Investigating the contribution of the right hemisphere to language processing in the damaged and healthy brain

Acquired language disorders after stroke are strongly associated with left hemisphere damage. When language difficulties are observed after right hemisphere damage, patients are commonly considered to have atypical functional anatomy (i.e. crossed aphasia). On the other hand, fMRI studies have reported right hemisphere activation when neurologically-normal participants perform language tasks, and have shown that the right hemisphere contributes to recovery of language function after left hemisphere damage. In this thesis I investigated (i) the degree to which language difficulties after right hemisphere stroke can reflect disruption to typical functional anatomy and (ii) how the damaged areas contribute to normal language processing. In Study 1 (Chapter 3), I investigated a group of patients with unilateral strokes that damaged either the right or the left hemisphere. The most frequently impaired language task was auditory sentence-to-picture matching after right hemisphere strokes, and spoken picture description after left hemisphere strokes. In 9 right hemisphere stroke patients, performance on the auditory sentence-to-picture matching task was selectively impaired and could not be explained by poor perceptual (visual or auditory) or linguistic processing (semantic, phonological or syntactic). I therefore hypothesised that the behavioural difficulties experienced by those patients arose as a consequence of impaired non-linguistic executive functions that are needed to support language processes. In Study 2 (Chapter 4), I investigated the lesions of the 9 patients with selective deficits in the auditory sentence-to-picture matching task, and found that they had significantly more damage to subcortical regions and parts of the superior longitudinal fasciculus impinging on the right inferior frontal sulcus compared to other right hemisphere stroke patients who were not impaired on the sentence comprehension task. Having identified these regions, their function (e.g. linguistic or executive) can be investigated using functional neuroimaging in neurologically-normal participants. In Study 3 (Chapter 5), I used fMRI to investigate whether any parts of the right hemisphere regions associated with impaired sentence comprehension, in Study 2, were activated when neurologically-normal participants performed similar language tasks to those administered to right hemisphere stroke patients in Study 1 (including the auditory sentence-to-picture matching task). I found that, within the brain areas derived from Study 2, the right inferior frontal sulcus and right mediodorsal thalamus were normally activated by auditory sentence-to-picture matching but there was no evidence that these regions were exclusively performing linguistic functions. In Study 4 (Chapter 6), I investigated the contribution of the identified regions further by using a new fMRI study of one-back matching tasks that varied demands on semantic and non-semantic working memory. By systematically integrating neuropsychological, lesion and fMRI data, I conclude that the right inferior frontal cortex and right mediodorsal thalamus contribute to non-semantic working memory capacity that is needed to accurately perform a range of language functions. This account helps to explain why auditory sentence-to-picture matching impairments occur after right hemisphere damage

Degeneracy in the neurological model of auditory speech repetition

Both classic and contemporary models of auditory word repetition involve at least four left hemisphere regions: primary auditory cortex for processing sounds; pSTS (within Wernicke's area) for processing auditory images of speech; pOp (within Broca's area) for processing motor images of speech; and primary motor cortex for overt speech articulation. Previous functional-MRI (fMRI) studies confirm that auditory repetition activates these regions, in addition to many others. Crucially, however, contemporary models do not specify how regions interact and drive each other during auditory repetition. Here, we used dynamic causal modelling, to test the functional interplay among the four core brain regions during single auditory word and pseudoword repetition. Our analysis is grounded in the principle of degeneracy-i.e., many-to-one structure-function relationships-where multiple neural pathways can execute the same function. Contrary to expectation, we found that, for both word and pseudoword repetition, (i) the effective connectivity between pSTS and pOp was predominantly bidirectional and inhibitory; (ii) activity in the motor cortex could be driven by either pSTS or pOp; and (iii) the latter varied both within and between individuals. These results suggest that different neural pathways can support auditory speech repetition. This degeneracy may explain resilience to functional loss after brain damage

The impact of sample size on the reproducibility of voxel-based lesion-deficit mappings

This study investigated how sample size affects the reproducibility of findings from univariate voxel-based lesion-deficit analyses (e.g., voxel-based lesion-symptom mapping and voxel-based morphometry). Our effect of interest was the strength of the mapping between brain damage and speech articulation difficulties, as measured in terms of the proportion of variance explained. First, we identified a region of interest by searching on a voxel-by-voxel basis for brain areas where greater lesion load was associated with poorer speech articulation using a large sample of 360 right-handed English-speaking stroke survivors. We then randomly drew thousands of bootstrap samples from this data set that included either 30, 60, 90, 120, 180, or 360 patients. For each resample, we recorded effect size estimates and p values after conducting exactly the same lesion-deficit analysis within the previously identified region of interest and holding all procedures constant. The results show (1) how often small effect sizes in a heterogeneous population fail to be detected; (2) how effect size and its statistical significance varies with sample size; (3) how low-powered studies (due to small sample sizes) can greatly over-estimate as well as under-estimate effect sizes; and (4) how large sample sizes (N ≥ 90) can yield highly significant p values even when effect sizes are so small that they become trivial in practical terms. The implications of these findings for interpreting the results from univariate voxel-based lesion-deficit analyses are discussed.</p

