The neural and computational bases of semantic cognition.

Semantic cognition refers to our ability to use, manipulate and generalize knowledge that is acquired over the lifespan to support innumerable verbal and non-verbal behaviours. This Review summarizes key findings and issues arising from a decade of research into the neurocognitive and neurocomputational underpinnings of this ability, leading to a new framework that we term controlled semantic cognition (CSC). CSC offers solutions to long-standing queries in philosophy and cognitive science, and yields a convergent framework for understanding the neural and computational bases of healthy semantic cognition and its dysfunction in brain disorders.

Distinct and common neural coding of semantic and non-semantic control demands.

The flexible retrieval of knowledge is critical in everyday situations involving problem solving, reasoning and social interaction. Current theories emphasise the importance of a left-lateralised semantic control network (SCN) in supporting flexible semantic behaviour, while a bilateral multiple-demand network (MDN) is implicated in executive functions across domains. No study, however, has examined whether semantic and non-semantic demands are reflected in a common neural code within regions specifically implicated in semantic control. Using functional MRI and univariate parametric modulation analysis as well as multivariate pattern analysis, we found that semantic and non-semantic demands gave rise to both similar and distinct neural responses across control-related networks. Though activity patterns in SCN and MDN could decode the difficulty of both semantic and verbal working memory decisions, there was no shared common neural coding of cognitive demands in SCN regions. In contrast, regions in MDN showed common patterns across manipulations of semantic and working memory control demands, with successful cross-classification of difficulty across tasks. Therefore, SCN and MDN can be dissociated according to the information they maintain about cognitive demands.

The degraded concept representation system in semantic dementia: damage to pan-modal hub, then visual spoke.

The core clinical feature of semantic dementia is a progressive yet selective degradation of conceptual knowledge. Understanding the cognitive and neuroanatomical basis for this deficit is a key challenge for both clinical and basic science. Some researchers attribute the deficit to damage to pan-modal conceptual representations that are independent of any particular sensory-motor modality and are represented in the ventrolateral anterior temporal lobes. Others claim that damage to modality-specific visual feature representations in the occipitotemporal 'ventral stream' is responsible. In the present study, we tested the hypothesis that concept degradation in semantic dementia involves a combination of these pan-modal and modality-specific elements. We investigated factors influencing knowledge of object concepts by analysing 43 sets of picture-naming data from patients with semantic dementia. We found a strong influence of two pan-modal factors: highly familiar and typical items were named more accurately than less familiar/atypical items at all stages of the disorder. Items associated with rich sensory-motor information were also named more successfully at all stages, and this effect was present for sound/motion knowledge and tactile/action knowledge when these modalities were studied separately. However, there was no advantage for items rich in visual colour/form characteristics; instead, this factor had an increasingly negative impact in the later stages of the disorder. We propose that these results are best explained by a combination of (i) degradation of modality-independent conceptual representations, which is present throughout the disorder and is a consequence of atrophy focused on the ventrolateral anterior temporal lobes; and (ii) a later additional deficit for concepts that depend heavily on visual colour/form information, caused by the spreading of atrophy to posterior ventral temporal regions specialized for representing this information. This explanation is consistent with a graded hub-and-spoke model of conceptual knowledge, in which there is a gradual convergence of information along the temporal lobes, with visual attributes represented in the posterior cortex giving way to pan-modal representations in the anterior areas.

The neural substrates of transdiagnostic cognitive-linguistic heterogeneity in primary progressive aphasia.

