rich sentence completion task. In contrast, we expected that modal controllability, a measure of the theoretical ability of a node to drive the brain into specifically hard-to-reach states, would be linked to retrieval on the low-context verb generation task. Boundary controllability was linked to selection and to the ability of TMS to reduce response latencies on the sentence completion task. In contrast, modal controllability was not linked to performance on the tasks or TMS effects. Overall, our results suggest a link between the network integrating role of the LIFG and selection and the overall semantic demands of sentence completion.

Variability in cTBS Aftereffects Attributed to the Interaction of Stimulus Intensity With BDNF Val66Met Polymorphism.

Objective: To evaluate whether a common polymorphism (Val66Met) in the gene for brain-derived neurotrophic factor (BDNF)-a gene thought to influence plasticity-contributes to inter-individual variability in responses to continuous theta-burst stimulation (cTBS), and explore whether variability in stimulation-induced plasticity among Val66Met carriers relates to differences in stimulation intensity (SI) used to probe plasticity. Methods: Motor evoked potentials (MEPs) were collected from 33 healthy individuals (11 Val66Met) prior to cTBS (baseline) and in 10 min intervals immediately following cTBS for a total of 30 min post-cTBS (0 min post-cTBS, 10 min post-cTBS, 20 min post cTBS, and 30 min post-cTBS) of the left primary motor cortex. Analyses assessed changes in cortical excitability as a function of BDNF (Val66Val vs. Val66Met) and SI. Results: For both BDNF groups, MEP-suppression from baseline to post-cTBS time points decreased as a function of increasing SI. However, the effect of SI on MEPs was more pronounced for Val66Met vs. Val66Val carriers, whereby individuals probed with higher vs. lower SIs resulted in paradoxical cTBS aftereffects (MEP-facilitation), which persisted at least 30 min post-cTBS administration. Conclusions: cTBS aftereffects among BDNF Met allele carriers are more variable depending on the SI used to probe cortical excitability when compared to homozygous Val allele carriers, which could, to some extent, account for the inconsistency of previously reported cTBS effects. Significance: These data provide insight into the sources of cTBS response variability, which can inform how best to stratify and optimize its use in investigational and clinical contexts.

Brain-Derived Neurotrophic Factor Polymorphism Influences Response to Single-Pulse Transcranial Magnetic Stimulation at Rest.

OBJECTIVES: The ability of noninvasive brain stimulation to modulate corticospinal excitability and plasticity is influenced by genetic predilections such as the coding for brain-derived neurotrophic factor (BDNF). Otherwise healthy individuals presenting with BDNF Val66Met (Val/Met) polymorphism are less susceptible to changes in excitability in response to repetitive transcranial magnetic stimulation (TMS) and paired associative stimulation paradigms, reflecting reduced neuroplasticity, compared to Val homozygotes (Val/Val). In the current study, we investigated whether BDNF polymorphism influences "baseline" excitability under TMS conditions that are not repetitive or plasticity-inducing. Cross-sectional BDNF levels could predict TMS response more generally because of the ongoing plasticity processes. MATERIALS AND METHODS: Forty-five healthy individuals (23 females; age: 25.3 ± 7.0 years) participated in the study, comprising two groups. Motor evoked potentials (MEP) were collected using single-pulse TMS paradigms at fixed stimulation intensities at 110% of the resting motor threshold in one group, and individually-derived intensities based on MEP sizes of 1 mV in the second group. Functional variant Val66Met (rs6265) was genotyped from saliva samples by a technician blinded to the identity of DNA samples. RESULTS: Twenty-seven participants (60.0%) were identified with Val/Val, sixteen (35.5%) with Val/Met genotype, and two with Met/Met genotype. MEP amplitudes were significantly diminished in the Val/Met than Val/Val individuals. These results held independent of the single-pulse TMS paradigm of choice (p = 0.017110% group; p = 0.035 1 mV group), age, and scalp-to-coil distances. CONCLUSIONS: The findings should be further substantiated in larger-scale studies. If validated, intrinsic differences by BDNF polymorphism status could index response to TMS prior to implementing plasticity-inducing protocols.

Mapping articulatory and grammatical subcomponents of fluency deficits in post-stroke 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.

Continuous theta burst stimulation over right pars triangularis facilitates naming abilities in chronic post-stroke aphasia by enhancing phonological access.

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. METHODS: Eleven participants with chronic aphasia following left hemisphere stroke named pictures prior to and immediately following cTBS of the rPTr and a control site (vertex) in separate sessions. Prior to stimulation, we obtained two baseline measurements of picture naming ability to determine the extent and type (i.e., phonological vs. semantic) of naming impairment. Items presented for naming during stimulation were those that were named incorrectly in one or both of the baseline sessions (i.e., inconsistent vs. wrong items, respectively). Analyses assessed whether cTBS effects differed depending on the severity and/or type of naming impairment. RESULTS: Relative to vertex, cTBS of the rPTr improved naming of inconsistent, but not wrong, items for individuals with more severe baseline naming impairment. Critically, baseline phonological but not semantic naming impairment severity marginally correlated with improved accuracy overall, and significantly correlated with decreased phonological errors following rPTr stimulation. CONCLUSION: CTBS of the rPTr enhances naming by facilitating phonological access during word retrieval, indicating that individuals whose naming impairment is localized to this stage of processing may be most likely to benefit from this rTMS approach.

Semantic interference in speech error production in a randomized continuous naming task: Evidence from aphasia.