Enhanced left superior parietal activation during successful speech production in patients with left dorsal striatal damage and error-prone neurotypical participants

Functional imaging studies of neurotypical adults report activation in the left putamen during speech production. The current study asked how stroke survivors with left putamen damage are able to produce correct spoken responses during a range of speech production tasks. Using functional magnetic resonance imaging, activation during correct speech production responses was assessed in 5 stroke patients with circumscribed left dorsal striatal lesions, 66 stroke patient controls who did not have focal left dorsal striatal lesions, and 54 neurotypical adults. As a group, patients with left dorsal striatal damage (our patients of interest) showed higher activation than neurotypical controls in the left superior parietal cortex during successful speech production. This effect was not specific to patients with left dorsal striatal lesions as we observed enhanced activation in the same region in some patient controls and also in more error-prone neurotypical participants. Our results strongly suggest that enhanced left superior parietal activation supports speech production in diverse challenging circumstances, including those caused by stroke damage. They add to a growing body of literature indicating how upregulation within undamaged parts of the neural systems already recruited by neurotypical adults contributes to recovery after stroke

Network anatomy in logopenic variant of primary progressive aphasia

The logopenic variant of primary progressive aphasia (lvPPA) is a neurodegenerative syndrome characterized linguistically by gradual loss of repetition and naming skills resulting from left posterior temporal and inferior parietal atrophy. Here, we sought to identify which specific cortical loci are initially targeted by the disease (epicenters) and investigate whether atrophy spreads through predetermined networks. First, we used cross-sectional structural MRI data from individuals with lvPPA to define putative disease epicenters using a surface-based approach paired with an anatomically fine-grained parcellation of the cortical surface (i.e., HCP-MMP1.0 atlas). Second, we combined cross-sectional functional MRI data from healthy controls and longitudinal structural MRI data from individuals with lvPPA to derive the epicenter-seeded resting-state networks most relevant to lvPPA symptomatology and ascertain whether functional connectivity in these networks predicts longitudinal atrophy spread in lvPPA. Our results show that two partially distinct brain networks anchored to the left anterior angular and posterior superior temporal gyri epicenters were preferentially associated with sentence repetition and naming skills in lvPPA. Critically, the strength of connectivity within these two networks in the neurologically-intact brain significantly predicted longitudinal atrophy progression in lvPPA. Taken together, our findings indicate that atrophy progression in lvPPA, starting from inferior parietal and temporoparietal junction regions, predominantly follows at least two partially nonoverlapping pathways, which may influence the heterogeneity in clinical presentation and prognosis

Damage to Broca’s area does not contribute to long-term speech production outcome after stroke

Broca’s area in the posterior half of the left inferior frontal gyrus has long been thought to be critical for speech production. The current view is that long-term speech production outcome in patients with Broca’s area damage is best explained by the combination of damage to Broca’s area and neighbouring regions including the underlying white matter, which was also damaged in Paul Broca’s two historic cases. Here, we dissociate the effect of damage to Broca’s area from the effect of damage to surrounding areas by studying long-term speech production outcome in 134 stroke survivors with relatively circumscribed left frontal lobe lesions that spared posterior speech production areas in lateral inferior parietal and superior temporal association cortices. Collectively, these patients had varying degrees of damage to one or more of nine atlas-based grey or white matter regions: Brodmann areas 44 and 45 (together known as Broca’s area), ventral premotor cortex, primary motor cortex, insula, putamen, the anterior segment of the arcuate fasciculus, uncinate fasciculus and frontal aslant tract. Spoken picture description scores from the ComprehensiveAphasia Test were used as the outcome measure. Multiple regression analyses allowed us to tease apart the contribution of other variables influencing speech production abilities such as total lesion volume and time post-stroke. We found that, in our sample of patients with left frontal damage, long-term speech production impairments (lasting beyond 3 months post-stroke) were solely predictedby the degree of damage to white matter, directly above the insula, in the vicinity of the anterior part of the arcuate fasciculus, with no contribution from the degree of damage to Broca’s area (as confirmed with Bayesian statistics). The effect of white matter damage cannot be explained by a disconnection of Broca’s area, because speech production scores were worse after damage to the anterior arcuate fasciculus with relative sparing of Broca’s area than after damage to Broca’s area with relative sparing of the anterior arcuate fasciculus. Our findings provide evidence for three novel conclusions: (i) Broca’s area damage does not contribute to long-term speech production outcome after left frontal lobe strokes; (ii) persistent speech production impairments after damage to the anterior arcuate fasciculus cannot be explained by a disconnection of Broca’s area; and (iii) the prior association between persistent speech production impairments and Broca’s area damage can be explained by co-occurring white matter damage, above the insula, in the vicinity of the anterior part of the arcuate fasciculus