BACKGROUND: Clinical variants of primary progressive aphasia (PPA) are diagnosed based on characteristic patterns of language deficits, supported by corresponding neural changes on brain imaging. However, there is (i) considerable phenotypic variability within and between each diagnostic category with partially overlapping profiles of language performance between variants and (ii) accompanying non-linguistic cognitive impairments that may be independent of aphasia magnitude and disease severity. The neurobiological basis of this cognitive-linguistic heterogeneity remains unclear. Understanding the relationship between these variables would improve PPA clinical/research characterisation and strengthen clinical trial and symptomatic treatment design. We address these knowledge gaps using a data-driven transdiagnostic approach to chart cognitive-linguistic differences and their associations with grey/white matter degeneration across multiple PPA variants. METHODS: Forty-seven patients (13 semantic, 15 non-fluent, and 19 logopenic variant PPA) underwent assessment of general cognition, errors on language performance, and structural and diffusion magnetic resonance imaging to index whole-brain grey and white matter changes. Behavioural data were entered into varimax-rotated principal component analyses to derive orthogonal dimensions explaining the majority of cognitive variance. To uncover neural correlates of cognitive heterogeneity, derived components were used as covariates in neuroimaging analyses of grey matter (voxel-based morphometry) and white matter (network-based statistics of structural connectomes). RESULTS: Four behavioural components emerged: general cognition, semantic memory, working memory, and motor speech/phonology. Performance patterns on the latter three principal components were in keeping with each variant's characteristic profile, but with a spectrum rather than categorical distribution across the cohort. General cognitive changes were most marked in logopenic variant PPA. Regardless of clinical diagnosis, general cognitive impairment was associated with inferior/posterior parietal grey/white matter involvement, semantic memory deficits with bilateral anterior temporal grey/white matter changes, working memory impairment with temporoparietal and frontostriatal grey/white matter involvement, and motor speech/phonology deficits with inferior/middle frontal grey matter alterations. CONCLUSIONS: Cognitive-linguistic heterogeneity in PPA closely relates to individual-level variations on multiple behavioural dimensions and grey/white matter degeneration of regions within and beyond the language network. We further show that employment of transdiagnostic approaches may help to understand clinical symptom boundaries and reveal clinical and neural profiles that are shared across categorically defined variants of PPA.

An efficient, accurate and clinically-applicable index of content word fluency in Aphasia.

Background: Despite the clinical importance of assessing the efficiency and accuracy of fluency in terms of content words production during connected speech, assessments based on discourse tasks are very time-consuming and thus not clinically feasible. Aims: (1) Examine the relationship between single-word naming and word retrieval during discourse production. (2) Investigate the relationship between word retrieval and content word fluency derived from a simple versus naturalistic discourse tasks. (3) Develop and validate an efficient and accurate index of content word fluency that is clinically viable. Methods: Two discourse tasks (simple picture description and naturalistic storytelling narrative) were collected from 46 participants with post-stroke aphasia, and 20 age/education matched neuro-typical controls. Each discourse sample was fully transcribed and quantitative analysis was applied to each sample to measure word retrieval and content word fluency. Three single-word naming tasks were also administered to each participant with aphasia. Results: Correlational analyses between single-word naming and word retrieval in connected speech revealed weak/moderate relationships. Conversely, strong correlations were found between measures derived from simple picture description against naturalistic storytelling discourse tasks. Moreover, we derived a novel, transcription-less index of content word fluency from the discourse samples of an independent group (neuro-typical controls), and then we validated this index across two discourse tasks in the tested group (persons with aphasia). Correlation and regression analyses revealed extremely strong relationships between participants' (neuro-typical controls and persons with aphasia) scores on the novel index and measures of content word fluency derived from the formal transcription and quantitative analyses of discourse samples, indicating high accuracy and validity of the new index. Conclusions: Simple picture description rather than picture naming provides a better estimate of word retrieval in naturalistic connected speech. The novel developed index is transcription-less and can be implemented online to provide an accurate and efficient measure of content word fluency. Thus, it is viable during clinical practice for assessment purposes, and possibly as an outcome measure to monitor therapy effectiveness, which can also be used in randomised clinical trials.

Deregulated semantic cognition follows prefrontal and temporo-parietal damage: evidence from the impact of task constraint on nonverbal object use.

Semantic cognition, which encompasses all conceptually based behavior, is dependent on the successful interaction of two key components: conceptual representations and regulatory control. Qualitatively distinct disorders of semantic knowledge follow damage to the different parts of this system. Previous studies have shown that patients with multimodal semantic impairment following CVA--a condition referred to as semantic aphasia (SA)--perform poorly on a range of conceptual tasks due to a failure of executive control following prefrontal and/or temporo-parietal infarction [Jefferies, E., & Lambon Ralph, M. A. Semantic impairment in stroke aphasia versus semantic dementia: A case-series comparison. Brain, 129, 2132-2147, 2006]. Although a deficit of core semantic control would be expected to impair all modalities in parallel, most research exploring this condition has focused on tasks in the verbal domain. In a novel exploration of semantic control in the nonverbal domain, therefore, we assessed eight patients with SA on two experiments that examined object use knowledge under different levels of task constraint. Patients exhibited three key characteristics of semantic deregulation: (a) difficulty using conceptual knowledge flexibly to support the noncanonical uses of everyday objects; (b) poor inhibition of semantically related distractor items; and (c) improved object use with the provision of more tightly constraining task conditions following verbal and pictorial cues. Our findings are consistent with the notion that a neural network incorporating the left inferior prefrontal and temporo-parietal areas (damaged in SA) underpins regulation of semantic activation across both verbal and nonverbal modalities.