Naming pictures from the same semantic category hinders subsequent naming from that category (i.e., semantic interference), irrespective of the number of intervening different-category exemplars named. Persistent semantic interference has been well documented in chronometric studies, and has been attributed to experience-driven adjustments in the strength of connections between semantic and lexical representations. However, whether parallel effects exist in speech error data remains unclear. In the current study, people with aphasia, a speaker population prone to naming errors, provided naming responses to a large picture corpus presented in random order that comprised multiple exemplars drawn from several different categories. We found persistent semantic interference in the task in semantic error rates specifically, and that semantic similarity between consecutive related exemplars modulated the effect. The results provide further evidence for the presumed lexical-semantic locus and mechanism(s) underlying semantic interference.

Uncovering the association between fatigue and fatigability in multiple sclerosis using cognitive control.

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.

Network Controllability in the Inferior Frontal Gyrus Relates to Controlled Language Variability and Susceptibility to TMS.

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.SIGNIFICANCE STATEMENT This work illustrates that network control statistics applied to anatomical connectivity data demonstrate relationships with cognitive variability during controlled language tasks and TMS effects.

Functional Reorganization of Right Prefrontal Cortex Underlies Sustained Naming Improvements in Chronic Aphasia via Repetitive Transcranial Magnetic Stimulation.

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).

Different Loci of Semantic Interference in Picture Naming vs. Word-Picture Matching Tasks.

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.

Distinct loci of lexical and semantic access deficits in aphasia: Evidence from voxel-based lesion-symptom mapping and diffusion tensor imaging.

Naming pictures and matching words to pictures belonging to the same semantic category negatively affects language production and comprehension. By most accounts, semantic interference arises when accessing lexical representations in naming (e.g., Damian, Vigliocco, & Levelt, 2001) and semantic representations in comprehension (e.g., Forde & Humphreys, 1997). 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 (ROI) 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 versus 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 (ILF), connecting posterior with anterior temporal regions related to semantic interference in comprehension. These neuroanatomical-behavioral findings have implications for models of the lexical-semantic language network by demonstrating that semantic interference in language production and comprehension involves different representations which differentially recruit a cognitive control mechanism for interference resolution.

Neuropsychological evidence for the functional role of the uncinate fasciculus in semantic control.

Understanding a word requires mapping sounds to a word-form and then identifying its correct meaning, which in some cases necessitates the recruitment of cognitive control processes to direct the activation of semantic knowledge in a task appropriate manner (i.e., semantic control). Neuroimaging and neuropsychological studies identify a fronto-temporal network important for word comprehension. However, little is known about the connectional architecture subserving controlled retrieval and selection of semantic knowledge during word comprehension. We used diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rs-fMRI) in aphasic individuals with varying degrees of word comprehension deficits to examine the role of three white matter pathways within this network: the uncinate fasciculus (UF), inferior longitudinal fasciculus (ILF), and inferior fronto-occipital fasciculus (IFOF). Neuroimaging data from a group of age-matched controls were also collected in order to establish that the patient group had decreased structural and functional connectivity profiles. We obtained behavioral data from aphasic participants on two measures of single word comprehension that involve semantic control, and assessed pathway functional significance by correlating patients' performance with indices of pathway structural integrity and the functional connectivity profiles of regions they connect. Both the structural integrity of the UF and the functional connectivity strength of regions it connects predicted patients' performance. This result suggests the semantic control impairment in word comprehension resulted from poor neural communication between regions the UF connects. Inspections of other subcortical and cortical structures revealed no relationship with patients' performance. We conclude that the UF mediates semantic control during word comprehension by connecting regions specialized for cognitive control with those storing word meanings. These findings also support a relationship between structural and functional connectivity measures, as the rs-fMRI results provide converging evidence with those obtained using DTI.

Neural adaptation across viewpoint and exemplar in fusiform cortex.

The visual system has the remarkable ability to generalize across different viewpoints and exemplars to recognize abstract categories of objects, and to discriminate between different viewpoints and exemplars to recognize specific instances of particular objects. Behavioral experiments indicate the critical role of the right hemisphere in specific-viewpoint and -exemplar visual form processing and the left hemisphere in abstract-viewpoint and -exemplar visual form processing. Neuroimaging studies indicate the role of fusiform cortex in these processes, however results conflict in their support of the behavioral findings. We investigated this inconsistency in the present study by examining adaptation across viewpoint and exemplar changes in the functionally defined fusiform face area (FFA) and in fusiform regions exhibiting adaptation. Subjects were adapted to particular views of common objects and then tested with objects appearing in four critical conditions: same-exemplar, same-viewpoint adapted, same-exemplar, different-viewpoint adapted, different-exemplar adapted, and not adapted. In line with previous results, the FFA demonstrated a release from neural adaptation for repeated different viewpoints and exemplars of an object. In contrast to previous work, a (non-FFA) right medial fusiform area also demonstrated a release from neural adaptation for repeated different viewpoints and exemplars of an object. Finally, a left lateral fusiform area demonstrated neural adaptation for repeated different viewpoints, but not exemplars, of an object. Test-phase task demands did not affect adaptation in these regions. Together, results suggest that dissociable neural subsystems in fusiform cortex support the specific identification of a particular object and the abstract recognition of that object observed from a different viewpoint. In addition, results suggest that areas within fusiform cortex do not support abstract recognition of different exemplars of objects within a category.