How distributed processing produces false negatives in voxel-based lesion-deficit analyses

In this study, we hypothesized that if the same deficit can be caused by damage to one or another part of a distributed neural system, then voxel-based analyses might miss critical lesion sites because preservation of each site will not be consistently associated with preserved function. The first part of our investigation used voxelbased multiple regression analyses of data from 359 right-handed stroke survivors to identify brain regions where lesion load is associated with picture naming abilities after factoring out variance related to object recognition, semantics and speech articulation so as to focus on deficits arising at the word retrieval level. A highly significant lesion-deficit relationship was identified in left temporal and frontal/premotor regions. Post-hoc analyses showed that damage to either of these sites caused the deficit of interest in less than half the affected patients (76/162 = 47%). After excluding all patients with damage to one or both of the identified regions, our second analysis revealed a new region, in the anterior part of the left putamen, which had not been previously detected because many patients had the deficit of interest after temporal or frontal damage that preserved the left putamen. The results illustrate how (i) false negative results arise when the same deficit can be caused by different lesion sites; (ii) some of the missed effects can be unveiled by adopting an iterative approach that systematically excludes patients with lesions to the areas identified in previous analyses, (iii) statistically significant voxel-based lesion-deficit mappings can be driven by a subset of patients; (iv) focal lesions to the identified regions are needed to determine whether the deficit of interest is the consequence of focal damage or much more extensive damage that includes the identified region; and, finally, (v) univariate voxel-based lesiondeficit mappings cannot, in isolation, be used to predict outcome in other patients

Assessing processing speed and its neural correlates in the three variants of primary progressive aphasia with a non-verbal tablet-based task

Prior research has revealed distinctive patterns of impaired language abilities across the three variants of Primary Progressive Aphasia (PPA): nonfluent/agrammatic (nfvPPA), logopenic (lvPPA) and semantic (svPPA). However, little is known about whether, and to what extent, non-verbal cognitive abilities, such as processing speed, are impacted in PPA patients. This is because neuropsychological tests typically contain linguistic stimuli and require spoken output, being therefore sensitive to verbal deficits in aphasic patients. The aim of this study is to investigate potential differences in processing speed between PPA patients and healthy controls, and among the three PPA variants, using a brief non-verbal tablet-based task (Match) modeled after the WAIS-III digit symbol coding test, and to determine its neural correlates. Here, we compared performance on the Match task between PPA patients (n&nbsp;=&nbsp;61) and healthy controls (n&nbsp;=&nbsp;59) and across the three PPA variants. We correlated performance on Match with voxelwise gray and white matter volumes. We found that lvPPA and nfvPPA patients performed significantly worse on Match than healthy controls and svPPA patients. Worse performance on Match across PPA patients was associated with reduced gray matter volume in specific parts of the left middle frontal gyrus, superior parietal lobule, and precuneus, and reduced white matter volume in the left parietal lobe. To conclude, our behavioral findings reveal that processing speed is differentially impacted across the three PPA variants and provide support for the potential clinical utility of a tabled-based task (Match) to assess non-verbal cognition. In addition, our neuroimaging findings confirm the importance of a set of fronto-parietal regions that previous research has associated with processing speed and executive control. Finally, our behavioral and neuroimaging findings combined indicate that differences in processing speed are largely explained by the unequal distribution of atrophy in these fronto-parietal regions across the three PPA variants

Network anatomy in logopenic variant of primary progressive aphasia

The logopenic variant of primary progressive aphasia (lvPPA) is a neurodegenerative syndrome characterized linguistically by gradual loss of repetition and naming skills resulting from left posterior temporal and inferior parietal atrophy. Here, we sought to identify which specific cortical loci are initially targeted by the disease (epicenters) and investigate whether atrophy spreads through predetermined networks. First, we used cross-sectional structural MRI data from individuals with lvPPA to define putative disease epicenters using a surface-based approach paired with an anatomically fine-grained parcellation of the cortical surface (i.e., HCP-MMP1.0 atlas). Second, we combined cross-sectional functional MRI data from healthy controls and longitudinal structural MRI data from individuals with lvPPA to derive the epicenter-seeded resting-state networks most relevant to lvPPA symptomatology and ascertain whether functional connectivity in these networks predicts longitudinal atrophy spread in lvPPA. Our results show that two partially distinct brain networks anchored to the left anterior angular and posterior superior temporal gyri epicenters were preferentially associated with sentence repetition and naming skills in lvPPA. Critically, the strength of connectivity within these two networks in the neurologically-intact brain significantly predicted longitudinal atrophy progression in lvPPA. Taken together, our findings indicate that atrophy progression in lvPPA, starting from inferior parietal and temporoparietal junction regions, predominantly follows at least two partially nonoverlapping pathways, which may influence the heterogeneity in clinical presentation and prognosis