At the edge of semantic space: the breakdown of coherent concepts in semantic dementia is constrained by typicality and severity but not modality.

Hub-and-spoke models of semantic representation suggest that coherent concepts are formed from the integration of multiple, modality-specific information sources with additional modality-invariant representations-most likely stored in the ventrolateral anterior temporal lobe (vATL). As well as providing the necessary computational mechanisms for the complexities of feature integration, these modality-invariant representations also license a key aspect of semantic memory-semantic-based generalization. Semantic dementia allows us to investigate this aspect of conceptual knowledge because (a) the patients have a selective and progressive semantic degradation and (b) this is associated with profound ventrolateral ATL atrophy. Specifically, the boundaries between concepts become degraded in semantic dementia and, when tested using the appropriate materials, the patients make simultaneous under- and overgeneralization errors. We found that the rate of these errors were a function of typicality and pseudotypicality of the items as well as the severity of the patients' semantic impairment. Following the modality-invariant nature of the vATL hub representation, we also confirmed that the patients were impaired on both verbal- and picture-based versions of the same task.

Semantic diversity accounts for the "missing" word frequency effect in stroke aphasia: insights using a novel method to quantify contextual variability in meaning.

Word frequency is a powerful predictor of language processing efficiency in healthy individuals and in computational models. Puzzlingly, frequency effects are often absent in stroke aphasia, challenging the assumption that word frequency influences the behavior of any computational system. To address this conundrum, we investigated divergent effects of frequency in two comprehension-impaired patient groups. Patients with semantic dementia have degraded conceptual knowledge as a consequence of anterior temporal lobe atrophy and show strong frequency effects. Patients with multimodal semantic impairments following stroke (semantic aphasia [SA]), in contrast, show little or no frequency effect. Their deficits arise from impaired control processes that bias activation toward task-relevant aspects of knowledge. We hypothesized that high-frequency words exert greater demands on cognitive control because they are more semantically diverse--they tend to appear in a broader range of linguistic contexts and have more variable meanings. Using latent semantic analysis, we developed a new measure of semantic diversity that reflected the variability of a word's meaning across different context. Frequency, but not diversity, was a significant predictor of comprehension in semantic dementia, whereas diversity was the best predictor of performance in SA. Most importantly, SA patients did show typical frequency effects but only when the influence of diversity was taken into account. These results are consistent with the view that higher-frequency words place higher demands on control processes, so that when control processes are damaged the intrinsic processing advantages associated with higher-frequency words are masked.

The role of plasticity-related functional reorganization in the explanation of central dyslexias.

This investigation explored the hypothesis that patterns of acquired dyslexia may reflect, in part, plasticity-driven relearning that dynamically alters the division of labour (DOL) between the direct, orthography → phonology (O → P) pathway and the semantically mediated, orthography → semantics → phonology (O → S → P) pathway. Three simulations were conducted using a variant of the triangle model of reading. The model demonstrated core characteristics of normal reading behaviour in its undamaged state. When damage was followed by reoptimization (mimicking spontaneous recovery), the model reproduced the deficits observed in the central dyslexias-acute phonological damage combined with recovery matched data taken from a series of 12 phonological dyslexic patients-whilst progressive semantic damage interspersed with recovery reproduced data taken from 100 observations of semantic dementia patients. The severely phonologically damaged model also produced symptoms of deep dyslexia (imageability effects, production of semantic and mixed semantic/visual errors). In all cases, the DOL changed significantly in the recovery period, suggesting that postmorbid functional reorganization is important in understanding behaviour in chronic-stage patients.

The ventral and inferolateral aspects of the anterior temporal lobe are crucial in semantic memory: evidence from a novel direct comparison of distortion-corrected fMRI, rTMS, and semantic dementia.

Although there is an emerging consensus that the anterior temporal lobes (ATLs) are involved in semantic memory, it is currently unclear which specific parts of this region are implicated in semantic representation. Answers to this question are difficult to glean from the existing literature for 3 reasons: 1) lesions of relevant patient groups tend to encompass the whole ATL region; 2) while local effects of repetitive transcranial magnetic stimulation (rTMS) are spatially more specific, only the lateral aspects of the ATL are available to stimulation; and 3) until recently, functional magnetic resonance imaging (fMRI) studies were hindered by technical limitations such as signal distortion and dropout due to magnetic inhomogeneities and also, in some cases, by methodological factors, including a restricted field of view and the choice of baseline contrast for subtraction analysis. By utilizing the same semantic task across semantic dementia, rTMS, and distortion-corrected fMRI in normal participants, we directly compared the results across the 3 methods for the first time. The findings were highly convergent and indicated that crucial regions within the ATL for semantic representation include the anterior inferior temporal gyrus, anterior fusiform gyrus, and the anterior superior temporal sulcus.

Selective functional integration between anterior temporal and distinct fronto-mesolimbic regions during guilt and indignation.

It has been hypothesized that the experience of different moral sentiments such as guilt and indignation is underpinned by activation in temporal and fronto-mesolimbic regions and that functional integration between these regions is necessary for the differentiated experience of these moral sentiments. A recent fMRI study revealed that the right superior anterior temporal lobe (ATL) was activated irrespective of the context of moral feelings (guilt or indignation). This region has been associated with context-independent conceptual social knowledge which allows us to make fine-grained differentiations between qualities of social behaviours (e.g. "critical" and "faultfinding"). This knowledge is required to make emotional evaluations of social behaviour. In contrast to the context-independent activation of the ATL, there were context-dependent activations within different fronto-mesolimbic regions for guilt and indignation. However, it is unknown whether functional integration occurs between these regions and whether regional patterns of integration are distinctive for the experience of different moral sentiments. Here, we used fMRI and psychophysiological interaction analysis, an established measure of functional integration to investigate this issue. We found selective functional integration between the right superior ATL and a subgenual cingulate region during the experience of guilt and between the right superior ATL and the lateral orbitofrontal cortex for indignation. Our data provide the first evidence for functional integration of conceptual social knowledge representations in the right superior ATL with representations of different feeling contexts in fronto-mesolimbic regions. We speculate that this functional architecture allows for the conceptually differentiated experience of moral sentiments in healthy individuals.

Distortion correction for diffusion-weighted MRI tractography and fMRI in the temporal lobes.

Single shot echo-planar imaging (EPI) sequences are currently the most commonly used sequences for diffusion-weighted imaging (DWI) and functional magnetic resonance imaging (fMRI) as they allow relatively high signal to noise with rapid acquisition time. A major drawback of EPI is the substantial geometric distortion and signal loss that can occur due to magnetic field inhomogeneities close to air-tissue boundaries. If DWI-based tractography and fMRI are to be applied to these regions, then the distortions must be accurately corrected to achieve meaningful results. We describe robust acquisition and processing methods for correcting such distortions in spin echo (SE) EPI using a variant of the reversed direction k space traversal method with a number of novel additions. We demonstrate that dual direction k space traversal with maintained diffusion-encoding gradient strength and direction results in correction of the great majority of eddy current-associated distortions in DWI, in addition to those created by variations in magnetic susceptibility. We also provide examples to demonstrate that the presence of severe distortions cannot be ignored if meaningful tractography results are desired. The distortion correction routine was applied to SE-EPI fMRI acquisitions and allowed detection of activation in the temporal lobe that had been previously found using PET but not conventional fMRI.

Anterior temporal lobes mediate semantic representation: mimicking semantic dementia by using rTMS in normal participants.

Studies of semantic dementia and PET neuroimaging investigations suggest that the anterior temporal lobes (ATL) are a critical substrate for semantic representation. In stark contrast, classical neurological models of comprehension do not include ATL, and likewise functional MRI studies often fail to show activations in the ATL, reinforcing the classical view. Using a novel application of low-frequency, repetitive transcranial magnetic stimulation (rTMS) over the ATL, we demonstrate that the behavioral pattern of semantic dementia can be mirrored in neurologically intact participants: Specifically, we show that temporary disruption to neural processing in the ATL produces a selective semantic impairment leading to significant slowing in both picture naming and word comprehension but not to other equally demanding, nonsemantic cognitive tasks.

RELEASE: a protocol for a systematic review based, individual participant data, meta- and network meta-analysis, of complex speech-language therapy interventions for stroke-related aphasia.

Background: Speech and language therapy (SLT) benefits people with aphasia following stroke. Group level summary statistics from randomised controlled trials hinder exploration of highly complex SLT interventions and a clinically relevant heterogeneous population. Creating a database of individual participant data (IPD) for people with aphasia aims to allow exploration of individual and therapy-related predictors of recovery and prognosis. Aim: To explore the contribution that individual participant characteristics (including stroke and aphasia profiles) and SLT intervention components make to language recovery following stroke. Methods and procedures: We will identify eligible IPD datasets (including randomised controlled trials, non-randomised comparison studies, observational studies and registries) and invite their contribution to the database. Where possible, we will use meta- and network meta-analysis to explore language performance after stroke and predictors of recovery as it relates to participants who had no SLT, historical SLT or SLT in the primary research study. We will also examine the components of effective SLT interventions. Outcomes and results: Outcomes include changes in measures of functional communication, overall severity of language impairment, auditory comprehension, spoken language (including naming), reading and writing from baseline. Data captured on assessment tools will be collated and transformed to a standardised measure for each of the outcome domains. Conclusion: Our planned systematic-review-based IPD meta- and network meta-analysis is a large scale, international, multidisciplinary and methodologically complex endeavour. It will enable hypotheses to be generated and tested to optimise and inform development of interventions for people with aphasia after stroke. Systematic review registration: The protocol has been registered at the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD42018110947).

Deficits of knowledge versus executive control in semantic cognition: insights from cued naming.

Deficits of semantic cognition in semantic dementia and in aphasia consequent on CVA (stroke) are qualitatively different. Patients with semantic dementia are characterised by progressive degradation of central semantic representations, whereas multimodal semantic deficits in stroke aphasia reflect impairment of executive processes that help to direct and control semantic activation in a task-appropriate fashion [Jefferies, E., & Lambon Ralph, M. A. (2006). Semantic impairment in stroke aphasia vs. semantic dementia: A case-series comparison. Brain 129, 2132-2147]. We explored interactions between these two aspects of semantic cognition by examining the effects of cumulative phonemic cueing on picture naming in case series of these two types of patient. The stroke aphasic patients with multimodal semantic deficits cued very readily and demonstrated near-perfect name retrieval when cumulative phonemic cues reached or exceeded the target name's uniqueness point. Therefore, knowledge of the picture names was largely intact for the aphasic patients, but they were unable to retrieve this information without cues that helped to direct activation towards the target response. Equivalent phonemic cues engendered significant but much more limited benefit to the semantic dementia patients: their naming was still severely impaired even when most of the word had been provided. In contrast to the pattern in the stroke aphasia group, successful cueing was mainly confined to the more familiar un-named pictures. We propose that this limited cueing effect in semantic dementia follows from the fact that concepts deteriorate in a graded fashion [Rogers, T. T., Lambon Ralph, M. A., Garrard, P., Bozeat, S., McClelland, J. L., & Hodges, J. R., et al. (2004). The structure and deterioration of semantic memory: A neuropsychological and computational investigation. Psychological Review 111, 205-235]. For partially degraded items, the residual conceptual knowledge may be insufficient to drive speech production to completion but these items might reach threshold when they are bolstered by cues.

Do deep dyslexia, dysphasia and dysgraphia share a common phonological impairment?

This study directly compared four patients who, to varying degrees, showed the characteristics of deep dyslexia, dysphasia and/or dysgraphia--i.e., they made semantic errors in oral reading, repetition and/or spelling to dictation. The "primary systems" hypothesis proposes that these different conditions result from severe impairment to a common phonological system, rather than damage to task-specific mechanisms (i.e. grapheme-phoneme conversion). By this view, deep dyslexic/dysphasic patients should show overlapping deficits but previous studies have not directly compared them. All four patients in the current study showed poor phonological production across different tasks, including repetition, reading aloud and spoken picture naming, in line with the primary systems hypothesis. They also showed severe deficits in tasks that required the manipulation of phonology, such as phoneme addition and deletion. Some of the characteristics of the deep syndromes - namely lexicality and imageability effects - were typically observed in all of the tasks, regardless of whether semantic errors occurred or not, suggesting that the patients' phonological deficits impacted on repetition, reading aloud and spelling to dictation in similar ways. Differences between the syndromes were accounted for by variation in other primary systems--particularly auditory processing. Deep dysphasic symptoms occurred when the impact of phonological input on spoken output was disrupted or reduced, either as a result of auditory/phonological impairment, or for patients with good phonological input analysis, when repetition was delayed. 'Deep' disorders of reading aloud, repetition and spelling can therefore be explained in terms of damage to interacting primary systems such as phonology, semantics and vision, with phonology playing a critical role.

Refractory effects in stroke aphasia: a consequence of poor semantic control.

This study examined the full range of effects associated with "semantic access impairment" - namely, refractory variables (semantic relatedness, speed of presentation and item repetition), inconsistency, the absence of frequency effects and facilitation by cues - in a series of stroke patients with multimodal semantically impairment. By investigating all of these factors in a group of patients who were not specifically selected to show "access" effects, we were able to establish (1) whether this pattern is a common consequence of infarcts that produce semantic impairment and (2) if these symptoms co-occur. All of the patients showed effects of cueing and an absence of frequency effects in comprehension. Patients whose brain damage included the left inferior prefrontal cortex (LIPC) also showed marked effects of refractory variables; in contrast, two patients with temporal-parietal but not frontal lesions were less sensitive to these variables. Parallel results were obtained for cyclical naming and word-picture matching tasks suggesting that the LIPC plays a role in semantic selection as well as lexical retrieval. Rapid presentation and item repetition is likely to have increased the selection demands in both of these tasks in a similar fashion. Unlike patients with classical "semantic access impairment", our semantically impaired stroke patients showed significant test-retest consistency, indicating that their difficulties did not result from an unpredictable failure of semantic access--instead, their deficits were interpreted as arising from failures of semantic control.

SD-squared: on the association between semantic dementia and surface dyslexia.

Within the connectionist triangle model of reading aloud, interaction between semantic and phonological representations occurs for all words but is particularly important for correct pronunciation of lower frequency exception words. This framework therefore predicts that (a) semantic dementia, which compromises semantic knowledge, should be accompanied by surface dyslexia, a frequency-modulated deficit in exception word reading, and (b) there should be a significant relationship between the severity of semantic degradation and the severity of surface dyslexia. The authors evaluated these claims with reference to 100 observations of reading data from 51 cases of semantic dementia. Surface dyslexia was rampant, and a simple composite semantic measure accounted for half of the variance in low-frequency exception word reading. Although in 3 cases initial testing revealed a moderate semantic impairment but normal exception word reading, all of these became surface dyslexic as their semantic knowledge deteriorated further. The connectionist account attributes such cases to premorbid individual variation in semantic reliance for accurate exception word reading. These results provide a striking demonstration of the association between semantic dementia and surface dyslexia, a phenomenon that the authors have dubbed SD-squared.

Using a combination of fMRI and anterior temporal lobe rTMS to measure intrinsic and induced activation changes across the semantic cognition network.

By developing and applying a method which combines fMRI and rTMS to explore semantic cognition, we identified both intrinsic (related to automatic changes in task/stimulus-related processing) and induced (i.e., associated with the effect of TMS) activation changes in the core, functionally-coupled network elements. Low-frequency rTMS applied to the human anterior temporal lobe (ATL) induced: (a) a local suppression at the site of stimulation; (b) remote suppression in three other ipsilateral semantic regions; and (c) a compensatory up-regulation in the contralateral ATL. Further examination of activity over time revealed that the compensatory changes appear to be a modulation of intrinsic variations that occur within the unperturbed network. As well as providing insights into the dynamic collaboration between core regions, the ability to observe intrinsic and induced changes in vivo may provide an important opportunity to understand the key mechanisms that underpin recovery of function in neurological patient groups.

Disorders of representation and control in semantic cognition: Effects of familiarity, typicality, and specificity.

We present a case-series comparison of patients with cross-modal semantic impairments consequent on either (a) bilateral anterior temporal lobe atrophy in semantic dementia (SD) or (b) left-hemisphere fronto-parietal and/or posterior temporal stroke in semantic aphasia (SA). Both groups were assessed on a new test battery designed to measure how performance is influenced by concept familiarity, typicality and specificity. In line with previous findings, performance in SD was strongly modulated by all of these factors, with better performance for more familiar items (regardless of typicality), for more typical items (regardless of familiarity) and for tasks that did not require very specific classification, consistent with the gradual degradation of conceptual knowledge in SD. The SA group showed significant impairments on all tasks but their sensitivity to familiarity, typicality and specificity was more variable and governed by task-specific effects of these factors on controlled semantic processing. The results are discussed with reference to theories about the complementary roles of representation and manipulation of semantic knowledge.